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[Current Therapies for Amyotrophic Lateral Sclerosis in Japan].Publié le 29 01 2020

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive muscle wasting and weakness. Riluzole was the sole drug available for treating ALS until 2015, when edaravone was approved as a new anti-ALS drug. Recent discoveries of the disease-causal genes and proteins, as well as the rapid advancement of induced pluripotent stem (iPS) cell manipulations, drug deliveries, and molecular modifications have provided diverse and promising drug candidates. In particular, antisense-oligonucleotide therapy appears to significantly prevent disease progression when introduced early. Moreover, the in vitro modeling of ALS using patients' own iPS cells enables effective screening of approved drugs. Drug repositioning is a robust short-cut to bedside use in patients with ALS, due to the availability of data for safety concerns. Currently, five investigator-initiated drug trials are underway in Japan. These include trials of hepatocyte growth factor, perampanel, ultra-high-dose methylcobalamin, ropinirole, and bosutinib. This is a review of new ALS drugs that are either currently available or in on-going trials. We additionally review the pathogenic pathways that these drugs target.

Emergency room visits and admission rates of children with neuromuscular disorders: A 10-year experience in a medical center in Taiwan.Publié le 29 01 2020

BACKGROUND: No previous studies have explored emergency medical care for children with chronic neuromuscular disorders (NMDs). We aimed to determine the major reasons for the emergency room (ER) readmission of pediatric patients with NMDs and suggest changes to the care plan to decrease readmissions.
METHODS: Children with chronic NMDs (aged <18 years) who visited a medical center-based ER between January 2005 and January 2015 were included. The following data were extracted from the patient's ER records: presentations; demographic data, including sex and age; NMD diagnosis; triage classification; emergency examination; initial management and outcomes. The outcomes were death inside or outside the ER, admission to the ward or pediatric intensive care unit (PICU), uneventful discharge, and repeated ER visits.
RESULTS: In 10 years, 44 children with heterogeneous NMDs (boys/girls: 30/14, mean age: 9.9 years) visited the ER for a total of 204 times. Repeated ER visits and readmissions occurred in 56.8% and 55.6% of the patients, respectively. Most NMD children belonged to triage class 3 (35.3%), with underlying congenital hereditary muscular dystrophy (44.1%). The major symptoms were usually multiple and concurrent, and primarily respiratory (62.3%) or gastrointestinal (28.9%). The most common causes of hospitalization were pneumonia (48.5%) or acute gastritis (20.4%), and approximately half of the ER visits required further hospitalization, of which 28.2% involved PICU admission. Twenty of the 36 children admitted to the ER required readmission. The most commonly prescribed examinations were complete blood count (38%) and C-reactive protein (38%), and the most common therapy was intravenous fluid administration (34%). Although respiratory compromise caused most ER visits and admissions, pulmonary assessments, including chest films (28%), pulse oximetry (15%), and blood gas analysis (11%), were performed in a relatively small proportion.
CONCLUSION: The ER staff must recognize patients' unmet needs for respiratory and gastrointestinal care related to underlying NMDs.

Spinal bracing and lung function in type-2 spinal muscular atrophy.Publié le 29 01 2020

BACKGROUND: Respiratory muscle weakness associated with scoliosis in type-2 spinal muscular atrophy (SMA) leads to respiratory impairment. Spinal brace, generally utilized to slow scoliosis progression and support sitting, could worsen lung function and hamper cough maneuvers.
CASE SERIES: Six home-treated type-2 SMA children (aged 6-15 years, subtype 2.1-2.5) were assessed to evaluate time-dependent influence of "static-balanced brace" on pulmonary function. Lung function tests, including peak expiratory flow (PEF), peak cough flow (PCF), maximal static inspiratory pressure (MIP), maximal static expiratory pressure (MEP), forced vital capacity (FVC), were performed. PEF, MEP, FVC parameters were higher in tests after wearing braces three-hours, PCF slightly higher and MIP slightly lower compared to upon awakening values.
CLINICAL REHABILITATION IMPACT: "Static-balanced brace" did not impair lung function in our sample of six type-2 SMA children; in addition, it seemed to support cough maneuvers. Double assessment is determinant for decisions concerning use/non-use of brace differently from the usual one time evaluation procedure (base level compared to level wearing brace).

New treatments in spinal muscular atrophy: an overview of currently available data.Publié le 25 01 2020

Introduction: Spinal muscular atrophy (SMA) is one of the most common inherited neuromuscular disorders. It causes progressive muscle weakness and results in significant disability. Until recently, there were no drugs available for the treatment of SMA. Several phase 1-3 studies, including three double-blind randomized placebo-controlled studies have demonstrated the efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers.Areas covered: This article covers the publically available data on therapeutic strategies that address the underlying cause of SMA and clinical data available on approved treatments and drugs in the pipeline.Expert opinion: The newer therapeutic options in SMA have a good safety profile and deliver a therapeutic benefit in most patients. It is essential that the recommended standards of care are delivered along with the drugs for the best outcomes. No biomarkers to distinguish responders from non-responders are available; it is important that biomarkers be identified. Early treatment is essential for the maximum efficacy of the newly available treatments.

Nusinersen for Type 1 Spinal Muscular Atrophy: A Father's Perspective.Publié le 25 01 2020

PMID: 31506303 [PubMed - indexed for MEDLINE]

Nested PCR Amplification Secures DNA Template Quality and Quantity in Real-time mCOP-PCR Screening for SMA.Publié le 21 01 2020

BACKGROUND: Spinal Muscular Atrophy (SMA) is a common autosomal recessive disorder caused by SMN1 gene deletion. SMA has been considered an incurable disease. However, a newly-developed antisense oligonucleotide drug, nusinersen, brings about a good outcome to SMA patients in the clinical trials. Now, a screening for SMA is required for early diagnosis and early treatment so as to give a better clinical outcome to the patients. We have invented a new technology, mCOP-PCR, for SMA screening using dried blood spot (DBS) on the filter paper. One of the problems encountered in SMA screening is poor quality and quantity of DNA extracted from DBS.
METHODS: DNA was extracted from DBS of six individuals. Fresh blood DNA of each individual had already been genotyped using PCR/RFLP. The fragments including the sequence of SMN1/SMN2 exon 7 were pre-amplified with conventional PCR. To determine which pre-amplified product is a better template for the real-time mCOP-PCR, we did pre-amplification with a single PCR or pre-amplification with a nested PCR.
RESULTS: The real-time mCOP-PCR using pre-amplified products with a single PCR brought about ambiguous results in some SMN1-carrying individuals. However, the results of real-time mCOP-PCR following pre-amplification with a nested PCR were completely matched with those of PCR-RFLP.
CONCLUSION: In our study on the real-time mCOP-PCR screening system for SMA, a nested PCR secured the DNA template quality and quantity, leading to unambiguous results of SMA screening.

The ICF-CY as a framework for the management of spinal muscular atrophy in the era of gene therapy: a proof-of-concept study.Publié le 16 01 2020

BACKGROUND: Management of Spinal Muscular Atrophy (SMA) has progressed enormously and reached unprecedented levels with nusinersen gene therapy. We are finally able to counter the progression of this devastating genetic disease, contributing to the definition of new trajectories in its natural history and the identification of new SMA phenotypes post-gene therapy.
AIM: To use the ICF-CY as a comprehensive documentation tool to better understand and improve care provided to a child with SMA and to illustrate its use in a multidisciplinary perspective.
DESIGN: A proof-of-concept study.
SETTING: Pediatric Neurorehabilitation Care Unit.
POPULATION: An SMA child under gene therapy receiving a rehabilitation program.
METHODS: Clinical and functional outcome measures assessed at all levels of the ICF-CY, including impairment by Hammersmith Infant Neurological Examination, activity by Hammersmith Functional Motor Scale and Functional Independence Measure for Children, and participation by Pediatric Quality of Life InventoryTM - PedsQLTM and Neuromuscular ModuleTM as well as by parent report. Treatment outcomes were assessed at two main time points: at T0: prior to administration of nusinersen, and T1: immediately before the first administration of maintenance doses, 6 months after the first administration of nusinersen.
RESULTS: A significant clinical improvement was seen on all domains between T0 and T1. The patient improved especially in motor skills and motor disability severity. The HRQOL showed a substantial improvement, too. ICF-CY codes were used to document change in body functions or structures, performance of activities or participation in social roles both in terms of gradient and hierarchy of change.
CONCLUSIONS: This proof-of-concept study is the first attempt to explore SMA in a comprehensive manner from the perspective of the ICF-CY using a selected set of codes. These codes define essential child dimensions that can make up an ICF-CY core set, as identified by a trained multidisciplinary team, to guide assessment, treatment and rehabilitation.
CLINICAL REHABILITATION IMPACT: Although limited to a single patient, this study makes nonetheless a strong point: we suggest using the ICF-CY as an essential tool in SMA management at a time when gene therapy with nusinersen is changing the phenotypes of activity and functioning in these children.

Presentation and Management Patterns of Lower Urinary Tract Symptoms in Adults Due to Rare Inherited Neuromuscular Diseases.Publié le 16 01 2020

OBJECTIVE: To describe the urologic sequalae of several rare congenital neuromuscular diseases.
METHODS: We retrospectively reviewed medical records at Gillette Specialty Healthcare (2014-2018) of patients presenting to urology clinic with lower urinary tract symptoms and select rare congenital diseases: muscular dystrophy, spinal muscular atrophy, and Rett syndrome.
RESULTS: Muscular dystrophies (n?=?19) are X-linked myogenic disorders characterized by progressive muscle wasting and weakness. Men present to the urologist at variable ages, typically with complaints of functional incontinence and normal cystometrograms; we manage them with oral anticholinergic medications, condom catheter, or suprapubic catheter. Spinal muscular atrophy (n?=?6) is a rare autosomal recessive disease characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem leading to progressive muscle weakness and atrophy. Patients typically present with nephrolithiasis and urinary retention in late adolescence/early adulthood, but timing varies. Filling cystometrograms have been normal. We allow passive retention with intermittent catheterization and creation of catheterizable channels, when indicated. Rett syndrome (n?=?5) is a rare, noninheritable genetic condition affecting females characterized by a brief period of normal development followed by loss of speech and purposeful hand use; there are characteristic behaviors. Patients present in early adulthood with complaints of urinary retention. We manage retention with permissive retention or sphincter chemodenervation.
CONCLUSION: Several congenital neuromuscular conditions can cause lower urinary tract symptoms when these individuals become adults. We have discussed the clinical characteristics and management of select neurogenic and myogenic bladder conditions seen in adults with congenital conditions.

Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy.Publié le 15 01 2020

INTRODUCTION: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied.
METHODS: Post hoc analyses were used to examine changes in 6-minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open-label CS2 study and were ambulatory during CS2 or the extension study, CS12.
RESULTS: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by -3.8% (-19.7%, 1.4%).
DISCUSSION: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA.

Spinal Muscular Atrophy Diagnosed by Newborn Screening.Publié le 14 01 2020

A panel of experts representing academic centers, family foundations and pharmaceutical industry came together to formulate a treatment algorithm for infants diagnosed via newborn screening (NBS) with Spinal muscular atrophy (SMA).

Spinal muscular atrophy - new therapies, new challenges.Publié le 12 01 2020

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course - from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide - nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.

Newborn Screening for Spinal Muscular Atrophy in China Using DNA Mass Spectrometry.Publié le 12 01 2020

Background: Spinal muscular atrophy (SMA) is the most common neurodegenerative disorder and the leading genetic cause of infant mortality. Early detection of SMA through newborn screening (NBS) is essential to selecting pre-symptomatic treatment and ensuring optimal outcome, as well as, prompting the urgent need for effective screening methods. This study aimed to determine the feasibility of applying an Agena iPLEX SMA assay in NBS for SMA in China. Methods: We developed an Agena iPLEX SMA assay based on the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and evaluated the performance of this assay through assessment of 167 previously-genotyped samples. Then we conducted a pilot study to apply this assay for SMA NBS. The SMN1 and SMN2 copy number of screen-positive patients were determined by multiplex ligation-dependent probe amplification analysis. Results: The sensitivity and specificity of the Agena iPLEX SMA assay were both 100%. Three patients with homozygous SMN1 deletion were successfully identified and conformed by multiplex ligation-dependent probe amplification analysis. Two patients had two SMN2 copies, which was correlated with severe SMA type I phenotype; both of them exhibited neurogenic lesion and with decreased muscle power. Another patient with four SMN2 copies, whose genotype correlated with milder SMA type III or IV phenotype, had normal growth and development without clinical symptoms. Conclusions: The Agena iPLEX SMA assay is an effective and reliable approach for population-based SMA NBS. The first large-scale pilot study using this assay in the Mainland of China showed that large-scale implementation of population-based NBS for SMA is feasible.

The modified Kostuik transilial bar technique has acceptable results in neuromuscular spinal deformity correction.Publié le 09 01 2020

The aim of this study is to evaluate the results of the modified Kostuik transilial bar technique for neuromuscular scoliosis (NS). We reviewed the records of 21 patients treated for NS with this instrumentation. There were 14 females and seven males, with an average age of 15.6 years (range: 9-21 years). We determined patients' demographics, correction ratio of both curve and pelvic obliquity, loss of correction, screw loosening at first sacral vertebra, and clinical outcomes. Mean follow-up was 56 months (range: 34-96 months). There were no reoperations, no screw breakage, and no significant loss of correction. The mean preoperative coronal Cobb angle was 71.4°±8.7°, the initial postoperative measurements had a mean Cobb angle of 19.2°±7.2°, and at the last follow-up, the mean Cobb angle was 23.6°±6.9° (P<0.001). Pelvic obliquity decreased from 27.7°±12.4° to 9.1°±5.3° at follow-up and to 11.9°±6.3° at the last follow-up (P<0.001). The preoperative pelvic obliquity angle was significantly higher at the patients with screw loosening (P=0.016). There was one established as well as one possible pseudoarthrosis in our patients. The new technique does appear to possibly become an alternative to conventional lumbosacral fixation techniques. Integration of the bar with pipe-type connector onto the long spinal instrumentation with oblique connectors can prevent the most unenviable complications such as wide exposure, hardware prominence, reoperation, and pseudoarthrosis.

Drosophila SMN2 minigene reporter model identifies moxifloxacin as a candidate therapy for SMA.Publié le 08 01 2020

Spinal muscular atrophy is a rare and fatal neuromuscular disorder caused by the loss of alpha motor neurons. The affected individuals have mutated the ubiquitously expressed SMN1 gene resulting in the loss or reduction in the survival motor neuron (SMN) protein levels. However, an almost identical paralog exists in humans: SMN2. Pharmacological activation of SMN2 exon 7 inclusion by small molecules or modified antisense oligonucleotides is a valid approach to treat SMA. Here we describe an in vivo SMN2 minigene reporter system in Drosophila motor neurons that serves as a cost-effective, feasible, and stringent primary screening model for identifying chemicals capable of crossing the conserved Drosophila blood-brain barrier and modulating exon 7 inclusion. The model was used for the screening of 1100 drugs from the Prestwick Chemical Library, resulting in 2.45% hit rate. The most promising candidate drugs were validated in patient-derived fibroblasts where they proved to increase SMN protein levels. Among them, moxifloxacin modulated SMN2 splicing by promoting exon 7 inclusion. The recovery of SMN protein levels was confirmed by increased colocalization of nuclear gems with Cajal Bodies. Thus, a Drosophila-based drug screen allowed the discovery of an FDA-approved small molecule with the potential to become a novel therapy for SMA.

Healthcare utilisation in children with SMA type 1 treated with nusinersen: a single centre retrospective review.Publié le 08 01 2020

Background: Nusinersen has been used to treat spinal muscular atrophy type 1 (SMA1) in the UK since 2017. While initial trials showed neuromuscular benefit from treating SMA1, there is little information on the respiratory effects of nusinersen. We aimed to look at the respiratory care, hospital utilisation and associated costs in newly treated SMA1.
Methods: We reviewed the medical records of all children within the West Midlands with SMA1 treated with nusinersen at Royal Stoke University Hospital. Baseline demographics and hospital admission data were collected including: the reason for admission, total hospital days, days of critical care, days intubated, discharge diagnosis, doses of nusinersen and treatment complications.
Results: 11 children (six girls) received nusinersen between May 2017 and April 2019. Their median (range) age was 29 (7-97) months. The median (range) number of nusinersen doses per child was 6 (4-8). All children were receiving long-term ventilatory support; this was mask ventilation in nine and tracheostomy ventilation in two. The total number of hospital days since diagnosis was 1101 with a median (range) of 118 (7-235) days per child. This included general paediatric ward days 0 (0-63), High Dependency Unit 79 (7-173) days and Paediatric Intensive Care Unit 13 (0-109) days per child. This equated to a median (range) of 20 (2-72) % of their life in hospital. The estimated cost of this care was £2.2M.
Conclusion: Patients with SMA1 treated with nusinersen initially spend a considerable proportion of their early life in hospital. Parents should be counselled accordingly. These data suggest that for every 10 children started on nusinersen an extra HDU bed is required. This has a significant cost implication.

Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy.Publié le 08 01 2020

Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes of the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and sex-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PXD016757. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.

Natural course of scoliosis and lifetime risk of scoliosis surgery in spinal muscular atrophy.Publié le 08 01 2020

OBJECTIVE: To investigate the natural course of scoliosis and to estimate lifetime probability of scoliosis surgery in spinal muscular atrophy (SMA).
METHODS: We analyzed cross-sectional data from 283 patients from our population-based cohort study. Additional longitudinal data on scoliosis progression and spinal surgery were collected from 36 consecutive patients who received scoliosis surgery at our center.
RESULTS: The lifetime probability of receiving scoliosis surgery was ?80% in SMA types 1c and 2. Patients with type 2 who only learned to sit (type 2a) were significantly younger at time of surgery than those who learned to sit and stand (type 2b). The lifetime risk of surgery was lower in type 3a (40%) and strongly associated with age at loss of ambulation: 71% in patients losing ambulation before 10 years of age vs 22% losing ambulation after the age of 10 years (p = 0.005). In type 3a, preserving the ability to walk 1 year longer corresponded to a 15% decrease in lifetime risk of scoliosis surgery (hazard ratio 0.852, p = 0.017). Scoliosis development was characterized by initial slow progression, followed by acceleration in the 1.5- to 2-year period before surgery.
CONCLUSION: The lifetime probability of scoliosis surgery is high in SMA types 1c and 2 and depends on age at loss of ambulation in type 3. Motor milestones such as standing that are not part of the standard classification system are of additional predictive value. Our data may act as a reference to assess long-term effects of new SMA-specific therapies.

The prevalence of muscular dystrophy and spinal muscular atrophy in Croatia: data from national and non-governmental organization registries.Publié le 03 01 2020

AIM: To determine the prevalence of muscular dystrophy (MD) and spinal muscular atrophy (SMA) in Croatia by use of multiple epidemiological tools.
METHODS: This epidemiological study collected data from three national patient registries and one database of a non-governmental organization (NGO) of MD and SMA patients. The study involved all individuals who either had undergone hospital treatment for MD or SMA, had consulted their primary health care providers for MD- and SMA-related symptoms, were listed as disabled due to MD or SMA, or were members of the mentioned NGO in 2016. In order to prevent double entries, we created a new database of all living individuals, each with a unique identification number. The prevalence rates for 2016 were calculated by age and sex groups.
RESULTS: There were 926 patients diagnosed with MD (544 men). Most men diagnosed with MD were in the age group 10-19, whereas most women were in the age group 50-59. MD prevalence in Croatia was 22.2 per 100000 population. There were 392 patients diagnosed with SMA (198 men). Most men with SMA were in the age group 50-59, whereas most women were in the age group 60-69. SMA prevalence in Croatia was 9.3 per 100000 population.
CONCLUSION: SMA prevalence rate in Croatia is similar to SMA prevalence worldwide. However, MD prevalence rate is higher than worldwide estimates. This difference could be attributed to the fact that we could not confirm whether every patient registered in these databases actually met the diagnostic criteria for MD and SMA.

Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening.Publié le 01 01 2020

Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration ofalpha motor neuronsin the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5' splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases.

Intrathecal nusinersen treatment after ventriculo-peritoneal shunt placement: A case report focusing on the neurofilament light chain in cerebrospinal fluid.Publié le 01 01 2020

BACKGROUND: In July 2018, a rare and serious adverse effect (AE), namely, communicating hydrocephalus unrelated to meningitis or bleeding, was reported in relation to five patients treated with nusinersen for spinal muscular atrophy (SMA). Some patients were managed using a ventriculo-peritoneal shunt (VPS) implant and continued to receive nusinersen treatment. However, there is limited information concerning the effectiveness and safety of nusinersen treatment for patients with a VPS.
CASE REPORT: A female patient exhibited general hypotonia soon after birth and was diagnosed, using genetic analysis, with spinal muscular atrophy. She required permanent invasive ventilation from 2 months of age. She developed a progressive hydrocephalus and underwent placement of a VPS in infancy. Treatment with nusinersen was initiated when she was 7 years old. The neurofilament light-chain (NfL) concentration in the cerebrospinal fluid (CSF) decreased over time with nusinersen treatment. Twelve months have passed since the start of nusinersen treatment and no AEs have been observed.
CONCLUSION: Nusinersen treatment may be effective and safe, even after placement of a VPS. NfL levels in the CSF could be valuable markers of disease activity/treatment response even in advanced stages of SMA.

Limitations of six-minute Walk Test Reference Values for Spinal Muscular Atrophy.Publié le 31 12 2019

INTRODUCTION: The six-minute walk test (6MWT) is a well-established clinical assessment of functional endurance, validated as a measure of walking ability in spinal muscular atrophy (SMA). The current availability of disease-modifying therapies for SMA indicates a growing need for normative reference data to compare SMA patients to healthy controls.
METHODS: The literature was searched in two scientific databases. Studies were evaluated and selected based on adherence to American Thoracic Society guidelines for administering the 6MWT. Reference equations from the selected studies were applied to 6MWT data collected from SMA patients to calculate and compare %predicted values.
RESULTS: Three pediatric and 6 adult studies were selected for comparison. The %predicted values using the pediatric and adult equations ranged from 47.7 + 18.2% to 67.6 + 26.2% and 43.0 + 4.6% to 59.5 + 6.8%, respectively, and were significantly different (p<0.001).
DISCUSSION: Results suggest significant variability between %predicted values derived from published reference equations in children and adults despite adherence to 6MWT standardization. This article is protected by copyright. All rights reserved.

High-intensity training in patients with spinal and bulbar muscular atrophy.Publié le 31 12 2019

OBJECTIVE: Long duration, moderate-intensity exercise is not well tolerated in patients with spinal and bulbar muscular atrophy (SBMA). This study investigated whether patients with SBMA can benefit from high-intensity training (HIT).
METHODS: Ten patients with SBMA were randomized to 8 weeks of supervised HIT [n?=?5; age?=?50 (25-63) years] followed by 8 weeks of self-training or 8 weeks of no training followed by 8 weeks of non-supervised HIT [n?=?5; age?=?50 (26-54) years]. Training consisted of 2?×?5-min exercise periods with 1-min cyclic blocks of intermittent maximal intensity exercise on an ergometer bike. Maximal oxygen capacity (VO2max) and workload (Wmax) were measured before and after training by incremental exercise tests. Plasma creatine kinase levels, self-rated muscle pain, muscle fatigue, and activity level were monitored throughout the training period.
RESULTS: Eight patients completed training. One patient dropped out after 5 weeks of training for private reasons. Another patient was excluded after 4 weeks due to lack of compliance. Eight weeks of training increased both VO2max (1.9?±?2.3 ml min-1 kg-1; p?=?0.04) and Wmax (15.6?±?17.9 W; p?=?0.03) in the 8 patients who completed training. There were no changes in plasma creatine kinase levels, self-reported muscle pain or muscle fatigue activity level after training.
CONCLUSION: This pilot study suggests that high-intensity training is safe and improves fitness in patients with SBMA. Unlike low- and moderate-intensity training, HIT is efficacious and favored over other training forms by the patients.

[Respiratory care for children with spinal muscular atrophy].Publié le 28 12 2019

PMID: 31594072 [PubMed - indexed for MEDLINE]

Benefits of Maxillary Expansion for a Patient With Spinal Muscular Atrophy Type 2.Publié le 28 12 2019

This case report involves a 10-yr-old boy diagnosed with spinal muscular atrophy type 2 who underwent nighttime mechanical ventilation with bilevel positive airway pressure. The oral examination revealed restricted mouth opening, lip interposition, dental crowding, and maxillary compression. After maxillary expansion, the upper airway volume increased 18.6%; 13 episodes of airway infections (20 days of hospitalization) were recorded in the 2 yrs before the maxillary expansion and only 4 episodes (no hospital admissions) in the 2 subsequent years. In conclusion, maxillary expansion in children with systemic disease that involves respiratory impairment may, in some cases, provide functional and clinical improvements, increase upper airway airflows, and possibly decrease the number of respiratory infections.

Mechanical In-exsufflation-Expiratory Flows as Indication for Tracheostomy Tube Decannulation: Case Studies.Publié le 27 12 2019

Mechanical insufflation exsufflation-expiratory flows (MIE-EFs) correlate with upper airway patency. Patients dependent on continuous noninvasive ventilatory support with severe spinal muscular atrophy type 1, now over 20 yrs old, have used MIE sufficiently effectively along with continuous noninvasive ventilatory support to avoid tracheotomy indefinitely. Although MIE-EFs can apparently decrease in amyotrophic lateral sclerosis to necessitate tracheotomy, they can increase over time and remain effective in all spinal muscular atrophy types. Two cases demonstrate an association between increasing MIE-EF and, ultimately, successful decannulation of a patient with spinal muscular atrophy type 2 who was continuous tracheostomy mechanical ventilation dependent and a patient with obesity hypoventilation syndrome. Only when MIE-EF increased to exceed 200 l/min did the decannulations succeed. Definitive noninvasive management (continuous noninvasive ventilatory support) of these patients may be possible only when MIE is effective, and the greater the MIE-EF, the greater its effectiveness. Thus, increasing MIE-EF can signal resolution of upper airway obstruction sufficiently to permit decannulation whether a patient is ventilator dependent or not.

Spinal Muscular Atrophy Modeling and Treatment Advances by Induced Pluripotent Stem Cells Studies.Publié le 23 12 2019

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease characterized by specific and predominantly lower motor neuron (MN) loss. SMA is the main reason for infant death, while about one in 40 children born is a healthy carrier. SMA is caused by decreased levels of production of a ubiquitously expressed gene: the survival motor neuron (SMN). All SMA patients present mutations of the telomeric SMN1 gene, but many copies of a centromeric, partially functional paralog gene, SMN2, can somewhat compensate for the SMN1 deficiency, scaling inversely with phenotypic harshness. Because the study of neural tissue in and from patients presents too many challenges and is very often not feasible; the use of animal models, such as the mouse, had a pivotal impact in our understanding of SMA pathology but could not portray totally satisfactorily the elaborate regulatory mechanisms that are present in higher animals, particularly in humans. And while recent therapeutic achievements have been substantial, especially for very young infants, some issues should be considered for the treatment of older patients. An alternative way to study SMA, and other neurological pathologies, is the use of induced pluripotent stem cells (iPSCs) derived from patients. In this work, we will present a wide analysis of the uses of iPSCs in SMA pathology, starting from basic science to their possible roles as therapeutic tools.

Advance care planning in progressive neurological diseases: lessons from ALS.Publié le 20 12 2019

BACKGROUND: There is increasing awareness of the need for an integrated palliative care approach in chronic progressive neurological diseases. Advance care planning (ACP) is an integral part of this approach. As a systematically organized and ongoing communication process about patients' values, goals and preferences regarding medical care during serious and chronic illness, ACP aims to involve patients in decision-making before they become cognitively and communicatively incapable. However, it remains underutilized in daily neurological practice except for speciality clinics such as ALS centers. Our aim was to study ACP in the tertiary ALS center Amsterdam and to investigate patients' reflections on it. Subsequently we used this knowledge to formulate recommendations for integration of ACP in the care of patients with other chronic progressive neurological diseases.
METHODS: Non-participating observations of all appointments of patients with amyotrophic lateral sclerosis (ALS) or progressive muscular atrophy (PMA) with the treating physician, in various stages of disease, during 6 consecutive months, followed by single in-depth interviews, and an inductive analysis.
RESULTS: Twenty-eight Dutch patients participated, varying in age, gender, disease onset and severity of physical decline. ACP started directly when the diagnosis was given, by means of a general outlook on the future with progressive disability and immediate introduction to a customized multidisciplinary team. During follow-up ACP was realized by regular appointments in which monitoring of the patient's status and clear communication strategies formed the basis of tailor-made discussions on treatment options. Patients accepted this policy as careful professional guidance.
CONCLUSIONS: ACP is a professional communication process throughout the whole course of progressive disease. It is feasible to integrate ACP into follow-up of patients with ALS and PMA from diagnosis onwards. Supported by recent literature, we argue that such a well-structured approach would also enhance the quality of care and life of patients with other chronic progressive neurological diseases.

[Spinal Muscular Atrophy - expert recommendations for the use of nusinersen in adult patients].Publié le 18 12 2019

With Nusinersen, a first causative treatment for 5q-associated spinal muscular atrophy (SMA) has been available in Europe since 2017. Real-world data from neuromuscular clinical centers in Germany increasingly show a therapeutic benefit of nusinersen also in adult SMA patients of both sexes: in many cases, relevant improvements in or at least a stabilization of motor functions are achieved, potentially leading to enhanced autonomy in activities of daily life and to improved quality of living. Even in patients with severe spinal deformities, intrathecal application is usually feasible and safe using imaging modalities. Regular systematic evaluation of the motor status with validated instruments is crucial for adequate monitoring of the therapeutic effects. The documentation in SMA registries enables systematic development of a database for further development of this novel treatment paradigm. Relevant aspects of this novel therapeutic principle were discussed at an experts conference in Frankfurt?/?Main in February 2019.

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy.Publié le 18 12 2019

Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery.

Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery.Publié le 15 12 2019

Adeno-associated viral (AAV) vectors have emerged as the leading gene delivery platform for gene therapy and vaccination. Three AAV-based gene therapy drugs, Glybera, LUXTURNA, and ZOLGENSMA were approved between 2012 and 2019 by the European Medicines Agency and the United States Food and Drug Administration as treatments for genetic diseases hereditary lipoprotein lipase deficiency (LPLD), inherited retinal disease (IRD), and spinal muscular atrophy (SMA), respectively. Despite these therapeutic successes, clinical trials have demonstrated that host anti-viral immune responses can prevent the long-term gene expression of AAV vector-encoded genes. Therefore, it is critical that we understand the complex relationship between AAV vectors and the host immune response. This knowledge could allow for the rational design of optimized gene transfer vectors capable of either subverting host immune responses in the context of gene therapy applications, or stimulating desirable immune responses that generate protective immunity in vaccine applications to AAV vector-encoded antigens. This review provides an overview of our current understanding of the AAV-induced immune response and discusses potential strategies by which these responses can be manipulated to improve AAV vector-mediated gene transfer.

Early Results of a Management Algorithm for Collapsing Spine Deformity in Young Children (Below 10-Year Old) With Spinal Muscular Atrophy Type II.Publié le 14 12 2019

BACKGROUND: Progressive C-shaped scoliosis with marked pelvic obliquity is common to spinal muscular atrophy (SMA). Reducing the number of procedures with effective deformity control is critical to minimize the risk of pulmonary complications. This study reports the preliminary results of magnetically controlled growing rods (MCGR) in SMA-related collapsing spine deformity.
METHODS: Inclusion criteria for this retrospective review were: (1) SMA type 2 patients, (2) early onset scoliosis (below 10?y), (3) collapsing spine deformity with pelvic obliquity, (4) growth-friendly scoliosis treatment with MCGR, (5) in between 2014 and 2017. Extracted data included demographic and clinical information, radiologic parameters, surgical details, and final status of the patients.
RESULTS: A total of 11 patients (7 boys, 4 girls) were included. The average age at index surgery was 8.2 (6 to 10) years. Dual MCGR was implanted in 8 patients. In 3 patients, because of curve rigidity and inability of apex to be brought into the stable zone, apical fusion with gliding connectors (convexity) and a single MCGR (concavity) was preferred. Instrumentation included the pelvis in 9 and stopped at the lumbar spine (L3) in 2 patients at the index procedure. Average preoperative deformity of 81.8 degrees (66 to 115) decreased to 29 degrees (11 to 57) postoperatively and was 26 degrees at average 35 months (16 to 59). Pelvic obliquity of 20.9 degrees (11 to 30) decreased to 4.9 degrees (2 to 8) after index surgery and was 6.5 degrees (2 to 16) at the last follow-up. T1-S1 height of 329?mm (280 to 376) after index surgery increased to 356?mm (312 to 390) after 9.2 (4 to 20) outpatient lengthening. No neurologic, infectious, or implant-related complication was recorded. Distal adding-on deformity occurred in 2 patients without initial pelvic fixation.One patient deceased secondary to pneumonia at 16 months after surgery.
CONCLUSIONS: Short-term results indicate that MCGR may be a good option in SMA-associated collapsing spine deformity to reduce the burden of repetitive lengthening procedures. The authors recommend apical deformity control in the convex side in case of curve rigidity. In addition, including the pelvis in the instrumentation at index surgery is critical to prevent distal adding-on.
LEVEL OF EVIDENCE: Level IV-retrospective case series.

ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy.Publié le 13 12 2019

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutation or deletion of the survival motor neuron 1 (SMN1) gene. A second copy, SMN2, is similar to SMN1 but produces ?10% SMN protein because of a single-point mutation that causes splicing defects. Chronic low levels of SMN cause accumulation of co-transcriptional R-loops and DNA damage leading to genomic instability and neurodegeneration in SMA. Severity of SMA disease correlates inversely with SMN levels. SMN2 is a promising target to produce higher levels of SMN by enhancing its expression. Mechanisms that regulate expression of SMN genes are largely unknown. We report that zinc finger protein ZPR1 binds to RNA polymerase II, interacts in vivo with SMN locus and upregulates SMN2 expression in SMA mice and patient cells. Modulation of ZPR1 levels directly correlates and influences SMN2 expression levels in SMA patient cells. ZPR1 overexpression in vivo results in a systemic increase of SMN levels and rescues severe to moderate disease in SMA mice. ZPR1-dependent rescue improves growth and motor function and increases the lifespan of male and female SMA mice. ZPR1 reduces neurodegeneration in SMA mice and prevents degeneration of cultured primary spinal cord neurons derived from SMA mice. Further, we show that the low levels of ZPR1 associated with SMA pathogenesis cause accumulation of co-transcriptional RNA-DNA hybrids (R-loops) and DNA damage leading to genomic instability in SMA mice and patient cells. Complementation with ZPR1 elevates senataxin levels, reduces R-loop accumulation and rescues DNA damage in SMA mice, motor neurons and patient cells. In conclusion, ZPR1 is critical for preventing accumulation of co-transcriptional R-loops and DNA damage to avert genomic instability and neurodegeneration in SMA. ZPR1 enhances SMN2 expression and leads to SMN-dependent rescue of SMA. ZPR1 represents a protective modifier and a therapeutic target for developing a new method for the treatment of SMA.

JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death.Publié le 11 12 2019

The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases.

Long acting GLP-1 analog liraglutide ameliorates skeletal muscle atrophy in rodents.Publié le 10 12 2019

BACKGROUND: Skeletal muscle atrophy is characterized by muscle wasting with partial or complete functional loss. Skeletal muscle atrophy severely affects the quality of life and currently, there is no available therapy except for spinal muscular atrophy.
OBJECTIVE: Drug repositioning is a promising strategy that reduces cost and time due to prior availability of safety and toxicity details. Here we investigated myogenic and anti-atrophy effects of glucagon-like peptide-1 (GLP-1) analog liraglutide.
METHODS: We used several in vitro atrophy models in C2C12 cells and in vivo models in Sprague Dawley rats to study Liraglutide's efficacy. QPCR and western blotting were used to assess cAMP-dependent signaling pathways specifically activated by liraglutide. Therapeutic efficacy of liraglutide was investigated by histological analysis of transverse muscle sections followed by morphometry. Myogenic capacity was investigated by immunostaining for myogenic factors.
RESULTS: Liraglutide induced myogenesis in C2C12 myoblasts through GLP-1 receptor via a cAMP-dependent complex network of signaling events involving protein kinase A, phosphoinositide 3-kinase/protein kinase B, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase. Liraglutide imparted protection against freeze injury, denervation, and dexamethasone -induced skeletal muscle atrophy and improved muscular function in all these models. In a therapeutic mode, liraglutide restored myofibrillar architecture in ovariectomy-induced atrophy. Anti-atrophy actions of liraglutide involved suppression of atrogene expression and enhancement in expression of myogenic factors.
CONCLUSION: Liraglutide imparted protection and restored myofybrillar architecture in diverse models of muscle atrophy. Given its potent anti-atrophy, and recently reported osteoanabolic effects, we propose liraglutide's clinical evaluation in skeletal muscle atrophy and musculoskeletal disorders associated with diverse pathologies.

Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells.Publié le 09 12 2019

Spinal muscular atrophy (SMA) is a motor neuron disease caused by loss of function mutations in the Survival Motor Neuron 1 (SMN1) gene and reduced expression of the SMN protein, leading to spinal motor neuron death, muscle weakness and atrophy. Although humans harbour the highly homologous SMN2 gene, its defective splicing regulation yields a truncated and unstable SMN protein. The first therapy for SMA was recently approved by the Food and Drug Administration (FDA) and consists of an antisense oligonucleotide (Nusinersen) rendering SMN2 functional and thus improving patients' motor activity and quality of life. Nevertheless, not all patients equally respond to this therapy and the long-term tolerability and safety of Nusinersen are still unknown. Herein, in vivo splicing assays indicated that the HDAC inhibitor LBH589 is particularly efficient in rescuing the SMN2 splicing defect in SMA fibroblasts and SMA type-I mice-derived neural stem cells. Western blot analyses showed that LBH589 also causes a significant increase in SMN protein expression in SMA cells. Moreover, chromatin immunoprecipitation analyses revealed that LBH589 treatment induces widespread H4 acetylation of the entire SMN2 locus and selectively favour the inclusion of the disease-linked exon 7 in SMN2 mature mRNA. The combined treatment of SMA cells with sub-optimal doses of LBH589 and of an antisense oligonucleotide that mimic Nusinersen (ASO_ISSN1) elicits additive effects on SMN2 splicing and SMN protein expression. These findings suggest that HDAC inhibitors can potentiate the activity of Nusinersen and support the notion that "SMN-plus" combinatorial therapeutic approaches might represent an enhanced opportunity in the scenario of SMA therapy.

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights.Publié le 07 12 2019

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin ?-binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.

Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen.Publié le 06 12 2019

AIM: To determine factors associated with acquisition of a sitting position in patients with spinal muscular atrophy type 1 (SMA1) treated with nusinersen.
METHOD: Using data from the registry of patients with SMA1 treated with nusinersen, we compared the subgroups of sitters and non-sitters after 14 months of therapy as a function of baseline level, SMN2 copy number, age at treatment initiation, and improvement at 2 and 6 months post-treatment initiation. We used Hammersmith Infant Neurological Examination, Section 2 (HINE-2) and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for motor evaluation.
RESULTS: Fifty children (22 females, 28 males), mean age 22 months (SD 20.7; range 2.5-102.8mo) were treated. Data on sitting position acquisition were collected for 47 patients at month 14. Fifteen patients were able to sit unassisted; 11 of 15 had a baseline HINE-2 score of at least 2 points and 11 of 14 had an improvement over baseline of at least 2 points at month 6. Patients who improved by 2 or more points at month 6 were three times more likely to be sitters at month 14 than those who did not.
INTERPRETATION: High baseline motor function and improvement in HINE-2 score after 6 months of treatment are associated with the probability of acquiring a sitting position in patients with SMA1 treated with nusinersen.
WHAT THIS PAPER ADDS: Fifteen of 47 patients with spinal muscular atrophy could sit unaided 14 months after treatment with nusinersen. The number of SMN2 copies were not predictive of acquisition of a sitting position. Baseline condition and clinical response after 6 months of treatment were most predictive of sitting position acquisition.

A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy.Publié le 04 12 2019

The positive outcome of different therapeutic approaches for spinal muscular atrophy (SMA) in clinical trials and in clinical practice have highlighted the need to establish if functional changes are associated with possible changes of patient health-related quality of life or have an effect on activities of daily living and caregiver burden. The aim of this paper is to provide a critical review of the tools previously or currently used to measure quality of life, activity of daily living, and caregiver burden in SMA. We identified 36 measures. Only 6 tools were specifically developed for SMA while the others had been used and at least partially validated in wider groups of neuromuscular disorders including SMA. Twelve of the 36 focused on health-related quality of life, 5 on activities of daily living and 9 on caregiver burden. Ten included a combination of items. The review provides a roadmap of the different tools indicating their suitability for different SMA types or age groups. Scales assessing activities of daily living and care burden can provide patients and carers perspective on functional changes over time that should be added to the observer rated scales used in clinic.

Intravenous bisphosphonate therapy in children with spinal muscular atrophy.Publié le 04 12 2019

This is the first report on safety and efficacy of intravenous bisphosphonates (IV BP) for treatment of disuse osteoporosis and low bone mineral density (BMD) in children with spinal muscular atrophy (SMA). IV BP appears to be safe and effective in fracture rate reduction. However, caution is necessary given the occurrence of an atypical femur fracture.
INTRODUCTION: Children with SMA are at high risk for fragility fractures and low BMD. IV BP have been used for treatment of disuse osteoporosis in pediatrics. However, safety and efficacy of IV BP in the SMA population has not been reported.
METHODS: Retrospective chart review of IV BP for treatment of disuse osteoporosis and low BMD in children with SMA at a tertiary pediatric center from 2010 to 2018 RESULTS: Eight patients (50% female; 75% SMA type 1; median age at first infusion 6.7 years) receiving a total of 39 infusions (54% pamidronate, 46% zoledronic acid) were included in this report. Acute phase reactions occurred following 38% and 3% of initial and subsequent infusions, respectively. BMD trended toward improvement at 1 year post-treatment. Among six patients who had > 2 years of follow-up, fracture rate decreased from 1.4 to 0.1 fracture/year. An atypical femur fracture was observed in one patient.
CONCLUSION: These findings suggest that in children with SMA, IV BP therapy appears to be safe with minimal acute side effects and effective to reduce fracture rate. Caution is still needed given the occurrence of an atypical femur fracture in SMA population.

Routine Cerebrospinal Fluid (CSF) Parameters in Patients With Spinal Muscular Atrophy (SMA) Treated With Nusinersen.Publié le 04 12 2019

Background: Nusinersen is an antisense-oligonucleotide (ASO) approved for treatment of 5q-spinal muscular atrophy (SMA). Since the drug cannot cross the blood-brain barrier (BBB), it must be administered into the cerebrospinal fluid (CSF) space repeatedly by lumbar puncture. However, little is known whether ASOs have an impact on CSF routine parameters that may yield information on CSF flow and/or intrathecal inflammation. The objective of this study was to examine CSF routine parameters in SMA patients treated with nusinersen. Methods: Routine CSF parameters [white cell count, total protein, CSF/serum quotients of albumin (Qalb), lactate, and oligoclonal IgG bands (OCB)] of 60 SMA patients (type 1, 2, and 3, aged 7-60 years) were retrospectively analyzed. Results: White cells ranged from 0 to 4/?L in CSF; a singular case of pleocytosis (8/?L) was observed in a patient in parallel with a systemic infection. Total protein and Qalb showed a mild increase from baseline to the following lumbar punctures (except for total protein in CSF at the fourth injection of nusinersen). Lactate levels revealed a stable course. In one patient, positive OCB in CSF were transiently observed. The slight change in total CSF protein and Qalb may be caused by repeated lumbar puncture and/or intrathecal administration of the drug. Conclusion: Our data suggest that a regular examination of routine CSF parameters in patients in which intrathecal ASOs are administered is important to obtain information on possible side effects and to gain further insights into intrathecal processes.

Clinical Implication of Dosimetry of Computed Tomography- and Fluoroscopy-Guided Intrathecal Therapy With Nusinersen in Adult Patients With Spinal Muscular Atrophy.Publié le 04 12 2019

Background: Spinal muscular atrophy (SMA) is a genetic disorder that leads to progressive tetraparesis. Nusinersen is the first approved drug for the treatment of SMA and is administered via intrathecal injections. Neuromyopathic scoliosis and spondylodesis can impede lumbar punctures, thus necessitating the use of radiological imaging. Furthermore, dosimetry of this potentially lifelong therapy should be supervised. Methods: Fluoroscopy-assisted or computed tomography (CT)-guided intrathecal injections of nusinersen were performed in adult patients with SMA type 2 and 3. The mean effective dose was compared in patients with and without spondylodesis as well as in those with SMA type 2 and 3. The dosimetry was analyzed in relation to the motor function evaluated with the Revised Upper Limb module (RULM) score and the Hammersmith Functional Motor Scale-Expanded (HFMSE) score. Results: Fifteen patients with SMA type 2 and 3 underwent radiological imaging-assisted intrathecal injections. The mean effective dose per CT-guided injection per patient was 2.59 (±1.67) mSv (n = 12). The mean dose area product (DAP) per fluoroscopy-guided injection per patient was 200.48 (±323.67) ?Gym2 (n = 3). With increase in the number of injections, the effective dose (r = -0.23) (p < 0.05) and the DAP (r = -0.09) (p > 0.05) decreased. The mean effective dose in 4 patients without spinal fusion (SMA type 2) was 1.39 (±0.51) mSv, whereas that in 8 patients with spondylodesis (SMA type 2 and 3) was 3.21 (±1.73) mSv. The mean effective dose in 5 SMA type 2 patients with spondylodesis was 2.68 (±1.47) mSv (n = 5) and in 3 SMA type 3 patients was 4.00 (±1.82) mSv. Dosimetry did not show significant correlation with the clinical severity of the disease (RULM score: r = -0.045, p > 0.05 and HFMSE score: r = -0.001, p > 0.05). Conclusions: In SMA type 2 and 3 patients undergoing radiological imaging-assisted injections, the effective dose and DAP decreased during therapy with nusinersen. The mean effective dose in patients with spondylodesis was higher than that in patients without spondylodesis. Dosimetry should be monitored carefully in order to detect and prevent unnecessary radiation exposure.

An Unusual Cause of Obstructive Sleep Apnea in a Man With Spinal Muscular Atrophy Type III.Publié le 04 12 2019

PMID: 30176968 [PubMed - indexed for MEDLINE]

AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy.Publié le 02 12 2019

Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Our previous work on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle and restored contractile function, with affected dogs surviving more than 4 years post injection. This remarkable therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously described canine cohort that showed dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice but also identified transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created metrics to pinpoint potential biomarkers of disease progression and correction.

The Effectiveness and Value of Treatments for Spinal Muscular Atrophy.Publié le 30 11 2019

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions and MedSavvy, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Sanofi, Alnylam, Novartis, HealthPartners, Blue Cross Blue Shield of Massachusetts, Health Care Services Corporation, Mallinkrodt Pharmaceuticals, Prime Therapeutics, Regeneron, National Institute for Health Care Management, Commonwealth Fund, Partners Healthcare, New England States Consortium Systems, Allergan, Biogen, Editas, LEO Pharma, and HealthFirst. ICER has also received grants from Kaiser Foundation Health Plan, California Health Care Foundation, and the Laura and John Arnold Foundation. Pearson and Rind are employees of ICER. Thokala and Stevenson have no potential conflicts of interest to disclose.

Spinal Muscular Atrophy Therapies: ICER Grounds the Price to Value Conversation in Facts.Publié le 30 11 2019

DISCLOSURES: No funding supported the writing of this commentary. The authors are employed by Prime Therapeutics, a pharmacy benefits management company.

Nusinersen for older patients with SMA: a real-world clinical setting experience.Publié le 28 11 2019

INTRODUCTION: Clinical trials data concerning use of nusinersen in older spinal muscular atrophy (SMA) patients is lacking. We describe our center's experience in using intrathecal nusinersen for older patients in the clinical setting.
METHODS: Retrospective study.
RESULTS: 12 patients (12 - 52?years old) were treated with nusinersen. Mean follow-up duration was 17.4 months (4-26). All patients had scoliosis; 10 had spinal fusion/instrumentation. All procedures (30 cervical and 57 lumbar punctures) were technically successful. The only side effects were post-procedural headache (9%) and site pain (5.7%). Functional assessments showed stability in 6/9 patients and improvement in 3/9 patients. Subjective improvements in endurance, hand strength, and bulbar functioning critical for activities of daily living were reported in 8/12 patients. None of the patients has discontinued treatment so far.
DISCUSSION: Intrathecal nusinersen can be safely delivered in older SMA patients. Available functional outcome measures are not adequate to capture meaningful subjective improvements. This article is protected by copyright. All rights reserved.

Drugs, genes and screens: The ethics of preventing and treating spinal muscular atrophy.Publié le 27 11 2019

Spinal muscular atrophy (SMA) is the most common genetic disease that causes infant mortality. Its treatment and prevention represent the paradigmatic example of the ethical dilemmas of 21st-century medicine. New therapies (nusinersen and AVXS-101) hold the promise of being able to treat, but not cure, the condition. Alternatively, genomic analysis could identify carriers, and carriers could be offered in vitro fertilization and preimplantation genetic diagnosis. In the future, gene editing could prevent the condition at the embryonic stage. How should these different options be evaluated and compared within a health system? In this paper, we discuss the ethical considerations that bear on the question of how to prioritize the different treatments and preventive options for SMA, at a policy level. We argue that despite the tremendous value of what we call 'ex-post' approaches to treating SMA (such as using pharmacological agents or gene therapy), there is a moral imperative to pursue 'ex-ante' interventions (such as carrier screening in combination with prenatal testing and preimplantation genetic diagnosis, or gene editing) to reduce the incidence of SMA. There are moral reasons relating to autonomy, beneficence and justice to prioritize ex-ante methods over ex-post methods.

Expert Consensus for Early Onset Scoliosis Surgery.Publié le 27 11 2019

BACKGROUND: Despite a validated classification system, high-quality multicenter research databases (CSSG/GSSG), and a recent proliferation in publications, early-onset scoliosis (EOS) surgeons have no consensus on standards for surgical treatment. The 21st-century revolution in EOS care has only accelerated, with the arrival of a classification system, magnetically controlled growing rod, nusinersen, and improved nonoperative care (Mehta or Risser casting and compliance-monitored braces). This dizzying pace of change may have outstripped our ability to develop best-practice standards for EOS surgical indications. To learn where consensus is best (and worst) at this moment, we surveyed EOS world thought-leaders on a collection of representative cases.
METHODS: A 6-case survey was constructed and sent to 20 EOS world thought-leaders. The cases were selected to be representative of the major treatment categories: idiopathic, neuromuscular, syndromic, congenital, thoracic dysplasia, and spinal muscular atrophy (specifically to assess the impact of nusinersen and parasol deformity on surgical planning). Respondents were queried regarding treatment with specific attention to instrumentation and construct when surgery was selected. Responses regarding surgical timing and technique were analyzed for consensus (defined as >80%). ? analysis was performed to evaluate for differences in treatment preferences based on years of experience.
RESULTS: The survey response was 100%. Clinical experience ranged from 8 to 40 years (average 23.9?y). There was no consensus on any case. The greatest variability was on the congenital case; the closest to consensus was on the spinal muscular atrophy case. Three or more approaches were selected for all 6 cases; >4 approaches were selected for 5 cases. There is a trend towards screw fixation for proximal anchors. The management of thoracic dysplasia and parasol deformity is far from consensus.
CONCLUSION: The lack of consensus for surgical treatment of 6 representative EOS cases demands a renewed effort and commitment to develop best-practice guidelines based on multicenter outcome data.
LEVEL OF EVIDENCE: Level V-Expert Opinion.

A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy.Publié le 22 11 2019

Background: In December 2016, nusinersen gained FDA approval as the first pharmacologic treatment for spinal muscular atrophy (SMA), a disorder of motor neurons and the leading genetic cause of infant mortality. Nusinersen's intrathecal delivery requirement, strict dosage protocol, and accelerated FDA approval presented a challenge to health care centers hoping to implement treatment of patients with SMA. Scheduling logistics, combined with the specific ventilatory, anesthetic, and spinal access needs of this patient population, requires extensive coordination of care. This complexity, in addition to the high cost of treatment, may lead to overburdening of an institution's dosing resources, causing delays in treatment initiation and limiting patients' access to therapy and may result in barriers to coverage.
Methods: We initiated a comprehensive stepwise protocol to maximize patient inclusion, as well as safety and efficiency outcome measures. This retrospective cohort study reviews the dosing process.
Results: As a result of immense collaborative efforts involving care coordination of patients and families, in addition to health providers in the divisions of neurology, anesthesiology, pulmonology, orthopedics, interventional radiology, physical therapy, and neurosurgery, we have successfully dosed 62 SMA patients. Throughout this process, we have improved anesthetic techniques, as well as minimized procedural complications and missed scheduled doses.
Conclusion: We present here recommendations for safe and effective implementation of nusinersen utilizing a multidisciplinary approach, based on our 1 and a half year experience at a tertiary care children's hospital.

Estimation Of The Quality Of Life Benefits Associated With Treatment For Spinal Muscular Atrophy.Publié le 22 11 2019

Background: Spinal muscular atrophy (SMA) is a rare, genetic, progressive neuromuscular disorder characterized by severe muscle atrophy and weakness and is a leading genetic cause of death in infants and children. Nusinersen was the first treatment targeting the underlying cause of disease approved by the FDA, EMA and other countries for patients with SMA. There are currently very limited data available on the health-related quality of life (HRQoL) burden of SMA suitable for use in a cost-effectiveness analysis.
Objective: This study was designed to estimate quality of life weights or utilities for different SMA states.
Methods: SMA case studies were developed describing Type I (infantile onset) and Type II (later-onset) patients and different outcomes from treatment. These were developed so that quality of life weights or utilities (where the value of health ranges from 1 - full health to 0 - dead) could be estimated for cost-effectiveness analysis. Clinical experts (n=5) rated each of the case studies using standardized HRQoL instruments - the EQ-5D-Y and PedsQL-NMM (baseline states only).
Results: The SMA Type I utilities ranged from -0.33 (requires ventilation) to 0.71 (Type I patient reclassified as Type III following treatment), with quite substantial differences between some states. Most Type I states had a utility score below zero indicating the severity of the states. The SMA Type II utilities ranged from -0.13 (worsened) to 0.72 (stands/walks unaided). In general, the results showed HRQoL improved in line with better health states.
Conclusion: The utility scores obtained in this study highlight the very substantial burden experienced by SMA patients. Despite the limitations in the methods used, this study produced data with face validity and is a useful starting point for understanding the burden of SMA Types I and II in cost-effectiveness analysis.

Trends in incidence, prevalence, and mortality of neuromuscular disease in Ontario, Canada: A population-based retrospective cohort study (2003-2014).Publié le 22 11 2019

BACKGROUND: Population trends of disease prevalence and incidence over time measure burden of disease and inform healthcare planning. Neuromuscular disorders (NMD) affect muscle and nerve function with varying degrees of severity and disease progression.
OBJECTIVE: Using health administrative databases we described trends in incidence, prevalence, and mortality of adults and children with NMD. We also explored place of death and use of palliative care.
METHODS: Population-based (Ontario, Canada) cohort study (2003 to 2014) of adults and children with NMD identified using International Classification of Disease and health insurance billing codes within administrative health databases.
RESULTS: Adult disease prevalence increased on average per year by 8% (95% confidence interval (CI) 6% to 10%, P <.001), with the largest increase in adults18-39 years. Childhood disease prevalence increased by 10% (95% CI 8% to 11%, P <.0001) per year, with the largest increase in children 0 to 5 years. Prevalence increased across all diagnoses except amyotrophic lateral sclerosis and spinal muscular atrophy for adults and all diagnoses for children. Adult incidence decreased by 3% (95% CI -4% to -2%, P <.0001) but incidence remained stable in children. Death occurred in 34,336 (18.5%) adults; 21,236 (61.8%) of whom received palliative care. Death occurred in 1,009 (5.6%) children; 507 (50.2%) of whom received palliative care. Mortality decreased over time in adults (odds ratio (OR) 0.86, 95% CI 0.86-0.87, P <.0001) and children (OR 0.79, 95% CI 0.76-0.82, P <.0001). Use of palliative care over time increased for adults (OR 1.18, 95% CI 1.09 to 1.28, P <.0001) and children (OR 1.22, 95% CI 1.20 to 1.23, P <.0001).
CONCLUSIONS: In both adults and children, NMD prevalence is rising and mortality rates are declining. In adults incidence is decreasing while in children it remains stable. This confirms on a population-based level the increased survival of children and adults with NMD.

Treatment with Nusinersen - Challenges Regarding the Indication for Children with SMA Type 1.Publié le 21 11 2019

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Inhospital Complications of Patients With Neuromuscular Disorders Undergoing Total Joint Arthroplasty.Publié le 21 11 2019

INTRODUCTION: Orthopaedic surgeons are wary of patients with neuromuscular (NM) diseases as a result of perceived poor outcomes and lack of data regarding complication risks. We determined the prevalence of patients with NM disease undergoing total joint arthroplasty (TJA) and characterized its relationship with in-hospital complications, prolonged length of stay, and total charges.
METHODS: Data from the Nationwide Inpatient Sample from 2005 to 2014 was used for this retrospective cohort study to identify 8,028,435 discharges with total joint arthroplasty. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify 91,420 patients who had discharge diagnoses for any of the NM disorders of interest: Parkinson disease, multiple sclerosis, cerebral palsy, cerebrovascular disease resulting in lower extremity paralysis, myotonic dystrophy, myasthenia gravis, myositis (dermatomyositis, polymyositis, and inclusion-body myositis), spinal muscular atrophy type III, poliomyelitis, spinal cord injury, and amyotrophic lateral sclerosis. Logistic regression was used to estimate the association between NM disease and perioperative outcomes, including inpatient adverse events, length of stay, mortality, and hospital charges adjusted for demographic, hospital, and clinical characteristics.
RESULTS: NM patients undergoing TJA had increased odds of total surgical complications (odds ratio [OR] = 1.21; 95% confidence interval [CI], 1.17 to 1.25; P < 0.0001), medical complications (OR = 1.41; 95% CI, 1.36 to 1.46; P < 0.0001), and overall complications (OR = 1.32; 95% CI, 1.28 to 1.36; P < 0.0001) compared with non-NM patients. Specifically, NM patients had increased odds of prosthetic complications (OR = 1.09; 95% CI, 0.84 to 1.42; P = 0.003), wound dehiscence (OR = 5.00; 95% CI, 1.57 to 15.94; P = 0.0002), acute postoperative anemia (OR = 1.20; 95% CI, 1.16 to 1.24; P < 0.0001), altered mental status (OR = 2.59; 95% CI, 2.24 to 2.99; P < 0.0001), urinary tract infection (OR = 1.45; 95% CI, 1.34 to 1.56; P < 0.0001), and deep vein thrombosis (OR = 1.27; 95% CI, 1.02 to 1.58; P = 0.021). No difference of in-hospital mortality was observed (P = 0.155).
DISCUSSION: Because more patients with NM disease become candidates of TJA, a team of neurologists, anesthesiologists, therapists, and orthopaedic surgeon is required to anticipate, prevent, and manage potential complications identified in this study.
LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Surgical management of camptocormia in Parkinson's disease: systematic review and meta-analysis.Publié le 21 11 2019

OBJECTIVE: Camptocormia is a potentially debilitating condition in the progression of Parkinson's disease (PD). It is described as an abnormal forward flexion while standing that resolves when lying supine. Although the condition is relatively common, the underlying pathophysiology and optimal treatment strategy are unclear. In this study, the authors systematically reviewed the current surgical management strategies for camptocormia.
METHODS: PubMed was queried for primary studies involving surgical intervention for camptocormia in PD patients. Studies were excluded if they described nonsurgical interventions, provided only descriptive data, or were case reports. Secondarily, data from studies describing deep brain stimulation (DBS) to the subthalamic nuclei were extracted for potential meta-analysis. Variables showing correlation to improvement in sagittal plane bending angle (i.e., the vertical angle caused by excessive kyphosis) were subjected to formal meta-analysis.
RESULTS: The query resulted in 9 studies detailing treatment of camptocormia: 1 study described repetitive trans-spinal magnetic stimulation (rTSMS), 7 studies described DBS, and 1 study described deformity surgery. Five studies were included for meta-analysis. The total number of patients was 66. The percentage of patients with over 50% decrease in sagittal plane imbalance with DBS was 36.4%. A duration of camptocormia of 2 years or less was predictive of better outcomes (OR 4.15).
CONCLUSIONS: Surgical options include transient, external spinal stimulation; DBS targeting the subthalamic nuclei; and spinal deformity surgery. Benefit from DBS stimulation was inconsistent. Spine surgery corrected spinal imbalance but was associated with a high complication rate.

Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy.Publié le 19 11 2019

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.Publié le 15 11 2019

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2.

Nusinersen Administration Via an Intrathecal Port in a 16-Year-Old Spinal Muscular Atrophy Patient with Profound Scoliosis.Publié le 14 11 2019

INTRODUCTION: Spinal muscular atrophy (SMA) is a genetic disease affecting the second motor neuron, causing progressive muscle atrophy and weakness due to decreased expression of the survival motor neuron. Different subtypes exist, type 2 being one of the most frequent ones. These patients show a high incidence of scoliosis requiring surgery. In 2016 and 2017, the Federal Drug Administration and European Medical Agency approved nusinersen for all types of SMA. It is a splicing modifier that enhances the expression of survival motor neuron and it has to be administered intrathecally. In patients with profound scoliosis, intrathecal administration can be challenging. Here, we present our experience with the implantation of an intrathecal port in a patient with SMA type 2.
CASE PRESENTATION: A 16-year-old girl with SMA type 2 was referred for intrathecal nusinersen therapy. Because of severe scoliosis, spondylodesis of the segments TH7-S1 was performed at 14 years of age. The first two loading doses were given by spinal tap under sedation and computed tomography guidance, but we were unable to administer the following dose because of severe scoliotic spinal deformation. To ensure further drug therapy, an intrathecal port catheter (Celsite® Safety; Braun, Germany) was implanted via microsurgical hemilaminectomy L4. Further intrathecal nusinersen administration was uneventful.
CONCLUSION: We conclude that the implantation of an intrathecal port system in patients with SMA and profound scoliosis is a safe and feasible procedure and allows the administration of nusi-nersen while reducing the need for sedation and exposure to radiation.

Note: Zolgensma data manipulation.Publié le 14 11 2019

PMID: 31581156 [PubMed - indexed for MEDLINE]

Genetic therapies for spinal muscular atrophy type 1.Publié le 12 11 2019

PMID: 29229374 [PubMed - indexed for MEDLINE]

Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care.Publié le 11 11 2019

Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.

Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort.Publié le 11 11 2019

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous survival of motor neuron 1 (SMN1) gene disruption. Despite a genetic etiology, little is known about subtype concordance among siblings.
OBJECTIVE: To investigate subtype concordance among siblings with SMA.
METHODS: Cure SMA maintains a database of newly diagnosed patients with SMA, which was utilized for this research.
RESULTS: Among 303 sibships identified between 1996 and 2016, 84.8% were subtype concordant. Of concordant sibships, subtype distribution was as follows: Type I, 54.5%; Type II, 31.9%; Type III, 13.2%; Type IV, 0.4%. Subtype and concordance/discordance association was significant (Fisher's exact test; p?<?0.0001). Among discordant sibships (chi-square test, p?<?0.0001), Types II/III (52.2%) and Types I/II (28.3%) were the most common pairs. No association was found between sibling sex and concordance. Our findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I).
CONCLUSIONS: These data are valuable for understanding familial occurrence of SMA subtypes, enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives.

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study.Publié le 11 11 2019

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ?6 h/day for ?7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Staged bilateral pallidotomy for dystonic camptocormia: case report.Publié le 10 11 2019

Camptocormia is a rare, involuntary movement disorder, presenting as truncal flexion while standing or walking, and is mainly observed as a feature of Parkinson's disease (PD) and primary dystonia. Deep brain stimulation (DBS) of the globus pallidus internus is effective for refractory camptocormia observed with PD or dystonia. However, the effectiveness of pallidotomy for camptocormia has not been investigated. The authors report the case of a 38-year-old man with anterior truncal bending that developed when he was 36 years old. Prior to the onset of the symptom, he had been taking antipsychotic drugs for schizophrenia. There were no features of PD; the symptom severely interfered with his walking and daily life. He was given anticholinergics, clonazepam, and botulinum toxin injections, which did not result in much success. Because of the patient's unwillingness to undergo implantation of a hardware device, he underwent staged bilateral pallidotomy with complete resolution for a diagnosis of tardive dystonic camptocormia. The Burke-Fahn-Marsden dystonia rating scale subscore for the trunk before and after bilateral pallidotomy was 3 and 0, respectively. No perioperative adverse events were observed. Effects have persisted for 18 months. Bilateral pallidotomy can be a treatment option for medically refractory dystonic camptocormia without the need for device implantation.

Methods for Correction of the Single-Nucleotide Substitution c.840C>T in Exon 7 of the SMN2 Gene.Publié le 08 11 2019

The CRISPR/Cas technology has a great potential in the treatment of many hereditary diseases. One of the prospective models for the CRISPR/Cas-mediated therapy is spinal muscular atrophy (SMA), a disease caused by deletion of the SMN1 gene that encodes the SMN protein required for the survival of motor neurons. SMA patients' genomes contain either single or several copies of SMN2 gene, which is a paralog of SMN1. Exon 7 of SMN2 has the single-nucleotide substitution c.840C>T leading to the defective splicing and decrease in the amounts of the full-length SMN. The objective of this study was to create and test gene-editing systems for correction of the single-nucleotide substitution c.840C>T in exon 7 of the SMN2 gene in fibroblasts, induced pluripotent stem cells, and motor neuron progenitors derived from a SMA patient. For this purpose, we used plasmid vectors expressing CRISPR/Cas9 and CRISPR/Cpf1, plasmid donor, and 90-nt single-stranded oligonucleotide templates that were delivered to the target cells by electroporation. Although sgRNA_T2 and sgRNA_T3 guiding RNAs were more efficient than sgRNA_T1 in fibroblasts (p < 0.05), no significant differences in the editing efficiency of sgRNA_T1, sgRNA_T2, and sgRNA_T3 was observed in patient-specific induced pluripotent stem cells and motor neuron progenitors. The highest editing efficiency in induced pluripotent stem cells and motor neuron progenitors was demonstrated by the sgRNA_T1 and 90-nt single-stranded oligonucleotide donors.

Long-Term Mechanical Insufflation-Exsufflation Cough Assistance in Neuromuscular Disease: Patterns of Use and Lessons for Application.Publié le 08 11 2019

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) devices increase expiratory air flow and thereby promote increased cough peak flow (CPF) in conjunction with a cough. There is little research looking at long-term use of MI-E in subjects with neuromuscular disease (NMD), and no long-term study has reported CPF, MI-E device settings, and adherence.
METHODS: We evaluated 181 patient records (130 adults, 51 children) of individuals who received a MI-E device from our center between February 2014 and February 2018. Median age (interquartile range [IQR]) was 27 (14-51) y. Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS) were the 3 most common diagnoses.
RESULTS: MI-E devices were provided to the weakest subjects with a CPF < 160 L/min. Median (IQR) settings were insufflation, 25 (23-30) cm H2O, exsufflation -35 (-30 to -40) cm H2O, insufflation time 1.5 (1.3-1.7) s, exsufflation time 1.8 (1.5-2.0) s, and pause 1.5 (1.3-2.0) s. The inspiratory flow profile was set to high in all subjects, and no subject used supplemental oxygen with the MI-E device. When comparing insufflation pressures to exsufflation pressures, a greater negative pressure was used relative to positive pressure (P < .001). When comparing insufflation to exsufflation time, there was a significantly longer exsufflation duration (P < .001). Median (IQR) CPF at the start of MI-E was 60 (10-100) L/min. There was no correlation between either insufflation or exsufflation pressures and CPF. Median (IQR) usage for the group was 60% (13.5-100%) of days for the total days. Subjects with tracheostomies or SMA type I had the greatest adherence to treatment. Median (IQR) duration of MI-E use was 17 (8.5-32) months. Ninety-six percent of subjects were receiving ventilatory support.
CONCLUSIONS: Greater exsufflation pressures than insufflation pressures, together with a shorter insufflation time than exsufflation time, were used. Predicting good adherence among the subjects was difficult. Subjects who produced daily secretions were more likely to use MI-E every day.

Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen.Publié le 02 11 2019

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

More is needed to complement the available therapies of spinal muscular atrophy.Publié le 01 11 2019

PMID: 31668092 [PubMed - as supplied by publisher]

Does albuterol have an effect on neuromuscular junction dysfunction in spinal muscular atrophy?Publié le 01 11 2019

PMID: 30177455 [PubMed - indexed for MEDLINE]

Advanced therapies in rare diseases: the example of spinal muscular atrophy.Publié le 29 10 2019

PMID: 29685310 [PubMed - indexed for MEDLINE]

Functional outcome measures for infantile Charcot-Marie-Tooth disease: a systematic review.Publié le 28 10 2019

A functional outcome measure for infants (aged 0-3 years) with Charcot-Marie-Tooth (CMT) disease is needed for upcoming disease-modifying trials. A systematic review of outcome measures for infants with neuromuscular disorders was completed to determine if validated measures were available for the CMT infant population. We assessed 20,375 papers and identified seven functional outcome measures for infants with neuromuscular disorders. Six were developed and validated for spinal muscular atrophy (SMA). There were no CMT-specific outcome measures identified; however, one (motor function measure) assessed a range of neuromuscular disorders including 13 infants and children with CMT. The included studies exhibited "good" face, discriminant, convergent and concurrent validity, and reported excellent intra- and inter-rater reliability. No outcome measure was subjected to item response theory. Studies reported outcome measures comprising of 51 different items assessing six domains of function: reflexive movement, axial movement, limb movement, positioning, gross motor, and fine-motor skills. Scoring of items ranged from 2- to 7-point rating scales; and none were scaled to normative reference values to account for changes in growth and development. The SMA focus of most items is likely to produce ceiling effects and lack sensitivity and responsiveness for within and between types of CMT in infants. Nevertheless, several items across scales assessing distal strength, gross- and fine-motor function, could be included in the development of a composite functional outcome measure for infants with CMT to assess disease-modifying interventions.

Critical period of neuromuscular development: Importance for a new treatment of SMA.Publié le 26 10 2019

Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion. There is a critical period during which the presence of the SMN protein is mandatory for the survival of the motor unit and the individual. This period coincides with the most important events involved in the development of the motor unit. Results from normal genetically unaffected rats and mice show that during a critical period of development the function of the nerve terminal and the release of transmitter play a crucial role in the development of the motor neurone and muscle. The possibility that targeting the function of the nerve terminal to overcome its inability to release transmitter could benefit patients with the deletion of the SMN gene.

Molecular based newborn screening in Germany: Follow-up for cystinosis.Publié le 24 10 2019

Background: Newborn screening (NBS) programs for treatable metabolic disorders have been enormously successful, but molecular-based screening has not been broadly implemented so far.
Methods: This prospective pilot study was performed within the German NBS framework. DNA, extracted from dried blood cards was collected as part of the regular NBS program. As cystinosis has a prevalence of only 1:100,000-1:200,000, a molecular genetic assay for detection of the SMN1 gene mutation with a higher prevalence was also included in the screening process, a genetic defect that leads to spinal muscular atrophy (SMA). First tier multiplex PCR was employed for both diseases. The cystinosis screening employed assays for the three most common CTNS mutations covering 75% of German patients; in case of heterozygosity for one of these mutations, samples were screened by next generation sequencing (NGS) of the CTNS exons for 101 CTNS mutations. A detection rate of 98.5% is predicted using this approach.
Results: Between January 15, 2018 and May 31, 2019, 257,734 newborns were screened in Germany for cystinosis. One neonate was diagnosed with cystinosis, consistent with the known incidence of the disease. No false positive or false negatives were detected so far. Screening, communication of findings to parents, and confirmation of diagnosis were accomplished in a multi-disciplinary setting. This program was accomplished with the cooperation of hospitals, physicians, and parents. In the neonate diagnosed with cystinosis, oral cysteamine treatment began on day 18. After 16?months of treatment the child has no clinical signs of renal tubular Fanconi syndrome.
Conclusions: This pilot study demonstrates the efficacy of a molecular-based neonatal screening program for cystinosis using an existing national screening framework.

Functional Tasks Performed by People with Severe Muscular Atrophy Using an sEMG Controlled Robotic Manipulator.Publié le 24 10 2019

For paralyzed people activities of daily living like eating or drinking are impossible without external assistance. Robotic assistance systems can give these people a part of their independence back. Especially if the operation with a joystick is not possible anymore due to a missing hand function, people need innovative interfaces to control assistive robots in 3D. Besides brain computer interfaces an approach based on surface electromyography (sEMG) can present an opportunity for people with a strong muscular atrophy. In this work we show that two people with proceeded spinal muscular atrophy can perform functional tasks using an sEMG controlled robotic manipulator. The interface provides a continuous control of three degrees of freedom of the endeffector of the robot. The performance was assessed with two clinical measures of upper limb functionality: the Box and Blocks Test and the Action Research Arm Test. Additionally, the participant could show that they can drink by themselves with the provided system.

Nusinersen in type 1 SMA infants, children and young adults: Preliminary results on motor function.Publié le 23 10 2019

We report preliminary data on the six month use of Nusinersen in 104 type 1 patients of age ranging from three months to 19 years, 9 months. Ten of the 104 were classified as 1.1, 58 as 1.5 and 36 as 1.9. Three patients had one SMN2 copy, 65 had two and 24 had three copies. In 12 the SMN2 copy number was not available. After six months an improvement of more than two points was found in 58 of the 104 (55.7%) on the CHOP INTEND and in 21 of the 104 (20.19%) on the Hammersmith Infant Neurological Examination (HINE). Changes more than two points were found in 26/71 patients older than two years, and in seven of the 20 older than 10 years. Changes???four points were found in 20/71 older than two years, and in six of the 20 patients older than 10 years. The difference between baseline and six months on both CHOP INTEND and HINE was significant for the whole group (p?<?0.001) as well as for the subgroups with two (p?<?0.001), and three SMN2 copies (p?<?0.001). Our preliminary results suggest that functional improvement can be observed in type 1 patients outside the range of the inclusion criteria used in the Endear study.

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.Publié le 23 10 2019

This is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease.

Clinical Evidence Supporting Early Treatment Of Patients With Spinal Muscular Atrophy: Current Perspectives.Publié le 22 10 2019

Recent advances in the treatment of spinal muscular atrophy (SMA) have dramatically altered prognosis. Rather than a rapidly lethal disease, SMA type 1, the most severe form with the earliest onset of SMA, has become a disease in which long-term event-free survival with the acquisition of important motor milestones is likely. Prognosis for patients with SMA type 2 has shifted from slow and progressive deterioration to long-term stability. Nevertheless, there is a large heterogeneity in terms of clinical response to currently available treatments, ranging from absence of response to impressive improvement. The only factor identified that is predictive of treatment success is the age of the patient at the initiation of treatment, which is closely related to disease duration. The aim of this paper is to review available evidence that support early intervention using currently available treatment approaches.

Magnetic resonance imaging of the cervical spinal cord in spinal muscular atrophy.Publié le 18 10 2019

OBJECTIVE: In this study we investigated the potential value of magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in characterizing changes in the cervical spinal cord and peripheral nerve roots in vivo in patients with spinal muscular atrophy (SMA).
METHODS: We developed an MRI protocol with 4 sequences to investigate the cervical spinal cord and nerve roots on a 3 Tesla MRI system. We used 2 anatomical MRI sequences to investigate cross-sectional area (CSA) at each spinal segment and the diameter of ventral and dorsal nerve roots, and two diffusion tensor imaging (DTI) techniques to estimate the fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) in 10 SMA patients and 20 healthy controls.
RESULTS: There were no significant differences in CSA (p?>?.1), although an 8.5% reduction of CSA in patients compared to healthy controls was apparent at segment C7. DTI data showed a higher AD in grey matter of patients compared to healthy controls (p?=?.033). Significantly lower MD, AD and RD values were found in rostral nerve roots (C3-C5) in patients (p?<?.045).
CONCLUSIONS: We showed feasibility of an advanced 3?T MRI protocol that allowed differences to be determined between patients and healthy controls, confirming the potential of this technique to assess pathological mechanisms in SMA. After further development and confirmation of findings in a larger sample, these techniques may be used to study disease course of SMA in vivo and evaluate response to survival motor neuron (SMN) augmenting therapy.

Mechanisms of Neuronal Alternative Splicing and Strategies for Therapeutic Interventions.Publié le 18 10 2019

Many cellular and physiological processes are coordinated by regulatory networks that produce a remarkable complexity of transcript isoforms. In the mammalian nervous system, alternative pre-mRNA splicing generates functionally distinct isoforms that play key roles in normal physiology, supporting development, plasticity, complex behaviors, and cognition. Neuronal splicing programs controlled by RNA-binding proteins, are influenced by chromatin modifications and can exhibit neuronal subtype specificity. As highlighted in recent publications, aberrant alternative splicing is a major contributor to disease phenotypes. Therefore, understanding the underlying mechanisms of alternative splicing regulation and identifying functional splicing isoforms with critical phenotypic roles are expected to provide a comprehensive resource for therapeutic development, as illuminated by recent successful interventions of spinal muscular atrophy. Here, we discuss the latest progress in the study of the emerging complexity of alternative splicing mechanisms in neurons, and how these findings inform new therapies to correct and control splicing defects.

Nusinersen Use in Spinal Muscular Atrophy.Publié le 18 10 2019

PMID: 30584063 [PubMed - indexed for MEDLINE]

Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides.Publié le 17 10 2019

The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and diversity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2'-O-methyl modified bases on a phosphorothioate backbone.

Genetic therapies for inherited neuromuscular disorders.Publié le 17 10 2019

Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders.

Respiratory support attitudes among pediatric intensive care staff for spinal muscular atrophy patients in Saudi Arabia.Publié le 17 10 2019

OBJECTIVE: To explore therapeutic attitude of healthcare providers practicing in pediatric critical care in Saudi Arabia toward patients with Spinal Muscular Atroph (SMA) Type I, and to explore their awareness about the International Consensus statement for SMA care.
METHODS: A cross-sectional survey was conducted in April 2015 during 6th Saudi Critical Care Conference, targeting physicians and respiratory therapists practicing in Pediatric Critical Care.
RESULTS: Sixty participants accepted to participate in this survey. Out of those who answered the questionnaire, 44 were included in the analysis. Majority (66%) of participants were unaware of the International Consensus guidelines for SMA. Endotracheal intubation was reported as an acceptable intervention in SMA patients with acute respiratory failure by 43% of participants. Similarly, chronic home ventilation was agreed by 41% of participants.
CONCLUSION: A nationwide adaptation of the International SMA Consensus guidelines for children with SMA I is recommended, aiming to decrease variability and standardize their management across various healthcare facilities in Saudi Arabia.

Industry update for May 2019.Publié le 16 10 2019

This industry update features a round-up of pharmaceutical news in May 2019 based on press releases and websites. The month was characterized by the achievement of significant milestones in gene therapy. The biggest of these was the US FDA's approval of Zolgensma®. This medicine sums up the promise and price of genetic medicine. On one hand the clinical results show Zolgensma can dramatically improve the prognosis for infants with spinal muscular atrophy after just one administration, while on the other, it has been priced at around US$2.1 million. With more such therapies likely to reach the market, the debate on Zolgensma goes beyond cost, to overall affordability, the true meaning of cost-effectiveness and how to reward companies for effective, innovative medicines.

The implementation of newborn screening for spinal muscular atrophy: the Australian experience.Publié le 16 10 2019

PURPOSE: To evaluate the implementation of the first statewide newborn screening (NBS) program for spinal muscular atrophy (SMA) in Australia. Processes that hinder and support clinical development, translation, and sustainability of the first primary genetic screening program in Australia are appraised.
METHODS: The study prospectively describes the course (timelines, health processes, and preliminary clinical outcomes) for SMA screen-positive newborns from 1 August 2018 to 31 July 2019 in New South Wales and Australian Capital Territory, Australia.
RESULTS: In the first year of the program, 103,903 newborns were screened. Ten newborns screened positive for SMA. Genetic confirmation of SMA occurred in 9/10 (90%) of infants. Clinical signs of SMA evolved in 4/9 (44%) within 4 weeks of life, heralded by hypotonia and weakness initially recognized in the neck. Median time to implementing a care plan (including commencement of disease-modifying therapies) was 26.5 days (16-37 days) from birth.
CONCLUSION: NBS is essential for early and equitable identification of patients with SMA. Expedient diagnosis and management are vital, as disease latency appears brief in some cases. NBS shows significant clinical utility to support early parental decision making, improve access to specialist neuromuscular expertise, and facilitate initiation of personalized therapeutic strategies.

Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy.Publié le 16 10 2019

The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed. Twenty patients were included, eight with early onset most severe phenotype, eight with the more typical type 1 phenotype and 4, who achieved some head control, with a milder phenotype. Both baseline values and trajectories of progression were different in the three subgroups (p?=?0.0001). Infants with the most severe phenotype had the lowest scores (below 20) on their first assessment and had the most rapid decline. Those with the typical phenotype had scores generally between 20 and 40 and also had a fast decline. The infants with the milder phenotype had the highest scores, generally above 35, and a much slower deterioration. Infants with three SMN2 copies had an overall milder phenotype and milder progression while two SMN2 copies were found in all three subgroups.

Treating neonatal spinal muscular atrophy: A 21st century success story?Publié le 13 10 2019

Severe spinal muscular atrophy is an autosomal recessive motor neuron disorder characterized by rapidly progressive hypotonia and weakness with respiratory complications and fatal outcome. It is caused by absence or pathogenic variants in the SMN1 gene. Knowledge and advances of the genetics of the disease allowed the development of tailored therapies that has changed clinical trajectories with evolving phenotypes. Several clinical investigations demonstrate that early diagnosis and intervention are essential for improved response to treatment and better prognosis. Therapeutic interventions that are effective at pre-symptomatic or early stages of the disease creates the need for awareness, expedite diagnosis and consideration of newborn screening programs.

Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd.Publié le 13 10 2019

Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) is an autosomal recessive disease that develops early during infancy. The gene responsible for disease development is immunoglobulin helicase ?-binding protein 2 (IGHMBP2). IGHMBP2 is a ubiquitously expressed gene but its mutation results in the loss of alpha-motor neurons and subsequent muscle atrophy initially of distal muscles. The current SMARD1 mouse model arose from a spontaneous mutation originally referred to as neuromuscular degeneration (nmd). The nmd mice have the C57BL/6 genetic background and contain an A to G mutation in intron 4 of the endogenous Ighmbp2 gene. This mutation causes aberrant splicing, resulting in only 20-25% of full-length functional protein. Several congenital conditions including hydrocephalus are common in the C57BL/6 background, consistent with our previous observations when developing a gene therapy approach for SMARD1. Additionally, a modifier allele exists on chromosome 13 in nmd mice that can partially suppress the phenotype, resulting in some animals that have extended life spans (up to 200 days). To eliminate the intrinsic complications of the C57BL/6 background and the variation in survival due to the genetic modifier effect, we created a new SMARD1 mouse model that contains the same intron 4 mutation in Ighmbp2 as nmd mice but is now on a FVB congenic background. FVB-nmd are consistently more severe than the original nmd mice with respect to survival, weigh and motor function. The relatively short life span (18-21 days) of FVB-nmd mice allows us to monitor therapeutic efficacy for a variety of novel therapeutics in a timely manner without the complication of the small percentage of longer-lived animals that were observed in our colony of nmd mice.

One year of newborn screening for SMA - Results of a German pilot project.Publié le 10 10 2019

OBJECTIVE: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The study was conducted to assess the impact of early detection of SMA by newborn screening (NBS) on the clinical course of the disease.
METHODS: Screening was performed in two federal states of Germany, Bavaria and North Rhine Westphalia, between January 2018 and February 2019. The incidence in the screening population was calculated as number of detected patients with a homozygous deletion in the SMN1-gene per number of screened patients. To get an idea about the incidence of newly diagnosed SMA in the year prior to screening a survey covering all neuropediatric centers in the state of Bavaria was conducted, identifying all SMA-cases in 2017 and 2018. Following positive NBS and confirmatory diagnostic test, treatment was advised according to the recommendations of the "American SMA NBS Multidisciplinary Working Group". Immediate treatment with Nusinersen was recommended in children with 2 and 3 SMN2 copies and a conservative strict follow-up strategy in children with ?4 copies. All children underwent regular standardized neuropediatric examination, CHOP INTEND and HINE-2 testing as well as electrophysiological exams every 2-3 months.
RESULTS: 165,525 children were screened. 22 cases of SMA were identified, meaning an incidence rate of 1:7524. SMN2 copy number analysis showed 2 SMN2 copies in 45% of patients, 3 SMN2 copies in 19 % and 4 SMN2 copies in 36% . Thesefindings are confirmed in the most recent statistical data-cut from 31st August 2019 (incidence 1:7089, 2 SMN2 copies in 44% , 3 in 15% and 4 in 38% ). Comparison with up-to-date German data on SMA incidence and the Bavarian survey give evidence that NBS did not lead to a relevant increase in incidence.10 patients with 2 or 3 SMN2 copies were treated with Nusinersen, starting between 15- 39 days after birth, in 7/10 patients before onset of symptoms.Presymptomatically treated patients (age at last examination: 1- 12 months, median 8 months) showed no muscle weakness by the age of one month to one year. One child with 4 SMN2 copies became symptomatic at the age of 8 months.
CONCLUSIONS: Newborn screening, resulting in presymptomatic treatment, improves outcome in children with genetically proven SMA. Newborn screening for SMA should be introduced in all countries where therapy is available. An immediate therapy in cases with 4 SMN2 copies should be considered.

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 - A Prospective Observational Study.Publié le 10 10 2019

OBJECTIVE: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3.
METHODS: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC % pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1-40, ß-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen's d and effect size r for evaluation of clinical meaningfulness.
RESULTS: 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6). Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years. Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline. For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6. RULM-score increased significantly at V6, and peak cough flow at visit 5. In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins. In safety analysis, overall, Nusinersen applications were well tolerated. Eleven patients reported adverse events that were related to the study procedures, comprising back pain in seven patients and post-lumbar-puncture headache following intrathecal administration in four patients. Post-lumbar-puncture headache was reported in three females and one male, in total eleven times of 108 punctures (10%). No serious adverse events occurred.
CONCLUSIONS: This prospective observational study indicates a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with Nusinersen, which had never occurred in the natural history of the disease. In our cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180.

[Clinical characteristics of non-invasive ventilation treatment in children with spinal muscular atrophy and sleep disordered breathing].Publié le 10 10 2019

Objective: To study the short-term and long-term efficacy of the non-invasive ventilation treatment in children with spinal muscular atrophy (SMA) and sleep-disordered breathing. Methods: This was a prospective research to study the effect of night-time non-invasive ventilation in children with SMA and moderate to severe sleep-disordered breathing during March 2016 to January 2018, from the Pulmonary Department of Capital Institute of Pediatrics Affiliated Children's Hospital. Patients were divided into the treated group (with night-time non-invasive ventilation) and the control group (without ventilator). Sleep breathing pressure titration was suggested to the patients who were prepared to receive non-invasive ventilation. All cases were followed up for one year. Parameters'changes in polysomnography were assessed (paired t-test) in titration patients. Frequency of respiratory tract infection during the next year in the patients with and without ventilation was collected and compared (Mann-Whitney U-test). Results: Seventeen cases were recruited. The average age was (5.1±2.9) years, 10 cases were boys and 7 cases were girls. In the titration group (8 patients), after non-invasive ventilation, the average apnea hypopnea index was (3.8±2.5) times/h (t=4.086, P=0.005), hypopnea index was (2.4±1.2) times/h (t=2.779, P=0.027), average oxygen saturation during total sleep time was 0.966±0.007 (t=-5.292, P=0.001), and the minimum oxygen saturation was 0.906±0.023 (t=-3.938, P=0.006). All the above parameters were significantly improved after treatment. Than before, which was (16.6±9.7) times/h, (7.2±4.7) times/h, 0.946±0.015, 0.786±0.092 respectively. Ventilator mode for the 9 children with long time non-invasive ventilation at home was Bi-level positive airway pressure S/T. The positive airway pressure was set at 8-14 cmH(2)O (1 cmH(2)O=0.098 kPa) in inspiratory phase and 4-6 cmH(2)O in expiratory phase. In the treated group (9 patients), the average frequency of upper respiratory tract infection was 1.0 (0, 3.0) times/year (Z=-2.245, P=0.023), the lower respiratory tract infection was 0 (0, 0) times/year (Z=-3.189, P=0.001), hospitalization was 0 (0, 0) times/year (Z=-3.420, P<0.01), and admission to intensive care unit was 0 (0, 0) times/year (Z=-3.353, P=0.029). All the above indexes were significantly decreased compared with the control group (8 patients), which was 3.0 (2.3, 7.0) times/year, 2.0 (1.3, 4.5) times/year, 1.0 (1.0, 4.3) times/year, 0.5 (0, 1.0) times/year respectively. Conclusion: Non-invasive ventilation is efficient to SMA children with sleep-disordered breathing, and also can reduce the incidence of respiratory tract infections for children with SMA.

"Getting ready for the adult world": how adults with spinal muscular atrophy perceive and experience healthcare, transition and well-being.Publié le 08 10 2019

BACKGROUND: Spinal muscular atrophy (SMA) has profound implications across a lifetime for people with the condition and their families. Those affected need long-term multidisciplinary medical and supportive care to maintain functional mobility, independence and quality of life. Little is known about how adults with SMA experience healthcare, or the components of care perceived as important in promoting well-being. The purpose of this study was to use qualitative research methodology to explore the lived experiences of healthcare and wellbeing of adults with SMA. Purposive sampling was used to recruit adolescents and adults with SMA, their parents and partners. Face-to-face or telephone-based semi-structured interviews were recorded and analysed using inductive thematic analysis.
RESULTS: Across a total of 25 interviews (19 people with SMA, 5 parents, 1 partner) many participants described disengagement from health services and major gaps in care throughout adulthood. Disengagement was attributed to the perceived low value of care, as well as pragmatic, financial and social barriers to navigating the complex healthcare system and accessing disability services. Adults with SMA valued healthcare services that set collaborative goals, and resources with a positive impact on their quality of life. Mental health care was highlighted as a major unmet need, particularly during times of fear and frustration in response to loss of function, social isolation, stigma, and questions of self-worth. Alongside this, participants reported resilience and pride in their coping approaches, particularly when supported by informal networks of family, friends and peers with SMA.
CONCLUSIONS: These findings provide insight into the lived experiences, values and perspectives of adults with SMA and their carers, revealing major, ongoing unmet healthcare needs, despite many realising meaningful and productive lives. Findings indicate the necessity of accessible, patient- and family-centered multidisciplinary care clinics that address currently unmet physical and mental health needs. Understanding the lived experiences of people with SMA, particularly during times of transition, is critical to advancing health policy, practice and research. Future studies are needed to quantify the prevalence, burden and impact of mental health needs whilst also exploring potential supportive and therapeutic strategies.

Better living through peptide-conjugated chemistry: next-generation antisense oligonucleotides.Publié le 01 10 2019

Two different antisense oligonucleotide-based (ASO-based) therapies are currently in clinical use to treat neuromuscular diseases. This success, for Duchenne muscular dystrophy and spinal muscular atrophy, offers hope not only for additional neuromuscular diseases, but also for other disorders that could benefit from RNA-targeted therapies. A major limitation for more widespread application of ASOs relates to relatively poor tissue penetration. In this issue of the JCI, Klein et al. showed that conjugating an ASO with an arginine-rich cell-penetrating peptide, Pip6a, enhanced delivery, resulting in corrective outcome for a mouse model of myotonic dystrophy. Linking ASOs to cell-penetrating peptides, or even other moieties, is an approach currently under development with treatment potential to expand to other disorders.

Improvement of spinal muscular atrophy via correction of the SMN2 splicing defect by Brucea javanica (L.) Merr. extract and Bruceine D.Publié le 30 09 2019

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disease and a leading genetic cause of infant mortality. SMA is caused primarily by the deletion of the survival motor neuron 1 (SMN1) gene, which leaves the duplicate gene SMN2 as the sole source of SMN protein. The splicing defect (exon 7 skipping) of SMN2 leads to an insufficient amount of SMN protein. Therefore, correcting this SMN2 splicing defect is considered to be a promising approach for the treatment of SMA.
PURPOSE: This study aimed to identify active compounds and extracts from plant resources to rescue SMA phenotypes through the correction of SMN2 splicing.
STUDY DESIGN: Of available plant resources, candidates with SMA-related traditional medicine information were selected for screening using a robust luciferase-based SMN2 splicing reporter. Primary hits were further evaluated for their ability to correct the splicing defect and resultant increase of SMN activity in SMA patient-derived fibroblasts. Confirmed hits were finally tested to determine the beneficial effects on the severe ?7 SMA mouse.
METHODS: SMN2 splicing was analyzed using a luciferase-based SMN2 splicing reporter and subsequent RT-PCR of SMN2 mRNAs. SMA phenotypes were evaluated by the survival, body weights, and righting reflex of ?7 SMA mice.
RESULTS: In a screen of 492 selected plant extracts, we found that Brucea javanica extract and its major constituent Bruceine D have SMN2 splicing-correcting activity. Their ability to correct the splicing defect and the resulting increased SMN activity were further confirmed in SMA fibroblasts. Importantly, both B. javanica and Bruceine D noticeably improved the phenotypic defects, especially muscle function, in SMA mice. Reduced expression of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributed to the correction of splicing by B. javanica.
CONCLUSION: Our work revealed that B. javanica and Bruceine D correct the SMN2 splicing defect and improve the symptoms of SMA in mice. These resources will provide another possibility for development of a plant-derived SMA drug candidate.

Combining Bilateral Magnetically Controlled Implants Inserted Parallel to the Spine With Rib to Pelvis Fixation: Surgical Technique and Early Results.Publié le 30 09 2019

Spine-based fixation of magnetically controlled lengthening devices has been successfully performed for children with early-onset scoliosis. However, spinal manipulation may lead to ossifications, stiffness, and autofusion as previously described. To avoid these problems, a surgical technique combining bilateral externally controlled magnetic device implantation with a rib cradle and pelvic hook fixation was introduced by us in 2011. By using a bilateral single-rib or double-rib cradle fixation and a pelvic hook, the magnetic device is percutaneously inserted. The spine corrects indirectly without further manipulation. In small rib diameter or severe osteoporosis, double-rib cradles are used. Our introduced technique enables modification of the rib vertebral angle, which may be beneficial in children with spinal muscular atrophy and rib-cage deformity. This nonrandomized prospective study describes 18 children with neuromuscular scoliosis treated first by this method. All patients followed the same protocol, with expansion procedures being performed 5 months after surgery and every 3 months thereafter. Clinical, radiologic, and complication data were analyzed, showing a significant reduction in scoliosis and pelvic obliquity and an increase in spinal length, which could be maintained over a follow-up period of 1.2 years. The overall complication rate was lower than previously described, with 8%, 2 of them requiring surgery.

Wrangling RNA: Antisense oligonucleotides for neurological disorders.Publié le 27 09 2019

Effective treatment of spinal muscular atrophy with antisense oligonucleotide therapy opens the door to treating other neurological disorders with this approach.

Neurofilament light chain in serum of adolescent and adult SMA patients under treatment with nusinersen.Publié le 26 09 2019

OBJECTIVE: To determine the diagnostic and monitoring value of serum neurofilament light chain (NfL) in spinal muscular atrophy (SMA).
METHODS: We measured serum NfL in 46 SMA patients at baseline and over 14 months of treatment with the antisense-oligonucleotide (ASO) nusinersen using the ultrasensitive single molecule array (Simoa) technology. Serum NfL levels of SMA patients were compared to controls and related to cerebrospinal fluid (CSF) NfL, blood-CSF barrier function quantified by the albumin blood/CSF ratio (Qalb) and motor scores (Hammersmith Functional Motor Scale Expanded, HFMSE; Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R).
RESULTS: Serum NfL levels of SMA patients were in the range of controls (p?=?0.316) and did not correlate with CSF NfL (??=?0.302, p?=?0.142) or Qalb (??=?-?0.160, p?=?0.293). During therapy, serum NfL levels were relatively stable with notable concentration changes in single SMA patients, however, within the control range. Higher NfL levels were associated with worse motor performance in SMA (baseline: HFMSE ??=?-?0.330, p?=?0.025, ALSFRS-R ??=?-?0.403, p?=?0.005; after 10 months: HFMSE ??=?-?0.525, p?=?0.008, ALSFRS-R ??=?-?0.537, p?=?0.007), but changes in motor scores did not correlate with changes in serum NfL.
CONCLUSION: Diagnostic and monitoring performance of serum NfL measurement seems to differ between SMA subtypes. Unlike to SMA type 1, in adolescent and adult SMA type 2 and 3 patients, neurodegeneration is not reflected by increased NfL levels and short-term therapeutic effects cannot be observed. Long-term follow-up has to be performed to see if even low levels of NfL might be good prognostic markers.

Combined noninvasive ventilation and mechanical insufflator-exsufflator for acute respiratory failure in patients with neuromuscular disease: effectiveness and outcome predictors.Publié le 25 09 2019

BACKGROUND: To determine the effectiveness of combined noninvasive ventilation (NIV) and mechanical insufflator-exsufflator (MI-E) for acute respiratory failure (ARF) in patients with neuromuscular disease (NMD), and outcome predictors.
METHODS: A prospectively observational study of patients with ARF was conducted in a pediatric intensive care unit (PICU). All received combined NIV/MI-E during PICU stays between 2007 and 2017. Pertinent clinical variables of heart rate (HR), respiratory rate (RR), pH, PaCO2, and PaO2/FiO2 ratio were collected at baseline and at 2 h, 4-8 h, and 12-24 h after initiating use of NIV/MI-E. Treatment success was defined as avoiding intubation.
RESULTS: A total of 62 ARF episodes in 56 patients with NMD (median age, 13 years) were enrolled. The most frequent underlying NMD was spinal muscular atrophy (32/62, 52%). ARF was primarily due to pneumonia (65%). The treatment success rate was 86%. PICU stay and hospitalization were shorter in the success group (9.4?±?6.1 vs. 21.9?±?13.9 days and 16.3?±?7.8 vs. 33.6?±?17.9 days, respectively; both p?<?0.05). HR, RR, pH, and PaCO2 showed a progressive improvement, particularly after 4 h following successful NIV/MI-E treatment. RR decrease at 4 h, and pH increase and PaCO2 decrease at 4-8 h might predict success of NIV/MI-E treatment. The multivariate analysis identified PaCO2 at 4-8 h of 58.0 mmHg as an outcome predictor of NIV/MI-E treatment.
CONCLUSIONS: Applying combined NIV/MI-E in the acute care setting is an efficient means of averting intubation in NMD patients with ARF. Clinical features within 8 h of the institution may predict treatment outcome. The reviews of this paper are available via the supplemental material section.

Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice.Publié le 25 09 2019

Symptoms of spinal muscular atrophy (SMA) disease typically begin in the late prenatal or the early postnatal period of life. The intrauterine (IU) correction of gene expression, fetal gene therapy, could offer effective gene therapy approach for early onset diseases. Hence, the overall goal of this study was to investigate the efficacy of human survival motor neuron (hSMN) gene expression after IU delivery in SMA mouse embryos. First, we found that IU-intracerebroventricular (i.c.v.) injection of adeno-associated virus serotype-9 (AAV9)-EGFP led to extensive expression of EGFP protein in different parts of the CNS with a great number of transduced neural stem cells. Then, to implement the fetal gene therapy, mouse fetuses received a single i.c.v. injection of a single-stranded (ss) or self-complementary (sc) AAV9-SMN vector that led to a lifespan of 93 (median of 63) or 171 (median 105) days for SMA mice. The muscle pathology and number of the motor neurons also improved in both study groups, with slightly better results coming from scAAV treatment. Consequently, fetal gene therapy may provide an alternative therapeutic approach for treating inherited diseases such as SMA that lead to prenatal death or lifelong irreversible damage.

Variations in prenatal screening in a US federal healthcare system: Same coverage, different options.Publié le 22 09 2019

The Military Health System (MHS) is a federally funded organization that provides care to active duty service members and their beneficiaries. Our objective was to determine what methods of prenatal screening are used by military treatment facilities (MTFs), assess variations between institutions, and determine how practice patterns align with national recommendations. We surveyed all MTFs offering comprehensive prenatal care (n = 49). Departments were asked about aneuploidy screening options, availability of diagnostic testing, and carrier screening. In all, 43 MTFs (88%) completed the survey. Most (39/43) patients were stratified based on risk (predominantly maternal age at delivery and history). The most commonly offered test was combined 1st/2nd trimester screening (59%). Sixty percent routinely offered diagnostic testing, though less than half routinely offered microarrays. The majority offered universal carrier screening for cystic fibrosis (98%) and complete blood count with screening for thalassemias and hemoglobinopathies (88%). At the time of data collection, only five facilities (12%) had implemented spinal muscular atrophy carrier screening. Considerable heterogeneity exists in prenatal aneuploidy testing and carrier screening within the MHS. Standardized guidelines, protocols, and laboratory support would improve processes across the system. Additional resources including genetic counseling support and provider education are needed.

Gene Therapy for ALS-A Perspective.Publié le 11 09 2019

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder-particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND-the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS.

A new therapeutic strategy with istradefylline for postural deformities in Parkinson's disease.Publié le 07 09 2019

AIM OF THE STUDY: Postural deformities are common in Parkinson's disease (PD) patients. Several treatment options have been reported, but responses to these treatments appear unpredictable. Istradefylline is a novel drug for PD. Cases of PD patients whose postural deformities were improved after withdrawal of dopamine agonists and initiation of istradefylline are presented.
MATERIALS AND METHODS: Four consecutive patients with postural deformities including antecollis, Pisa syndrome, and camptocormia were recruited and treated with istradefylline in combination with withdrawal of dopamine agonists, which are possible causes of postural deformities.
RESULTS: The dopamine agonists were discontinued an average of 26 months after the development of the postural deformities, and istradefylline was initiated an average of 1.3 months after dopamine agonist withdrawal. Three patients with preserved paraspinal muscle volume showed good responses to the treatment regimen at least two months after dopamine agonist withdrawal.
CONCLUSIONS AND CLINICAL IMPLICATIONS: Postural deformities caused by dopamine agonists generally improve less than two weeks after dopamine agonist withdrawal. Given the response time in the present study, the response was unlikely to be caused solely by dopamine agonist withdrawal. Istradefylline can be a potential therapeutic option; however, appropriate selection of patients for treatment with istradefylline is warranted.

Rethinking Eligibility for Experimental Clinical Trials.Publié le 07 09 2019

PMID: 29181505 [PubMed - indexed for MEDLINE]

[(S)un (M)ay (A)rise on SMA : the hope of a region without spinal muscular atrophy].Publié le 07 09 2019

The treatment of spinal muscular atrophy (SMA) has considerably changed over the last 3 years. Several approaches that aim to increase the deficient SMN protein have demonstrated an efficacy that is inversely correlated with disease duration. In this context, newborn screening (NBS) is increasingly considered as the next step in several countries or regions. In 2018, we initiated a pilot study for NBS of SMA in French- and German-speaking Belgium. We aim to evaluate the feasibility, the efficacy, and the cost-effectiveness of such a program. Initially covering the region of Liege, the program was recently extended to the whole Southern Belgium and currently covers about 55.000 newborns per year. On June 1st 2019, 35.000 newborns had been screened and 5 affected babies were identified and referred to neuromuscular centers for early treatment. A full evaluation of the program will take place after three years to consider the inclusion of SMA screening in the publically-funded NBS program in Southern Belgium.

Alternative gene therapy target identified in spinal muscular atrophy mice.Publié le 07 09 2019

PMID: 31485023 [PubMed - as supplied by publisher]

Biomarkers and the Development of a Personalized Medicine Approach in Spinal Muscular Atrophy.Publié le 05 09 2019

Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.

User perspectives on a psychosocial blended support program for partners of patients with amyotrophic lateral sclerosis and progressive muscular atrophy: a qualitative study.Publié le 29 08 2019

BACKGROUND: Partners are often the main caregivers in the care for patients with amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA). Providing care during the progressive and fatal disease course of these patients is challenging and many caregivers experience feelings of distress. A blended psychosocial support program based on Acceptance and Commitment Therapy was developed to support partners of patients with ALS and PMA. The aim of this qualitative study is to gather insight into experiences with different components of the support program (program evaluation) and to discover what caregivers gained from following the program (mechanisms of impact).
METHODS: Individual in-depth interviews, about caregivers' experiences with the support program were conducted with 23 caregivers of ALS/PMA patients enrolled in a randomized controlled trial designed to measure the effectiveness of the blended psychosocial support program. The program, performed under the guidance of a psychologist, consists of psychoeducation, psychological and mindfulness exercises, practical tips and information, and options for peer contact. Interviews were audio-recorded, transcribed verbatim and analyzed thematically.
RESULTS: The program evaluation showed that caregivers perceived each component of the program as beneficial but ambivalent reactions were expressed about the mindfulness exercises and peer contact functions. Caregivers expressed the need for a more personalized program with respect to the order and timing of the modules and wanted to continue the support program for a longer time. The main mechanism of impact of the program that caregivers reported was that they became more aware of their own situation. They further indicated that the program helped them to perceive control over the caregiving situation, to accept negative emotions and thoughts, to be there for their partner and feel acknowledged.
CONCLUSIONS: The blended psychosocial support program for caregivers of patients with ALS/PMA is valued by caregivers for enhancing self-reflection on their challenging situation which stimulated them to make choices in line with their own needs and increased their feeling of control over caregiving. The different components of the program were overall appreciated by caregivers, but the mindfulness and peer support components should be further adapted to the needs of the caregivers.
TRIAL REGISTRATION: Dutch Trialregister NTR5734 , registered 28 March 2016.

An observational study of functional abilities in infants, children, and adults with type 1 SMA.Publié le 29 08 2019

OBJECTIVE: To report cross-sectional clinical findings in a large cohort of patients affected by type 1 spinal muscular atrophy.
METHODS: We included 122 patients, of age ranging between 3 months and 22 years, 1 month. More than 70% (85/122) were older than 2 years and 25% (31/122) older than 10 years. Patients were classified according to the severity of phenotype and to the number of SMN2 copies.
RESULTS: Patients with the more common and the most severe phenotype older than 2 years were, with few exceptions, on noninvasive ventilation and, with increasing age, more often had tracheostomy or >16-hour ventilation and a gastrostomy inserted. In contrast, 25 of the 28 patients with the mildest phenotype older than 2 years had no need for tracheostomy or other ventilatory or nutritional support. In patients older than 2 years, the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were generally lower compared to those found in younger patients and showed distinct levels of functional abilities according to the severity of the phenotype. Similar findings were also observed on the Hammersmith Infant Neurological Examination.
CONCLUSIONS: Our findings confirm that, after the age of 2 years, patients with type 1 spinal muscular atrophy generally survive only if they have gastrostomy and tracheostomy or noninvasive ventilation >16 hours and have low scores on the functional scales. More variability, however, can be expected in those with the mildest phenotype, who achieve head control. These data provide important baseline information at the time treatments are becoming available.

Motor neuron disease in 2017: Progress towards therapy in motor neuron disease.Publié le 29 08 2019

PMID: 29348545 [PubMed - indexed for MEDLINE]

Patient Reported Impact of Symptoms in Spinal Muscular Atrophy (PRISM-SMA).Publié le 27 08 2019

OBJECTIVE: To determine the frequency and relative importance of symptoms experienced by adults with spinal muscular atrophy (SMA) and to identify factors that are associated with a higher burden of disease in this population.
METHODS: We conducted a cross-sectional study of 359 adults with SMA using the International SMA Patient Registry. Participants provided input regarding 20 symptomatic themes and 207 symptoms that potentially affect adults with SMA. Participants were asked about the relative importance of each symptom, and analysis was conducted to determine how age, sex, SMA type, education, mobility, and employment status relate to symptom prevalence.
RESULTS: Limitations with mobility or walking (98.6%) and the inability to do activities (98.6%) were the 2 themes with the highest prevalence in the study sample. Limitation with mobility or walking was the theme that was identified as having the greatest effect on the lives of adults with SMA. Employment status was associated with the prevalence of 4 of 20 themes and a reliance on an assistive device was associated with 7 of 20 themes. The prevalence of breathing difficulties, choking or swallowing difficulties, and communication difficulties differed among those with different SMA types.
CONCLUSIONS: There are many symptomatic themes that affect the lives of adults with SMA. These themes vary in prevalence and relative importance in the adult SMA population.

CSF transplantation of a specific iPSC-derived neural stem cell subpopulation ameliorates the disease phenotype in a mouse model of spinal muscular atrophy with respiratory distress type 1.Publié le 26 08 2019

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a genetic motor neuron disease affecting infants. This condition is caused by mutations in the IGHMBP2 gene and currently has no cure. Stem cell transplantation is a potential therapeutic strategy for motor neuron diseases such as SMARD1, exerting beneficial effects both by replacing cells and by providing support to endogenous motor neurons. In this work, we demonstrate that human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) selected for the expression of specific markers, namely, Lewis X, CXCR4 and beta 1 integrin, and pretreated with neurotrophic factors and apoptosis/necroptosis inhibitors were able to effectively migrate and engraft into the host parenchyma after administration into the cerebrospinal fluid in a SMARD1 mouse model. We were able to detect donor cells in the ventral horn of the spinal cord and observe improvements in neuropathological features, particularly preservation of the integrity of the motor unit, that were correlated with amelioration of the SMARD1 disease phenotype in terms of neuromuscular function and lifespan. This minimally invasive stem cell approach can confer major advantages in the context of cell-mediated therapy for patients with neurodegenerative diseases.

Exercise Combined with Electrotherapy Enhances Motor Function in an Adolescent with Spinal Muscular Atrophy Type III.Publié le 22 08 2019

Background: Electrotherapy is widely used in physical therapy to increase muscle mass, improve motor function, and assist physical activity in several neurologic conditions. However, concerning Spinal Muscular Atrophy (SMA), limited evidence exists on the role of electrotherapy as an adjunct for improving muscle strength and function.
Case Report: An adolescent (13 y.o.) with SMA type III underwent an 18-week strengthening program divided into two stages. During Phase I (weeks: 1-8), a home-based program for quadriceps strengthening through neuromuscular electrical stimulation (NMES) was provided. In Phase II (weeks: 9-18), at-home NMES was combined with functional electrical stimulation (FES) assisting volitional cycling for a broader, systemic conditioning. The treatment improved patient's structural and functional motor outcomes (quadriceps circumference and strength, Tinetti scale, and Hammersmith scale) as well as independence in stair climbing.
Clinical Rehabilitation Impact: The purpose of this report is to raise awareness of the potential role of electrotherapy to help improving motor performance in SMA patients and, secondly, to foster further research aimed at assessing the actual contribution this intervention may have as an add-on therapy to existing care.

Therapeutic advances in SMA.Publié le 20 08 2019

PURPOSE OF REVIEW: To review the advent of novel therapies and their impact on the field of chromosome 5q-associated spinal muscular atrophy (SMA).
RECENT FINDINGS: Antisense oligonucleotides (ASOs) enhancing SMN2 function are delivered intrathecally and small molecules will also be available soon delivered by the oral route; alternatively, systemic injection of viral vectors in order to replace the SMN gene are likely to be available in the future. In summer 2019, it remains the core finding that intrathecally delivered ASOs convincingly change the natural history of the disease in children and that the treatment effect is the better, the earlier ASO treatment is started. Therefore, postnatal screening for deletions and mutations in the SMN gene is presently discussed. Much has to be learnt, however, both on the challenges of the intrathecal mode of delivery and the efficacy of ASOs in adolescent and adult patients. Therapeutic outcome measures mirroring this phenotype are difficult to assess in this group of patients.
SUMMARY: Therapeutic advances in 5q-associated SMA have been convincing in the previous years and change the field. This includes newborn screening, changing phenotypes in the treated children, challenges for drug administration in adolescents and adults and the comparison of drug effects. Long-term studies are required.

An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials.Publié le 20 08 2019

BACKGROUND: Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA).
OBJECTIVE: The objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA.
METHODS: An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms.
RESULTS: Data were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6-1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure-treated participants. Rates of post-lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed.
CONCLUSIONS: Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures.
REGISTRATION: NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

Evidence-Based Physiatry: Pediatric Neuromuscular Rehabilitation in the Era of Precision Medicine.Publié le 20 08 2019

PMID: 30234519 [PubMed - indexed for MEDLINE]

Spinal muscular atrophy: A modifiable disease emerges.Publié le 17 08 2019

PMID: 30414816 [PubMed - indexed for MEDLINE]

Harnessing the power of the patient perspective for rare disease therapeutics.Publié le 17 08 2019

PMID: 30143562 [PubMed - indexed for MEDLINE]

Evaluation of Cell-Penetrating Peptide Delivery of Antisense Oligonucleotides for Therapeutic Efficacy in Spinal Muscular Atrophy.Publié le 15 08 2019

Antisense oligonucleotides (ASOs) are a widely used form of gene therapy, which is translatable to multiple disorders. A major obstacle for ASO efficacy is its bioavailability for in vivo and in vitro studies. To overcome this challenge we use cell-penetrating peptides (CPPs) for systemic delivery of ASOs. One of the most advanced clinical uses of ASOs is for the treatment of spinal muscular atrophy (SMA). In this chapter, we describe the techniques used for in vitro screening and analysing in vivo biodistribution of CPP-conjugated ASOs targeting the survival motor neuron 2, SMN2, the dose-dependent modifying gene for SMA.

The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular Atrophy Model.Publié le 14 08 2019

Spinal muscular atrophy (SMA) is an inherited disease characterized by progressive motor neuron death and subsequent muscle weakness and is caused by deletion or mutation of survival motor neuron (SMN) 1 gene. Protecting spinal motor neuron is an effective clinical strategy for SMA. The purpose of this study was to investigate the potential effect of an anti-epileptic drug levetiracetam on SMA. In the present study, we used differentiated spinal motor neurons (MNs) from SMA patient-derived induced pluripotent stem cells (SMA-iPSCs) to investigate the effect of levetiracetam. Levetiracetam promoted neurite elongation in SMA-iPSCs-MNs. TUNEL-positive spinal motor neurons were significantly reduced by levetiracetam in SMA-iPSCs-MNs. In addition, the expression level of cleaved-caspase 3 was decreased by levetiracetam in SMA-iPSCs-MNs. Furthermore, levetiracetam improved impaired mitochondrial function in SMA-iPSCs-MNs. On the other hand, levetiracetam did not affect the expression level of SMN protein in SMA-iPSCs-MNs. These findings indicate that levetiracetam has a neuroprotective effect for SMA.

Precious SMA natural history data: A benchmark to measure future treatment successes.Publié le 14 08 2019

PMID: 30045956 [PubMed - indexed for MEDLINE]

Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis.Publié le 14 08 2019

OBJECTIVE: To investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS).
METHODS: A total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale-Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model.
RESULTS: Compared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ?8 ?V (0.82 years) than in those with N20p-P25p <8 ?V (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival (p = 0.002).
CONCLUSION: Sensory cortex hyperexcitability predicts short survival in patients with ALS.

Decision-Making Regarding Ventilator Support in Children with SMA Type 1-A Cross-Sectional Survey among Physicians.Publié le 14 08 2019

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and severe proximal muscle weakness. In the absence of curative treatment, it has been controversial whether critically ill infants with SMA type 1 should receive ventilator support. The aim of this study was to investigate the process of decision-making regarding ventilator support in children with SMA type 1 from the perspectives of physicians. A web-based survey with 17 questions and 2 case vignettes was conducted in 671 physicians in Germany and Switzerland from 12/2016 to 03/2017. The survey focused on factors influencing the decision about ventilator support and the content in informed consent discussions. Additionally, physicians were asked about their general attitude towards mechanical ventilation in children with SMA type 1 and their hypothetical clinical management in emergency settings using case vignettes. Hundred and sixty-five physicians participated in the survey (50.3% child neurologists, 18.8% specialists for ventilator support, 6.1% pediatric palliative care physicians, and 6.1% with more than one of these specializations). Of all physicians, 44.2% confirmed to have experience with SMA type 1 patients using ventilator support. In summary, our results show that physicians' attitudes and experiences about mechanical ventilation in children with SMA type 1 vary considerably and are likely to influence the outcome in informed consent discussions and the hypothetical management in emergency settings.

Motor neuron biology and disease: A current perspective on infantile-onset spinal muscular atrophy.Publié le 10 08 2019

Infantile-onset spinal muscular atrophy (SMA) is a prototypical disease in which to investigate selective neurodegenerative phenotypes. Caused by low levels of the ubiquitously expressed Survival Motor Neuron (SMN) protein, the disease mainly targets the spinal motor neurons. This selective phenotype remains largely unexplained, but has not hindered the development of SMN repletion as a means to a treatment. Here we chronicle recent advances in the area of SMA biology. We provide a brief background to the disease, highlight major advances that have shaped our current understanding of SMA, trace efforts to treat the condition, discuss the outcome of two promising new therapies and conclude by considering contemporary as well as new challenges stemming from recent successes within the field.

Current evidence for treatment with nusinersen for spinal muscular atrophy: a systematic review.Publié le 08 08 2019

Recent discovery of nusinersen, an antisense oligonucleotide drug, has provided encouragement for improving treatment of spinal muscular atrophy. No therapeutic options currently exist for this autosomal recessive motor neuron disorder. Nusinersen is developed for intrathecal use and binds to a specific sequence within the survival motor neuron 2 pre-messenger RNA, modifying the splicing process to promote expression of full-length survival motor neuron protein. We performed a MEDLINE and CENTRAL search to investigate the current evidence for treatment with nusinersen in patients with spinal muscular atrophy. Four papers were withheld, including two phase-3 randomized controlled trials, one phase-2 open-label clinical trial and one phase-1 open-label clinical trial. Outcome measures concerned improvement in motor function and milestones, as well as event-free survival and survival. Results of these trials are hopeful with significant and clinically meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy, although this does not restore age-appropriate function. Intrathecal nusinersen has acceptable safety and tolerability. Further trials regarding long-term effects and safety aspects as well as trials including broader spinal muscular atrophy and age categories are required and ongoing.

Gene Therapy.Publié le 08 08 2019

PMID: 31365802 [PubMed - indexed for MEDLINE]

Alternative Splicing of ALS Genes: Misregulation and Potential Therapies.Publié le 07 08 2019

Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Parkinson's, Alzheimer's, and Huntington's disease affect a rapidly increasing population worldwide. Although common pathogenic mechanisms have been identified (e.g., protein aggregation or dysfunction, immune response alteration and axonal degeneration), the molecular events underlying timing, dosage, expression, and location of RNA molecules are still not fully elucidated. In particular, the alternative splicing (AS) mechanism is a crucial player in RNA processing and represents a fundamental determinant for brain development, as well as for the physiological functions of neuronal circuits. Although in recent years our knowledge of AS events has increased substantially, deciphering the molecular interconnections between splicing and ALS remains a complex task and still requires considerable efforts. In the present review, we will summarize the current scientific evidence outlining the involvement of AS in the pathogenic processes of ALS. We will also focus on recent insights concerning the tuning of splicing mechanisms by epigenomic and epi-transcriptomic regulation, providing an overview of the available genomic technologies to investigate AS drivers on a genome-wide scale, even at a single-cell level resolution. In the future, gene therapy strategies and RNA-based technologies may be utilized to intercept or modulate the splicing mechanism and produce beneficial effects against ALS.

R-Loops in Motor Neuron Diseases.Publié le 07 08 2019

R loops are transient three-stranded nucleic acid structures that form physiologically during transcription when a nascent RNA transcript hybridizes with the DNA template strand, leaving a single strand of displaced nontemplate DNA. However, aberrant persistence of R-loops can cause DNA damage by inducing genomic instability. Indeed, evidence has emerged that R-loops might represent a key element in the pathogenesis of human diseases, including cancer, neurodegeneration, and motor neuron disorders. Mutations in genes directly involved in R-loop biology, such as SETX (senataxin), or unstable DNA expansion eliciting R-loop generation, such as C9ORF72 HRE, can cause DNA damage and ultimately result in motor neuron cell death. In this review, we discuss current advancements in this field with a specific focus on motor neuron diseases associated with deregulation of R-loop structures. These mechanisms can represent novel therapeutic targets for these devastating, incurable diseases.

Zolgensma - one-time gene therapy for spinal muscular atrophy.Publié le 06 08 2019

PMID: 31381549 [PubMed - in process]

AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort.Publié le 06 08 2019

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma ®) gene replacement therapy, are emerging.
OBJECTIVE: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants.
METHODS: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n?=?16) and healthy infants (n?=?27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events.
RESULTS: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively).
CONCLUSIONS: In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.

Spinal Muscular Atrophy: Past, Present, and Future.Publié le 03 08 2019

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. SMA is characterized by loss of lower motor neurons (anterior horn cells) in the spinal cord and brainstem nuclei, leading to progressive symmetrical muscle weakness and atrophy. It affects approximately 1 in 6,000 to 1 in 10,000 individuals and is the most common inherited cause of childhood mortality, but this may soon change given recent developments. In December 2016, nusinersen, an antisense oligonucleotide drug, was approved by the United States Food and Drug Administration for the treatment of SMA, and in July 2018, SMA was added to the recommended uniform screening panel, a list of conditions that all states are encouraged to include in their newborn screening (NBS) panels. In this review, we begin with a brief clinical history of the diagnosis of SMA, discuss the current SMA clinical classification system, describe the current treatment, and discuss evolving treatment guidelines. We then discuss the path to include SMA in NBS programs as well as the controversies it engenders because the variability in age at symptom onset means early identification of asymptomatic patients who will not require therapy for years or decades. We also consider alternate population screening opportunities. Next, we consider experimental treatments. We conclude by supporting NBS for SMA with the caveat that a long-term follow-up registry is ethically essential to ensure that the benefits outweigh the harms for all screened infants, including those with milder and/or later-onset forms of SMA.

From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1.Publié le 03 08 2019

Spinal muscular atrophy is a devastating neurodegenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. Onasemnogene abeparvovec (Zolgensma, formerly AVXS-101) is a gene replacement therapy comprising an adeno-associated viral vector containing the human SMN gene under control of the chicken beta-actin promoter. This therapy addresses the genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnogene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying gene replacement therapy for spinal muscular atrophy, describes the onasemnogene abeparvovec clinical trial experience, and provides expert recommendations as a reference for the real-world use of onasemnogene abeparvovec in clinical practice. As of May 24, 2019, the Food and Drug Administration approved onasemnogene abeparvovec, the first gene therapy approved to treat children younger than two years with spinal muscular atrophy.

Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile.Publié le 01 08 2019

METHODS: Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population.
RESULTS: We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery.
CONCLUSION: Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

Hyperexcitability precedes motoneuron loss in the Smn2B/-mouse model of spinal muscular atrophy.Publié le 01 08 2019

Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state are unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of pre-symptomatic Smn2B/- mice older than one week of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/- mice exhibit more typical postnatal development until postnatal day (P)11/12 and have longer survival (~3 weeks of age). We demonstrate that Smn2B/-motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9-10 and preceded the loss of motor units. We determined that motor unit loss in this mouse model occurred two weeks after birth using MUNE studies. Smn2B/-motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process.

AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of Spinal Muscular Atrophy.Publié le 01 08 2019

Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide (ASO) therapy for SMA was an important milestone in SMA research, however, effective next generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology, and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

High-throughput genetic newborn screening for spinal muscular atrophy by rapid nucleic acid extraction from dried blood spots and 384-well qPCR.Publié le 01 08 2019

Establishing nucleic acid-based assays for genetic newborn screening (NBS) provides the possibility to screen for genetically encoded diseases like spinal muscular atrophy (SMA), best before the onset of symptoms. Such assays should be easily scalable to 384-well reactions that make the screening of up to 2000 samples per day possible. We developed a test procedure based on a cleanup protocol for dried blood spots and a quantitative (q)PCR to screen for a homozygous deletion of exon 7 of the survival of motor neuron 1 gene (SMN1) that is responsible for >95% of SMA patients. Performance of this setup is evaluated in detail and tested on routine samples. Our cleanup method for nucleic acids from dried blood spots yields enough DNA for diverse subsequent qPCR applications. To date, we have applied this approach to test 213,279 samples within 18 months. Thirty patients were identified and confirmed, implying an incidence of 1:7109 for the homozygous deletion. Using our cleanup method, a rapid workflow could be established to prepare nucleic acids from dried blood spot cards. Targeting the exon 7 deletion, no invalid, false-positive, or false-negative results were reported to date. This allows timely identification of the disease and grants access to the recently introduced treatment options, in most cases before the onset of symptoms. Carriers are not identified, thus, there are no concerns of whether to report them.

In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.Publié le 01 08 2019

We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.

Reliability of four tests to assess body posture and the range of selected movements in individuals with spinal muscular atrophy.Publié le 31 07 2019

BACKGROUND: The majority of individuals with spinal muscular atrophy (SMA) experience progressive skeletal deformities which may affect the quality of life and mobility. To date, no studies have evaluated the reliability of tests assessing body posture and joint mobility in SMA patients. The purpose of this study was to assess the reliability of Cervical Rotation test (CR), Supine Angle of Trunk Rotation test (SATR), Hip Extension test (HE) and Pelvic Obliquity test (PO) developed to evaluate the musculoskeletal system in SMA individuals.
METHODS: Thirty individuals (12 girls and 18 boys) aged 4-15 with SMA type II (n?=?24) and III (n?=?6) confirmed by genetic examinations were qualified for the study. The participants were examined twice by three physiotherapists on the same day. The examination included four tests, i.e. CR, SATR, HE and PO tests aimed at assessing ranges of rotation in the cervical spine, chest deformities, ranges of hip extension and pelvis position while sitting. Statistical calculations were made with the use of statistical software IBM SPSS Statistics version 20. Reliability was assessed using the Intraclass Correlation Coefficient (ICC).
RESULTS: Intraobserver reliability was excellent for CR (ICC range 0.839-0.911), SATR (ICC range 0.918-0.939 - the upper part of the sternum; ICC range 0.951-0.975 - the lower part of the sternum), HE (ICC range 0.988-0,991) and PO (ICC range 0.896-0.935) tests. The interobserver ICC reached the excellent values in CR (ICC range 0.912-0.920), SATR (ICC?=?0.888 - the upper part of the sternum, ICC?=?0.951 - the lower part of the sternum), HE (ICC range 0.922-0.923) and PO (ICC?=?0.928) tests.
CONCLUSIONS: CR, SATR, HE and PO tests are reliable and may be used for examining individuals with SMA. The application of these tests provides a possibility to detect early changes in the musculoskeletal system in children and adolescents and to assess the effectiveness of the implemented pharmacotherapy and rehabilitation.

Routine Cerebrospinal Fluid Cytology Reveals Unique Inclusions in Macrophages During Treatment With Nusinersen.Publié le 31 07 2019

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by degeneration of spinal motor neurons leading to muscular weakness. The antisense oligonucleotide nusinersen was approved for the treatment of patients with 5q-associated SMA. Treatment must be repeatedly administered intrathecally by lumbar puncture. So far, data regarding cerebrospinal fluid (CSF) parameters are sparse and examinations of CSF cytology during nusinersen treatment are completely missing. Methods: 87 CSF samples from 19 adult SMA patients who underwent repeated lumbar punctures for intrathecal injections of nusinersen were investigated. CSF specimens were quantitatively assessed regarding leukocyte subpopulations by routine cytology after Pappenheim staining. A control group with 38 CSF samples from 10 patients with repeated lumbar punctures due to other diseases was used. Results: Treatment with nusinersen did not result in persistent inflammatory cellular changes or a relevant shift of leukocyte subpopulations in the CSF. During nusinersen therapy unique macrophages with numerous sharply defined purple and granular inclusions were detected in all patients. These macrophages were not found in CSF of patients with other diseases who underwent repeated lumbar punctures. Discussion: Routine CSF cytology performed by experienced personnel represents an important and feasible tool for safety monitoring during treatment with intrathecally administered therapeutics. Analysis of leukocyte subpopulations did not raise safety concerns during nusinersen therapy. The potential significance of the unique phagocytic cells for disease course and treatment response needs to be further elucidated in the future.

Neonatal hypotonia and neuromuscular conditions.Publié le 21 07 2019

The differential diagnosis of neonatal hypotonia is a complex task, as in newborns hypotonia can be the presenting sign of different underlying causes, including peripheral and central nervous system involvement and genetic and metabolic diseases. This chapter describes how a combined approach, based on the combination of clinical signs and new genetic techniques, can help not only to establish when the hypotonia is related to peripheral involvement but also to achieve an accurate and early diagnosis of the specific neuromuscular diseases with neonatal onset. The early identification of such disorders is important, as this allows early intervention with disease-specific standards of care and, more importantly, because of the possibility to treat some of them, such as spinal muscular atrophy, with therapeutic approaches that have recently become available.

How RNA structure dictates the usage of a critical exon of spinal muscular atrophy gene.Publié le 20 07 2019

Role of RNA structure in pre-mRNA splicing has been implicated for several critical exons associated with genetic disorders. However, much of the structural studies linked to pre-mRNA splicing regulation are limited to terminal stem-loop structures (hairpins) sequestering splice sites. In few instances, role of long-distance interactions is implicated as the major determinant of splicing regulation. With the recent surge of reports of circular RNA (circRNAs) generated by backsplicing, role of Alu-associated RNA structures formed by long-range interactions are taking central stage. Humans contain two nearly identical copies of Survival Motor Neuron (SMN) genes, SMN1 and SMN2. Deletion or mutation of SMN1 coupled with inability of SMN2 to compensate for the loss of SMN1 due to exon 7 causes spinal muscular atrophy (SMA), one of the leading genetic diseases of children. In this review, we describe how structural elements formed by both local and long-distance interactions are being exploited to modulate SMN2 exon 7 splicing as a potential therapy for SMA. We also discuss how Alu-associated secondary structure modulate generation of a vast repertoire of SMN circRNAs. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.

Economic burden of spinal muscular atrophy in the United States: a contemporary assessment.Publié le 20 07 2019

Aims: To estimate healthcare resource utilization (HRU) and costs among patients with spinal muscular atrophy (SMA) type 1 (SMA1) in real-world practice, overall and among patients treated with nusinersen. As a secondary objective, HRU and costs were estimated among patients with other SMA types (i.e., 2, 3, or 4 combined), overall and among patients treated with nusinersen. Materials and methods: Patients with SMA were identified from the Symphony Health's Integrated Dataverse (IDV) open claims database (09/01/2016-08/31/2018) and were classified into four cohorts based on SMA type and nusinersen treatment (i.e., SMA1, SMA1 nusinersen, other SMA, and other SMA nusinersen cohorts). The index date was the date of the first SMA diagnosis after 12/23/2016 or, for nusinersen cohorts, the date of nusinersen initiation. The study period spanned from the index date to the earlier among the end of clinical activity or data availability. Results: Patients in the SMA1 (N?=?349) and SMA1 nusinersen (N?=?45) cohorts experienced an average of 59.4 and 56.6 days with medical visits per-patient-per-year (PPPY), respectively, including 14.1 and 4.6 inpatient days. Excluding nusinersen-related costs, total mean healthcare costs were $137,627 and $92,618 PPPY in the SMA1 and SMA1 nusinersen cohorts, respectively. Mean nusinersen-related costs were $191,909 per-patient-per-month (PPPM) for the first 3 months post-initiation (i.e., loading phase) and $36,882 PPPM thereafter (i.e., maintenance phase). HRU and costs were also substantial among patients in the other SMA (N?=?5,728) and other SMA nusinersen (N?=?404) cohorts, with an average of 44.5 and 63.7 days with medical visits PPPY and total mean healthcare costs (excluding nusinersen-related costs) of $49,175 and $76,371 PPPY, respectively. Limitations: The database may contain inaccuracies or omissions in diagnoses, procedures, or costs, and does not capture medical services outside of the IDV network. Conclusions: HRU and healthcare costs were substantial in patients with SMA, including in nusinersen-treated patients.

Neuromuscular Ultrasound: Clinical Applications and Diagnostic Values.Publié le 20 07 2019

Advances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented.

[Anabolic and molecular interventions on muscle : Meaningful anti-aging strategy?]Publié le 20 07 2019

PMID: 28808776 [PubMed - indexed for MEDLINE]

Nusinersen Improves Walking Distance and Reduces Fatigue in Later-Onset SMA.Publié le 14 07 2019

INTRODUCTION: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen but its impact on fatigue has not been studied.
METHODS: Post hoc analyses examined changes in 6-Minute Walk Test (6MWT) distance and fatigue in children and adolescents with SMA Type II and III who received their first dose of nusinersen in the phase Ib/IIa open-label CS2 study and were ambulatory during CS2 or the extension study CS12.
RESULTS: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, while median fatigue changed by -3.8% (-19.7%, 1.4%).
DISCUSSION: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA. This article is protected by copyright. All rights reserved.

The Complex Spine in Children with Spinal Muscular Atrophy: The Transforaminal Approach-A Transformative Technique.Publié le 14 07 2019

BACKGROUND AND PURPOSE: Spinal muscular atrophy, a genetic disease resulting in loss of motor function, presents from in utero to adulthood. Depending on progression and secondary scoliosis, spinal stabilization may be necessary. When planning intrathecal access in these patients, spinal anatomy is the most important factor. Therefore, when planning intrathecal nusinersen injections, we subdivided patients with spinal muscular atrophy into simple-versus-complex spine subgroups. Our purpose was to present our experience with our first 42 transforaminal intrathecal nusinersen injections.
MATERIALS AND METHODS: We reviewed 31 consecutive patients with spinal muscular atrophy types 1-3 who presented for intrathecal nusinersen injections from March 2017 to September 2018. Nine children had complex spines (ie, spinal instrumentation and/or fusion) and required preprocedural imaging for route planning for subarachnoid space access via transforaminal or cervical approaches.
RESULTS: A total of 164 intrathecal nusinersen injections were performed in 31 children 4-226 months of age, with 100% technical success in accessing the subarachnoid space. Nine patients with complex spinal anatomy underwent 45 intrathecal nusinersen injections; 42 of 45 procedures were performed via a transforaminal approach with the remaining 3 via cervical techniques. There were no complications.
CONCLUSIONS: Our initial experience has resulted in a protocol-driven approach based on simple or complex spinal anatomy. Patients with simple spines do not need preprocedural imaging or imaging-guided intrathecal nusinersen injections. In contrast, the complex spine subgroup requires preprocedural imaging for route planning and imaging guidance for therapy, with the primary approach being the transforaminal approach for intrathecal nusinersen injections.

Quantitative MR neurography biomarkers in 5q-linked spinal muscular atrophy.Publié le 13 07 2019

OBJECTIVE: To characterize and quantify peripheral nerve lesions and muscle degeneration in clinically, genetically, and electrophysiologically well-classified, nonpediatric patients with 5q-linked spinal muscular atrophy (SMA) by high-resolution magnetic resonance neurography (MRN).
METHODS: Thirty-one adult patients with genetically confirmed 5q-linked SMA types II, IIIa, and IIIb and 31 age- and sex-matched healthy volunteers were prospectively investigated. All patients received neurologic, physiotherapeutic, and electrophysiologic assessments. MRN at 3.0T with anatomic coverage from the lumbosacral plexus and proximal thigh down to the tibiotalar joint was performed with dual-echo 2D relaxometry sequences with spectral fat saturation and a 3D T2-weighted inversion recovery sequence. Detailed quantification of nerve injury by morphometric and microstructural MRN markers and qualitative classification of fatty muscle degeneration were conducted.
RESULTS: Established clinical scores and compound muscle action potentials discriminated well between the 3 SMA types. MRN revealed that peroneal and tibial nerve cross-sectional area (CSA) at the thigh and lower leg level as well as spinal nerve CSA were markedly decreased throughout all 3 groups, indicating severe generalized peripheral nerve atrophy. While peroneal and tibial nerve T2 relaxation time was distinctly increased at all analyzed anatomic regions, the proton spin density was clearly decreased. Marked differences in fatty muscle degeneration were found between the 3 groups and for all analyzed compartments.
CONCLUSIONS: MRN detects and quantifies peripheral nerve involvement in SMA types II, IIIa, and IIIb with high sensitivity in vivo. Quantitative MRN parameters (T2 relaxation time, proton spin density, CSA) might serve as novel imaging biomarkers in SMA to indicate early microstructural nerve tissue changes in response to treatment.

Nusinersen helps restore walking ability in childhood spinal muscular atrophy.Publié le 11 07 2019

PMID: 31290219 [PubMed - as supplied by publisher]

[Gene therapies for neuromuscular diseases].Publié le 11 07 2019

BACKGROUND: For a long time the treatment of neuromuscular diseases was considered to be purely symptomatic. Due to new technologies in recent years novel causal forms of treatment could be developed. Gene therapies for spinal muscular atrophy, Duchenne muscular dystrophy, limb-girdle muscular dystrophy, myotubular myopathy and hereditary motor and sensory neuropathy type 1A are currently being evaluated in clinical trials. Initial preliminary results are promising and the first preparation onasemnogene abeparvovec-xioi (Zolgensma®) for the treatment of spinal muscular atrophy has recently been approved by the U.S. Food and Drug Administration (FDA).
OBJECTIVE: This review describes the principles of gene therapy, summarizes the interim results published so far and provides an overview of currently active or soon to be initiated gene therapy trials.
CONCLUSION: Gene therapies have the potential to significantly influence the course of neuromuscular diseases. First positive intermediate results have been published and the first treatment has recently been approved in the USA. Long-term data on sustained effects and toxicity of gene therapies are not yet available. These novel treatment options will present new challenges for the healthcare systems concerning diagnosis, treatment and reimbursement.

Olesoxime in Neurodegenerative Diseases: Scrutinising a Promising Drug Candidate.Publié le 11 07 2019

Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.

Antisense Oligonucleotide Therapies for Neurodegenerative Diseases.Publié le 11 07 2019

Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.

Antisense therapies for movement disorders.Publié le 11 07 2019

Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing ?20 base pairs, that can potentially target any messenger RNA of interest. Antisense oligonucleotides often contain modifications to the phosphate backbone, the sugar moiety, and the nucleotide base. The development of antisense oligonucleotide therapies spinal muscular atrophy and Duchenne muscular dystrophy suggest potentially wide-ranging therapeutic applications for antisense oligonucleotides in neurology. Successes with these two diseases have heightened interest in academia and the pharmaceutical industry to develop antisense oligonucleotides for several movement disorders, including, spinocerebellar ataxias, Huntington's disease, and Parkinson's disease. Compared to small molecules, antisense oligonucleotide-based therapies have an advantage because the target disease gene sequence is the immediate path to identifying the therapeutically effective complementary antisense oligonucleotide. In this review we describe the different types of antisense oligonucleotide chemistries and their potential use for the treatment of human movement disorders. © 2019 International Parkinson and Movement Disorder Society.

Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy.Publié le 07 07 2019

BACKGROUND: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1).
METHODS: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ?20 (n = 3).
RESULTS: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months).
CONCLUSIONS: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.

Motor neuron loss in SMA is not associated with somal stress-activated JNK/c-Jun signaling.Publié le 06 07 2019

A pathological hallmark of spinal muscular atrophy (SMA) is severe motor neuron loss, which results in muscle weakness and often infantile or childhood mortality. Although it is well established that deficient expression of survival motor neuron protein causes SMA, the molecular pathways that execute motor neuron cell death are poorly defined. The c-Jun NH2-terminal kinases (JNKs) are stress-activated kinases with multiple substrates including c-Jun, which can be activated during neuronal injury and neurodegenerative disease leading to neuronal apoptosis. Recently, increased JNK-c-Jun signaling was reported in SMA raising the possibility that JNK inhibitors could be a novel treatment for this disease. We examined JNK-c-Jun activity in SMA mouse and human cultured cells and tissues. Anisomycin treatment of human SMA fibroblasts and sciatic nerve ligation in SMA mice provoked robust phosphorylated-c-Jun (p-c-Jun) expression indicating that SMN-deficiency does not prevent activation of the stress-induced JNK-c-Jun signaling pathway. Despite retained capacity to activate JNK-c-Jun, we observed no basal increase of p-c-Jun levels in SMA compared to control cultured cells, human or mouse spinal cord tissues, or mouse motor neurons during the period of motor neuron loss in severe SMA model mice. In both controls and SMA, approximately 50% of ?-motor neuron nuclei express p-c-Jun with decreasing expression during the early postnatal period. Together these studies reveal no evidence of stress-activated JNK-c-Jun signaling in motor neurons of SMA mice or human tissues, but do highlight the important role of JNK-c-Jun activity during normal motor neuron development raising caution about JNK antagonism in this pediatric neuromuscular disease.

Spinal muscular dystrophy - a revisit of the diagnosis and treatment modalities.Publié le 06 07 2019

Spinal Muscular Atrophy (SMA) is a pan-ethnic disorder and generally characterized as prevalent lethal genetic disease of infants. It is an autosomal recessive neuromuscular disease caused by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Due to the high carrier frequency (1:50), the burden of this genetic disorder is very heavy in developing countries. Till date no absolute cure or effective treatment of the disease is available in clinical practice, whereas minor enhancement of SMN protein levels can be beneficial. It can be achieved by augmenting SMN2 transcription, stimulating exon 7 splicing and protein stabilization. Due to its low prevalence among population, costly screening and diagnosis, the disease is still lacking proper management. SMN is expressed almost in all tissues of body, still the reason why only lower motor neurons are affected in SMA is unknown. Research is still going on and with advancement of innovative therapies and gene modification, improved outcome may come in near future. Presently, supportive care including respiratory, nutritional, psychiatric and orthopaedic management can ameliorate clinical symptoms and improve survival rates if SMA is diagnosed early in life. Routine prenatal and new-born screening can help with potential benefits and timely management. In this review, the concept of newer methodological system and recent advances for molecular diagnosis of SMA with the variability in the clinical features is stressed. The public health community should remain alert to the rapidly changing developments in early detection and treatment of SMA.

Onasemnogene Abeparvovec: First Global Approval.Publié le 06 07 2019

Onasemnogene abeparvovec (onasemnogene abeparvovec-xioi; formerly AVXS-101; ZOLGENSMA®) is an adeno-associated viral vector-based gene therapy designed to deliver a functional copy of the human survival motor neuron (SMN) gene to the motor neuron cells of patients with spinal muscular atrophy (SMA). It has been developed by AveXis, a Novartis company, and was approved in May 2019 in the USA for the treatment of paediatric patients aged?< 2 years with SMA and bi-allelic mutations in the SMN1 gene (the primary gene encoding survival motor neuron protein). Onasemnogene abeparvovec is the first gene therapy to be approved for SMA in the USA. The recommended dose is 1.1?×?1014 vector genomes per kg of bodyweight, administered as a single intravenous infusion over 60 min. Regulatory assessments for this formulation of onasemnogene abeparvovec are underway in the EU and Japan; an intrathecal formulation is currently undergoing clinical development in the USA. This article summarizes the milestones in the development of onasemnogene abeparvovec leading to this first approval for the treatment of paediatric patients aged?< 2 years with SMA and bi-allelic mutations in SMN1.

Evolution of bone mineral density, bone metabolism and fragility fractures in Spinal Muscular Atrophy (SMA) types 2 and 3.Publié le 04 07 2019

With recent advances in the treatment of Spinal Muscular Atrophy (SMA), there is a strong need to increase knowledge on the involvement of organs and systems outside the central nervous system. We investigated bone metabolism, bone mineral density (BMD) and fractures, and their possible correlation with age and motor capacities. Thirty-two children with SMA (27 type 2, 5 type 3), mean age 40?±?32.3 months, underwent two evaluations at an 18-month interval (V1 and V2). Twelve of these children also underwent a third evaluation at month 36 (V3). Diet, bone metabolism, BMD, X-rays, and motor function (by the Hammersmith Functional Motor Scale Expanded - HFMSE - and the Upper Limb Module - ULM) were assessed. At V1, 25-OH vitamin D3 (25OH D) therapy was started, and dietary calcium intake adjusted according to the recommended dietary allowance. Low 25OH D levels and asymptomatic vertebral fractures were mainly observed at V1. At all visits, bone resorption markers were higher than normal. At V2 and V3, decreased BMD was observed. Higher spine BMD values at follow-up were associated with HFMSE score >12 at baseline (p<0.03). This study suggests that even young children with SMA are at risk of severe bone fragility. Further investigations of the molecular mechanisms leading to altered bone metabolism in SMA could help identify novel therapeutic targets and establish better guidelines for bone fragility management.

Pathologic alterations in the proteome of synaptosomes from a mouse model of spinal muscular atrophy.Publié le 03 07 2019

Spinal muscular atrophy (SMA) is a human genetic disorder characterized by muscle weakness, muscle atrophy, and death of motor neurons. SMA is caused by mutations or deletions in a gene called survival motor neuron 1 (SMN1). SMN1 is a housekeeping gene, but the most prominent pathologies in SMA are atrophy of myofibers and death of motor neurons. Further, degeneration of neuromuscular junctions, synapses and axonal regions are also features of SMA disease. Here, we have investigated the proteome dynamics of central synapses in P14 Smn2B/- mice, a model of SMA. Label-free quantitative proteomics on isolated synaptosomes from spinal cords of these animals identified 2030 protein groups. Statistical data analysis revealed 65 specific alterations in the proteome of the central synapses at the early onset stage of disease. Functional analysis of the dysregulated proteins indicated a significant enrichment of proteins associated with mitochondrial dynamics, cholesterol biogenesis, and protein clearance. These pathways represent potential targets for therapy development with the goal of providing stability to the central synapses, thereby preserving neuronal integrity in the context of SMA disease. Data are available via ProteomeXchange with identifier PXD012850.

[Bilateral Pallidal Deep Brain Stimulation for Dystonic Camptocormia Induced by Repetitive Abdominal Muscle Exercise:A Case Report].Publié le 03 07 2019

Camptocormia is a rare and disabling movement disorder resulting in forward bending of the trunk. Camptocormia has many etiologies, although it is frequently observed patients with in Parkinson's disease and dystonia. Deep brain stimulation(DBS)of the globus pallidus internus(GPi)and subthalamic nucleus effectively treats camptocormia in Parkinson's disease and dystonia patients. Herein, we report a case of dystonic camptocormia induced by repetitive abdominal muscle exercise in which treatment was administered using bilateral GPi-DBS. A 54-year-old woman developed dystonic camptocormia at 53 years of age. Prior to the onset of symptoms, she regularly performed 200 abdominal muscle exercises per day. Oral medications, and botulinum toxin and lidocaine injections, were ineffective. Truncal anterior bending occurred while standing and walking. The patient underwent bilateral GPi-DBS, which instantly and dramatically improved her symptoms. The Burke-Fahn-Marsden dystonia rating scale subscore for the trunk before and after bilateral pallidotomy was 6 and 0, respectively. No perioperative adverse events were observed. Symptomatic relief persisted for 2 years. This case suggest that camptocormia can result from repeated abdominal muscle exercise, and that bilateral GPi-DBS may be a feasible and long-term efficacious procedure for dystonic camptocormia.

Spinal Muscular Atrophy and Common Therapeutic Advances.Publié le 10 05 2019

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive destructive motor neuron disease which is characterized primarily by the degeneration of ?-motor neurons in the ventral gray horn of the spinal cord. It mainly affects children and represents the most common reason of inherited infant mortality.
MATERIAL AND METHODS: We provide an overview of the recent therapeutic strategies for the treatment of SMA together with available and developing therapeutic strategies. For this purpose, Google Scholar and PubMed databases were searched for literature on SMA, therapy and treatment. Titles were reviewed and 96 were selected and assessed in this paper.
RESULT: Over the last two decades, different therapeutic strategies have been proposed for SMA. Some methods are in the pre-clinical, others the clinical phase.
CONCLUSION: By emergence of the new approaches, especially in gene therapy, effective treatment in the close future is probable.

Using Systems Biology and Mathematical Modeling Approaches in the Discovery of Therapeutic Targets for Spinal Muscular Atrophy.Publié le 10 05 2019

Systems biology uses a combination of experimental and mathematical approaches to investigate the complex and dynamic interactions with a given system or biological process. Systems biology integrates genetics, signal transduction, biochemistry and cell biology with mathematical modeling. It can be used to identify novel pathways implicated in diseases as well as to understand the mechanisms by which a specific gene is regulated. This review describes the development of mathematical models for the regulation of an endogenous modifier gene, SMN2, in spinal muscular atrophy-an early-onset motor neuron disease that is a leading genetic cause of infant mortality worldwide-by cAMP signaling. These mathematical models not only can aid in understanding how SMN2 expression is regulated but they can also be used to examine the best ways to manipulate cAMP signaling to maximally increase SMN2 expression. These models will lead to the development of therapeutic strategies for treating SMA. This systems biology approach can also be applied to other neurological diseases, particularly those in which a disease-causing gene or a modifier gene has been identified.

Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy.Publié le 10 05 2019

PMID: 28192393 [PubMed - indexed for MEDLINE]

Evaluating Benefit-Risk Decision-making in Spinal Muscular Atrophy: A first-Ever Study to Assess Risk Tolerance in the SMA Patient Community.Publié le 07 05 2019

PURPOSE: Patients' perceptions of benefit-risk are essential to informing the regulatory process and the context in which potential therapies are evaluated. To bring this critical information to regulators, Cure SMA launched a first-ever Benefit-Risk Survey for spinal muscular atrophy (SMA) to characterize decision-making and benefit-risk trade-offs in SMA associated with a potential therapy. We hypothesized that risk tolerance would be correlated with SMA type/severity and disease progression. This article presents the results of a benefit-risk survey to enhance understanding of how patients with SMA and caregivers evaluate specific benefits and risks associated with potential therapies.
METHODS: Affected adults, representing all SMA types (I-IV) within the Cure SMA database, and caregivers of affected individuals of all ages/types were invited via e-mail to participate. Best-worst scaling (BWS) was used to assess participants' priorities on benefit-risk trade-offs, as it provides higher discrimination and importance scaling among tested attributes. Twelve potentially clinically meaningful treatment benefits and 11 potential risks (ranging in severity and immediacy) were tested. Multiple factors were correlated with individual responses, including: SMA type/disease severity, stage of disease, respondent type, sex, and quality of life/level of independence (current and expected). Survey respondents were also evaluated for "risk-taking attitudes."
FINDINGS: A total of 298 responses were evaluated (28% affected adults and 72% caregivers, mostly parents). Most respondents were diagnosed >5 years ago (67.3%), with 22.1% SMA type I, 45.6% SMA type II, and 27.9% SMA type III. No strong correlation was found between risk tolerance and SMA type, stage of disease progression, respondent type, sex, quality of life assessment, or rated levels of independence. Irrespective of SMA type, respondents consistently rated the following risks, associated with a potential treatment, as "least tolerable": life-threatening allergic reactions; 1 in 1000 risk of life-threatening side effects leading to possible organ failure; or worsening quality of life. Furthermore, all SMA type respondents rated these risks as "most tolerable": invasive mode of treatment administration (including need for general anesthesia); side effect of dizziness; and other common side effects such as nausea, vomiting, loss of appetite, headaches, back pain, or fatigue.
IMPLICATIONS: With the approval of the first SMA treatment, these findings offer a unique opportunity to assess and characterize baseline risk-tolerance in SMA against which to evaluate future SMA treatment options. Although differences had been expected in risk tolerance among respondents based on disease baseline and certain patient attributes, this was not observed. Survey results should inform future SMA drug development and benefit-risk assessments.

Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors.Publié le 07 05 2019

Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder representing a continuous spectrum of muscular weakness ranging from compromised neonates to adults with minimal manifestations. Patients show homozygous absence or disease-causing variants of the SMN1 gene (-/- or 0/0) and in carriers only one copy is absent or mutated (1/0). Genetic diagnosis and counseling in SMA present several challenges, including the existence of carriers (2/0) that are undistinguishable of non-carriers (1/1) with current genetic testing methods and the report of patients (0/0) with very mild manifestations and even asymptomatic that are discovered when a full symptomatic case appears in the family. Younger asymptomatic siblings of symptomatic SMA patients are usually never tested until adolescence or adult life. However, following regulatory approval of the first tailored treatment for SMA, the prospects for care of these patients have changed. Early testing, including pre-symptomatic newborn screening and confirmation of diagnosis would change proactive measures and opportunities for therapy based in the actual landscape of new treatments. This review discusses the challenges and new perspectives of genetic counseling in SMA.

[Healing of Amyotrophic Lateral Sclerosis: A Case Report].Publié le 07 05 2019

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy.
CASE REPORT: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with ?-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely.
CONCLUSIONS: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.

Current Treatment Options in Neurology-SMA Therapeutics.Publié le 01 05 2019

PURPOSE OF REVIEW: In this review, we discuss the clinical and genetic features of 5q spinal muscular atrophy and highlight approved and upcoming therapies.
RECENT FINDINGS: We emphasize that multidisciplinary care has been a key component of the improved quality and length of life seen in these individuals in the past decade. We discuss the evidence leading to the approval of nusinersen and the evidence leading to the anticipated approval of onasemnogene abeparvovec-xioi. Additional clinical therapies that are on the horizon are discussed and the importance of continued multidisciplinary care even after treatment is emphasized. The pursuit of therapies for spinal muscular atrophy is becoming a success story and continued development of biomarkers will allow for more informed therapeutic decision making and eventual cost-effective utilization of available therapies.

Newborn screening for SMA in Southern Belgium.Publié le 01 05 2019

Approval was recently granted for a new treatment for spinal muscular atrophy (SMA). Given that the treatment is effective when administered early and the societal burden of SMA-related disability, the implementation of a newborn screening program is warranted. We describe the stepwise process that led us to launch a newborn screening program for SMA in Southern Belgium. Different political, ethical, and clinical partners were informed about this project and were involved in its governance, as were genetic and screening labs. We developed and validated a newborn screening method to specifically recognize homozygous deletions of exon 7 in the SMN1 gene. Subsequently, a 3-year pilot study has been recently initiated in one Belgian neonatal screening laboratory to cover 17.000 neonates per year. Coverage extension to all of Southern Belgium to screen 55.000 babies each year is underway.

Radiation exposure of image-guided intrathecal administration of nusinersen to adult patients with spinal muscular atrophy.Publié le 01 05 2019

PURPOSE: To examine diagnostic reference levels (DRL) and achievable doses (AD) of image-guided and size-specific dose estimates (SSDE) and organ and effective doses of CT-guided intrathecal nusinersen administration to adult patients with spinal muscular atrophy (SMA).
METHODS: This study involved a total of 60 image-guided intrathecal nusinersen treatments between August 2017 and June 2018. Patient cohort comprised 14 adult patients with the following SMA types: type 2 (n?=?9) and type 3 (n?=?5) with a mean age of 33.6 years (age range 25-57 years). DRL, AD, SSDE, organ, and effective doses were assessed with a dose-monitoring program based on the Monte Carlo simulation techniques.
RESULTS: DRL and AD for computed tomography are summarised as follows: in terms of CT-dose index (CTDIvol), DRL 56.4 mGy and AD 36.7 mGy; in terms of dose-length product (DLP), DRL 233.1 mGy cm and AD 120.1 mGy cm. DRL and AD for fluoroscopic guidance were distributed as follows: in terms of dose-area product (DAP), DRL 239.1 ?Gy m2 and AD 135.2 mGy cm2. Mean SSDE was 9.2 mGy. Mean effective dose of the CT-guided injections was 2.5 mSv (median 2.0 mSv, IQR 1.3-3.2 mSv). Highest organ doses in the primary beam of radiation were the small intestine 12.9 mSv, large intestine 9.5 mSv, and ovaries 3.6 mSv.
CONCLUSION: Radiation exposure of SMA patients measured as DRLs is generally not higher compared with patients without SMA despite severe anatomical hazards. Dose monitoring data may allow clinicians to stratify radiation risk, identify organs at risk, and adopt measures for specific radiation dose reduction.

Late onset of dropped head syndrome following mantle radiation therapy for Hodgkin lymphoma.Publié le 01 05 2019

Dropped head syndrome (DHS) is a rare condition, characterised by weakness of the cervical paraspinal muscles with sagging of the head. It is usually seen in association with neurological disorders and rarely can follow radiotherapy. We report a case of a 54-year-old man survivor of Hodgkin lymphoma (HL), who developed DHS 28 years after radiotherapy. He was referred to our department due to progressive weakness and atrophy of cervical paraspinal and shoulder girdle musculature. Physical and neurophysiological examination, electromyography and MRI confirmed the diagnosis of DHS. In the following years, there was no progression of symptoms.

Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.Publié le 26 04 2019

OBJECTIVE: To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).
METHODS: Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.
RESULTS: Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.
CONCLUSIONS: Nusinersen treatment over ?3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.
CLINICALTRIALSGOV IDENTIFIER: NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

"It's not just the wheelchair, it's everything else": Australian parents' perspectives of wheelchair prescription for children with neuromuscular disorders.Publié le 23 04 2019

PURPOSE: Standards of care for neuromuscular disorders recommend timely provision of wheelchair equipment to support independent and spontaneous movement, age-appropriate participation, and psychological, social, cognitive and communication skills. Parental engagement is crucial to initiating wheelchair prescription. No studies have investigated parents' perceptions of this process or their experiences of their child's transition to wheelchair equipment.
METHODS: Seventeen families of children with a neuromuscular disorder who were recommended wheelchair equipment participated in an interview (response rate: 53%). Diagnoses included muscular dystrophies, spinal muscular atrophy, and congenital myopathy.
RESULTS: Findings showed that wheelchair prescription represented a milestone for parents in their child's disease progression. Parents described experiencing strong emotional responses, with the potential to eclipse pragmatic factors. Perceiving wheelchair equipment as an adjunct to their child's functioning and participation positively influenced parents' receptivity to wheelchair recommendation. Parents' receptivity to wheelchair recommendation was also influenced by their emotional experience, their child's weight-bearing ability and participation in age appropriate activities.
CONCLUSIONS: Enablers to parental engagement in the wheelchair prescription process included timely psychological care and social support, a child- and family-centered approach to care, and ease of access to credible information. This study shows wheelchair prescription is a complex and multi-faceted process that represents more than just a piece of equipment to parents. Implications for rehabilitation Parents experience a range of emotions and challenges as their child's neuromuscular condition progresses, including the introduction of a wheelchair. Anticipatory care and education from health professionals is required to support families' transition to wheelchair equipment. Facilitators to parents' engagement in wheelchair prescription include a family-centered approach, collaborative decision-making between families and health professionals, and access to information and psychosocial support.

The identification of CCL18 as biomarker of disease activity in localized scleroderma.Publié le 23 04 2019

BACKGROUND: Localized Scleroderma (LoS) encompasses a group of idiopathic skin conditions characterized by (sub)cutaneous inflammation and subsequent development of fibrosis. Currently, lack of accurate tools enabling disease activity assessment leads to suboptimal treatment approaches.
OBJECTIVE: To investigate serum concentrations of cytokines and chemokines implicated in inflammation and angiogenesis in LoS and explore their potential to be utilized as biomarker of disease activity. Additionally, to investigate the implication of potential biomarkers in disease pathogenesis.
METHODS: A 39-plex Luminex immuno-assay was performed in serum samples of 74 LoS and 22 Healthy Controls. The relation between a validated clinical measure of disease activity (mLoSSI) and serum analytes was investigated. Additionally, gene and protein expression were investigated in circulating cells and skin biopsies.
RESULTS: From the total of 39, 10 analytes (CCL18, CXCL9, CXCL10, CXCL13, TNFRII, Galectin-9, TIE-1, sVCAM, IL-18, CCL19) were elevated in LoS serum. Cluster analysis of serum samples revealed CCL18 as most important analyte to discriminate between active and inactive disease. At individual patient level, CCL18 serum levels correlated strongest with mLoSSI-scores (rs?=?0.4604, P?<?0.0001) and in longitudinal measures CCL18 concentrations normalised with declining disease activity upon treatment initiation. Additionally, CCL18 was elevated in LoS serum, and not in (juvenile) dermatomyositis or spinal muscular atrophy. Importantly, CCL18 gene and protein expression was increased at the inflammatory border of cutaneous LoS lesions, with normal expression in unaffected skin and circulating immune cells.
CONCLUSION: CCL18 is specific for disease activity in LoS thereby providing relevance as a biomarker for this debilitating disease.

Lumbar laminotomy for the intrathecal administration of nusinersen for spinal muscular atrophy: technical note and outcomes.Publié le 20 04 2019

Nusinersen (Spinraza) is a US Food and Drug Administration-approved intrathecal medication for the treatment of spinal muscular atrophy (SMA). Adult patients with SMA often undergo thoracolumbar fusion to treat neurogenic scoliosis, preventing thecal access. The authors report a laminotomy technique and the ease of intrathecal access in three SMA patients with prior thoracolumbar fusions.Patients were positioned in the lateral decubitus position or prone. Lumbar laminotomy was performed below the conus, between the lateral longitudinal rods, to preserve mechanical stability. Fluoroscopy provided real-time identification of instruments. Hardware was contoured with a carbide drill bit to develop the surgical window. Fiducial screws were placed along the perimeter for demarcation. Sublaminar wire removal caused dural defects that were repaired with a layer of dural substitute onlay and sealant. All patients successfully received nusinersen thecal injections via lumbar puncture by an interventional radiologist. Fluoroscopy time ranged from 6 to 36 seconds. No postoperative pseudomeningoceles, cerebrospinal fluid leaks, or wound complications occurred.For patients with SMA and posterior fusion from prior scoliosis treatment, lumbar laminotomy is an effective method for creating thecal access for the administration of nusinersen.

Preoperative Variables Associated With Respiratory Complications After Pediatric Neuromuscular Spine Deformity Surgery.Publié le 19 04 2019

OBJECTIVE: The objective of this study is to identify preoperative laboratory values and patient factors that are associated with postoperative respiratory complications in pediatric neuromuscular scoliosis (NMS) populations undergoing posterior spinal fusion (PSF) with instrumentation.
SUMMARY OF BACKGROUND DATA: PSF in NMS patients are high-risk surgeries. Respiratory complications are the most common postoperative event, with rates up to 28.2% following surgery.
METHODS: A single-surgeon, two-hospital pediatric spine surgery database was reviewed to identify all patients who underwent PSF for NMS. Diagnoses included cerebral palsy (n=83), myelomeningocele (n=13), spinal muscular atrophy (n=4), and other (n=11). This study defined respiratory complications as postoperative pneumonia, pleural effusion, pneumothorax, need for reintubation, respiratory status requiring a return to the pediatric intensive care unit (PICU), or prolonged (>4-day) need for mechanical ventilation. Preoperative laboratory values for transferrin, prealbumin, hemoglobin/hematocrit, total protein, albumin, and total lymphocyte count were collected.
RESULTS: There were 50 males and 61 females with a mean age of 14 years 2.5 months (8-20 years). Seventeen patients (15.3%) experienced postoperative respiratory complications. On univariate analysis, any history of pneumonia, the presence of gastrostomy tube, and low transferrin levels were associated with postoperative respiratory complications, and a strong trend (p=.06) was observed for tracheostomy. On multivariate analysis, the presence of gastrostomy tube and history of pneumonia remained as clinically significant predictors of postoperative respiratory complications.
CONCLUSION: Pediatric NMS patients undergoing PSF that have history of pneumonia or gastrostomy tube present at time of surgery are at increased risk for postoperative respiratory complications. The univariate associations of tracheostomy presence and low transferrin levels with postoperative respiratory complications deserve further examination.

Physical exercise training for type 3 spinal muscular atrophy.Publié le 18 04 2019

BACKGROUND: Physical exercise training might improve muscle and cardiorespiratory function in spinal muscular atrophy (SMA). Optimization of aerobic capacity or other resources in residual muscle tissue through exercise may counteract the muscle deterioration that occurs secondary to motor neuron loss and inactivity in SMA. There is currently no evidence synthesis available on physical exercise training in people with SMA type 3.
OBJECTIVES: To assess the effects of physical exercise training on functional performance in people with SMA type 3, and to identify any adverse effects.
SEARCH METHODS: On 8 May 2018, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, and LILACS. On 25 April 2018 we searched NHSEED, DARE, and ClinicalTrials.gov and WHO ICTRP for ongoing trials.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) or quasi-RCTs lasting at least 12 weeks that compared physical exercise training (strength training, aerobic exercise training, or both) to placebo, standard or usual care, or another type of non-physical intervention for SMA type 3. Participants were adults and children from the age of five years with a diagnosis of SMA type 3 (Kugelberg-Welander syndrome), confirmed by genetic analysis.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.
MAIN RESULTS: We included one RCT that studied the effects of a six-month, home-based, combined muscle strength and recumbent cycle ergometry training program versus usual care in 14 ambulatory people with SMA. The age range of the participants was between 10 years and 48 years. The study was evaluator-blinded, but personnel and participants could not be blinded to the intervention, which placed the results at a high risk of bias. Participants performed strength training as prescribed, but 50% of the participants did not achieve the intended aerobic exercise training regimen. The trial used change in walking distance on the six-minute walk test as a measure of function; a minimal detectable change is 24.0 m. The change from baseline to six months' follow-up in the training group (9.4 m) was not detectably different from the change in the usual care group (-0.14 m) (mean difference (MD) 9.54 m, 95% confidence interval (CI) -83.04 to 102.12; N = 12). Cardiopulmonary exercise capacity, assessed by the change from baseline to six months' follow-up in peak oxygen uptake (VO2max) was similar in the training group (-0.12 mL/kg/min) and the usual care group (-1.34 mL/kg/min) (MD 1.22 mL/kg/min, 95% CI -2.16 to 4.6; N = 12). A clinically meaningful increase in VO2max is 3.5 mL/kg/min.The trial assessed function on the Hammersmith Functional Motor Scale - Expanded (HFMSE), which has a range of possible scores from 0 to 66, with an increase of 3 or more points indicating clinically meaningful improvement. The HFMSE score in the training group increased by 2 points from baseline to six months' follow-up, with no change in the usual care group (MD 2.00, 95% CI -2.06 to 6.06; N = 12). The training group showed a slight improvement in muscle strength, expressed as the manual muscle testing (MMT) total score, which ranges from 28 (weakest) to 280 (strongest). The change from baseline in MMT total score was 6.8 in the training group compared to -5.14 in the usual care group (MD 11.94, 95% CI -3.44 to 27.32; N = 12).The trial stated that training had no statistically significant effects on fatigue and quality of life. The certainty of evidence for all outcomes was very low because of study limitations and imprecision. The study did not assess the effects of physical exercise training on physical activity levels. No study-related serious adverse events or adverse events leading to withdrawal occurred, but we cannot draw wider conclusions from this very low-certainty evidence.
AUTHORS' CONCLUSIONS: It is uncertain whether combined strength and aerobic exercise training is beneficial or harmful in people with SMA type 3, as the quality of evidence is very low. We need well-designed and adequately powered studies using protocols that meet international standards for the development of training interventions, in order to improve our understanding of the exercise response in people with SMA type 3 and eventually develop exercise guidelines for this condition.

The influence of postural deformities on neck function and pain in patients with Parkinson's disease.Publié le 17 04 2019

BACKGROUND: Trunk alignment is thought to contribute to neck function. However, this common assumption is not clear in patients with Parkinson's disease (PwPD) suffering from different postural deformities such as: Pisa syndrome (PS), Camptocormia & Antecollis (C&A).
OBJECTIVES: to investigate the effect of different postural deformities including PS and C&A on neck function and pain in patient (PwPD).
METHODS: Forty-five participants belonging to three groups: 15 PD patients without postural disorders (PD), 15 with PS, and 15 with C&A. The function, disability and pain were assessed by Neck Disability Index (NDI), and Brief Pain Inventory (BPI) which used to assess the pain severity (BPI-PS) and Pain Interference (BPI-PI). All groups completed clinical assessments by the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoenh & Yahr (mH&Y) staging and the Levodopa Equivalent Daily Dose (LEDD).
RESULTS: PD group compared with PS and C&A groups showed differences in NDI, BPI-PS, BPI-PI, LEDD and mH&Y staging (P < 0.001), but no differences found in PD duration, UPDRS-II and III in the same groups. Moreover, no differences were observed between PS and C&A groups in the mentioned scales.
DISCUSSION AND CONCLUSION: These results demonstrated that PS and C&A are associated with severe impairment of neck functions, and pain in PwPD.

Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis.Publié le 17 04 2019

Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SODG93A mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.

Smooth muscle atrophy and colon pathology in SMN deficient mice.Publié le 12 04 2019

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by loss of motor neurons in the ventral horn of the spinal cord. Clinical features such as progressively lethal respiratory weakness and associated muscle wasting have been extensively studied but less attention has been given to gastrointestinal (GI) dysfunction, which is common symptomatology in SMA patients with 43% constipation, 15% abdominal pain, and 14% meteorism. In the current study, the PrP92-SMN mouse model of SMA was utilized, to complement previous studies in which cells of the Enteric Nervous system (ENS) were susceptible to Smn (survival motor neuron) deficiency and could possibly be the basis of the observed GI symptoms. Necropsy of our mouse model showed impairment in feces excretion and smaller bladder mass, compared to Wild-Type (WT) animals. Along with the reduction in bladder mass, we also observed a decrease in the size of smooth muscles, due to reduction in Cross-Sectional Area (CSA). Interstitial cells of Cajal (ICC) provide important regulatory functions in the GI tract. To investigate if ICC are implicated in Smn deficient-induced colonic dysmotility, we assessed ICC distribution and abundance, by c-Kit, a well-established marker. SMA mice exhibited fewer c-Kit positive cells with altered localization, compared to WT. In conclusion, the observed histopathological abnormalities of our mouse model, can be secondary to SMN deficiency and could possibly underlie the GI symptoms observed in SMA patients. Future therapeutic approaches for SMA, must address not only CNS symptoms, but also non-motor-neuron-related symptoms. The PrP92-SMN mouse model could be a useful model for assessing therapeutic rescue of GI dysfunction in SMA.

Changes in Central Motor Conduction Time and Its Implication on Dysfunction of Distal Upper Limb in Distal-Type Cervical Spondylotic Amyotrophy.Publié le 12 04 2019

PURPOSE: Distal-type cervical spondylotic amyotrophy (CSA) is an uncommon syndrome associated with cervical spondylosis. The pathogenic mechanism of distal-type CSA is still unclear. The aim of the current study was to analyze central motor conduction time (CMCT) in the cases with distal-type CSA and to investigate the role of cervical cord compressive injury in the distal-type CSA.
METHODS: Both 28 cases with distal-type CSA and 21 healthy subjects accepted CMCT measures, motor unit number estimation, handgrip strength examination, and magnetic resonance imaging evaluation.
RESULTS: In this study, nine (9/28, 32.1%) cases with CSA presented with prolonged CMCT, and both reduced number of motor units and decreased handgrip strength were found in these 9 cases (P < 0.05). Magnetic resonance imaging evaluation showed that 7 of these 9 patients presented with proximal cervical cord compression with or even without distal selective compression consistent with segmental atrophy. A negative relationship between CMCT and both number of motor units and handgrip strength was found on the symptomatic side (P < 0.05), and there was a positive correlation between CMCT and amplitude of single motor unit potentials on the less symptomatic side (P < 0.05).
CONCLUSIONS: Corticospinal tract damage caused by proximal spinal cord compression may induce distal motor unit loss to worsen in some cases with distal-type CSA, which may contribute to the dysfunction of the distal upper limb in some cases with distal-type CSA. Therefore, treatment and rehabilitation efforts should account for both distal selective compression and proximal cord compression in distal-type CSA.

ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy.Publié le 10 04 2019

AIM: To evaluate the utility of Ability Captured Through Interactive Video Evaluation (ACTIVE) scaled scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) types 2 or 3 due to disease progression or treatment.
METHOD: ACTIVE is a custom-designed video game that measures workspace volume (WSV). Participants included 62 individuals with SMA (mean age [SD] 10y 9mo [5y], range 2y 9mo-24y) and 362 frequency-matched controls (mean age [SD] 10y 9mo [3y 6mo], range 3y 2mo-24y 9mo). Participants completed ACTIVE, other traditional assessments, and patient-reported outcomes. Responsiveness to change was evaluated by comparing longitudinal data on untreated participants to those receiving Spinraza.
RESULTS: ACTIVE was significantly correlated to the Hammersmith Functional Motor Scales Expanded and Revised Upper Limb Module (?=0.85 and ?=0.92 respectively; p<0.001). Relevance to patients and families was established by strong correlations to the Patient Reported Outcomes Measurement Information System self- and parent proxy-measures of upper extremity ability (?=0.63 and ?=0.70 respectively; p<0.001). Responsiveness to change was demonstrated by significant change in scaled scores after treatment (median 15.9 points, Wilcoxon signed-rank test p<0.01). A preliminary minimum clinically important difference is presented.
INTERPRETATION: These results suggest that ACTIVE WSV scores are a meaningful assessment with which to quantify change over time in individuals with SMA types 2 and 3.
WHAT THIS PAPER ADDS: Ability Captured Through Interactive Video Evaluation (ACTIVE) quantifies upper extremity function in spinal muscular atrophy. ACTIVE's scaled workspace volume strongly correlates to self- and parent-report of function. ACTIVE quantifies meaningful change after treatment.

Participation and mental well-being of mothers of home-living patients with spinal muscular atrophy.Publié le 08 04 2019

Proximal spinal muscular atrophy (SMA) causes severe physical limitations but also has a major impact on the lives of parents. The aim of this study was to investigate participation and mental well-being (burden, emotional distress and satisfaction with participation) of parents of home-living patients with SMA. Caregiver burden was assessed with the Caregiver Strain Index, emotional distress with the Hospital Anxiety and Depression Scale and satisfaction with participation with the Utrecht Scale for Evaluation of Rehabilitation-Participation. Because the majority of parents were mothers of home-living SMA patients (76%), further analyses were restricted to mothers. Seventy-seven percent of mothers of patients with SMA had paid work. A substantial proportion of mothers (76%) perceived high caregiver burden. Burden, emotional distress and satisfaction with participation were comparable between mothers of children and mothers of adults with SMA. Caregivers' participation in leisure activities was significantly related to their perceived level of caregiver burden, emotional distress and satisfaction with participation. Mothers engaging in more social and leisure activities reported lower emotional distress and caregiver burden. Considering the high level of burden attention should be paid to mental well-being of primary caregivers of patients with SMA. Caregivers should be motivated to keep participating in social/leisure activities.

Severe ketoacidosis in a patient with spinal muscular atrophy.Publié le 05 04 2019

Spinal muscular atrophy (SMA) is a genetic neuromuscular disease characterized by progressive muscle weakness and atrophy. We report a case of a 36-year-old man with SMA type 3 who presented to our emergency department with epigastric pain and vomiting. He was found to have severe ketoacidosis on laboratory evaluation. The patient's symptoms and ketoacidosis resolved after dextrose infusion and a relatively small amount of sodium bicarbonate infusion. Given the severity of the ketosis that seemed inconsistent with moderate starvation alone, we postulate that there must have been other contributing factors besides moderate starvation that might explain the severity of acidosis in this particular patient. These factors include low muscle mass, disturbed fatty acid metabolism, hormonal imbalances and defective glucose metabolism. Ketoacidosis is an under-recognized entity in patients with neuromuscular diseases and requires a high index of suspicion for prompt diagnosis and management.

Monitoring Kidney Dysfunction in Kugelberg-Welander Syndrome.Publié le 04 04 2019

BACKGROUND Kugelberg-Welander (K-W) syndrome is a type of spinal muscular atrophy that causes weakness of the hip-girdle muscles. If severe enough, this weakness can confine patients to a wheelchair in adult life. Proteinuria, a manifestation of kidney dysfunction, is associated with disorders of many organ systems. The evaluation of kidney function in the context of K-W syndrome is challenging. CASE REPORT A 45-year-old man with K-W syndrome first diagnosed at 5 years of age developed peripheral edema and was found to have proteinuria under 1 g/24 h. His past history was significant for hypertension for 7 years. He was managed conservatively initially, but over the next year the serum creatinine concentration increased from 18 to 32 µmol/L (0.2 to 0.36 mg/dL). A percutaneous kidney biopsy was performed in the fetal position due to an inability of the patient to lay prone or supine. Minimal change disease (MCD) was diagnosed. Treatment consisted of dietary salt restriction, ramipril, amiloride, and hydrochlorothiazide, while avoiding corticosteroids. The serum creatinine concentration initially returned to the 18-20 µmol/L (0.2-0.22 mg/dL) range with increased fluid intake, but then slowly declined to 6 µmol/L (0.07 mg/dL) over the next 14 years. Muscle strength remained poor. CONCLUSIONS K-W syndrome, when associated with proteinuria, presents novel diagnostic and therapeutic challenges to the latter. The serum creatinine concentration may be unhelpful in assessing kidney function in K-W syndrome. A conservative management approach to MCD is reasonable to minimize comorbidity.

An Unusual Cause of Camptocormia.Publié le 04 04 2019

Background: Camptocormia is defined as forward flexion of the spine that manifests during walking and standing and disappears in recumbent position. The various etiologies include idiopathic Parkinson's disease, multiple system atrophy, myopathies, degenerative joint disease, and drugs.
Case Report: A 67-year-old diabetic female presented with bradykinesia and camptocormia that started 1 year prior to presentation. Evaluation revealed levosulpiride, a dopamine receptor blocker commonly used for dyspepsia, to be the culprit.
Discussion: It is well known that dopamine receptor blockers cause parkinsonism and tardive syndromes. We report a rare and unusual presentation of camptocormia attributed to this commonly used gastrointestinal drug in the Asian population.

Scoliosis and spinal muscular atrophy in the new world of medical therapy: providing lumbar access for intrathecal treatment in patients previously treated or undergoing spinal instrumentation and fusion.Publié le 02 04 2019

This study describes a new procedure for a safer and easier access for the intrathecal injection of the recently approved nusinersen therapy in spinal muscular atrophy. This therapy changed the natural history of the disease, but, to date, scoliosis surgery was an excluding criteria for nusinersen therapy. The bone mass, due to the posterior spinal fusion of the scoliosis surgery, prevents the needle for the Nusinersen administration from intervertebral access This is a single-center, single-surgeon case series descriptive study. A laminotomy at the L3-L4 level was performed to provide safer access for the intrathecal injection. The procedure was carried out during the scoliosis surgery in patients who underwent PSF after the nusinersen therapy was introduced, whereas for those who underwent posterior spinal fusion (PSF) earlier, a second procedure was necessary to perform a laminotomy. A fat grafting was used to prevent bone overgrowth in the laminotomy. Markers were applied as radiographic references for the intrathecal injection. Five patients were enrolled, four females and one male. The mean age of the patients was 11 years. Three patients underwent PSF before the introduction of the nusinersen therapy. Two patients underwent PSF after the nusinersen therapy was available. All of them underwent a laminotomy with a fat grafting at the L3-L4 laminotomy level and received nusinersen therapy without complications. The procedure described is simple and effective in providing safe intrathecal access to make these patients eligible for such important therapy.

Identifying Opportunities to Provide Family-centered Care for Families With Children With Type 1 Spinal Muscular Atrophy.Publié le 02 04 2019

STUDY PURPOSE: The purpose of this qualitative study was to understand, from the parent perspective, the experience of the family whose child has Type 1 spinal muscular atrophy (Type 1 SMA), in the emergency center, hospital, and clinical care settings to identify opportunities for improved family-centered care (FCC).
DESIGN AND METHODS: This study used a qualitative descriptive design with individual or small group interviews guided by a semi-structured questionnaire. Reviewers used framework analysis to identify gaps in the provision of FCC and opportunities for improvement with respect to services health professionals may provide families of children with Type 1 SMA.
RESULTS: Nineteen families with 22 children with Type 1 SMA participated. Results are organized according to eight basic tenets of FCC. Family-to-family interactions strongly impacted participants' decision-making and perceived level of support. Participants valued strong family/provider partnerships, feeling heard and respected by their providers, and receiving complete education regarding disease trajectory.
CONCLUSIONS: Our analyses revealed both successful application of FCC and gaps in care where FCC could have been used to benefit families who have children with Type 1 SMA. As a pediatric chronic illness affects the whole family, FCC is important in maintaining the providers' focus on the family during the child's care.
PRACTICE IMPLICATIONS: There are opportunities for nursing, social work, care managers and others to engage as care coordinators to explain the family's goals and values to the medical team. Care coordinators help ensure understanding between families and providers, empowering the family to articulate their hopes and concerns.

NMR solution structure of tricyclo-DNA containing duplexes: insight into enhanced thermal stability and nuclease resistance.Publié le 28 03 2019

Tc-DNA is a conformationally constrained oligonucleotide analogue which shows significant increase in thermal stability when hybridized with RNA, DNA or tc-DNA. Remarkably, recent studies revealed that tc-DNA antisense oligonucleotides (AO) hold great promise for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. To date, no high-resolution structural data is available for fully modified tc-DNA duplexes and little is known about the origins of their enhanced thermal stability. Here, we report the structures of a fully modified tc-DNA oligonucleotide paired with either complementary RNA, DNA or tc-DNA. All three investigated duplexes maintain a right-handed helical structure with Watson-Crick base pairing and overall geometry intermediate between A- and B-type, but closer to A-type structures. All sugars of the tc-DNA and RNA residues adopt a North conformation whereas the DNA deoxyribose are found in a South-East-North conformation equilibrium. The conformation of the tc-DNA strand in the three determined structures is nearly identical and despite the different nature and local geometry of the complementary strand, the overall structures of the examined duplexes are very similar suggesting that the tc-DNA strand dominates the duplex structure.

Drug screening with human SMN2 reporter identifies SMN protein stabilizers to correct SMA pathology.Publié le 27 03 2019

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by reduced levels of functional survival motor neuron (SMN) protein. To identify therapeutic agents for SMA, we established a versatile SMN2-GFP reporter line by targeting the human SMN2 gene. We then screened a compound library and identified Z-FA-FMK as a potent candidate. Z-FA-FMK, a cysteine protease inhibitor, increased functional SMN through inhibiting the protease-mediated degradation of both full-length and exon 7-deleted forms of SMN. Further studies reveal that CAPN1, CAPN7, CTSB, and CTSL mediate the degradation of SMN proteins, providing novel targets for SMA. Notably, Z-FA-FMK mitigated mitochondriopathy and neuropathy in SMA patient-derived motor neurons and showed protective effects in SMA animal model after intracerebroventricular injection. E64d, another cysteine protease inhibitor which can pass through the blood-brain barrier, showed even more potent therapeutic effects after subcutaneous delivery to SMA mice. Taken together, we have successfully established a human SMN2 reporter for future drug discovery and identified the potential therapeutic value of cysteine protease inhibitors in treating SMA via stabilizing SMN proteins.

Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy.Publié le 25 03 2019

BACKGROUND: Advances in treatment for Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) hold promise for children with these disorders. Accurate genetic diagnosis, early in the disease process, will allow these treatments to be most effective. Newborn screening (NBS) for SMA has been recommended in the United States, and a pilot DMD NBS program is underway in Hangzhou, China.
DATA SOURCES: A PubMed search, limited to the past 5 years, was conducted to identify: (1) therapeutic advancements for DMD/SMA approved by the United States Food and Drug Administration or the European Medicine Agency and (2) The status of NBS for DMD/SMA.
RESULTS: We review the current state of approved treatments for DMD/SMA. We present recommendations regarding the future of NBS for these diseases, with a focus on the outcomes and challenges of SMA NBS in New York, USA, and the DMD NBS pilot program in Hangzhou, China.
CONCLUSIONS: Approved treatments for DMD and SMA may change the natural history of these diseases. Long-term studies of these treatments are underway. To avoid the known diagnostic delay associated with these disorders and provide optimal effectiveness of these treatments, early identification of patients through NBS will be necessary. Establishing comprehensive follow-up plans for positively identified patients will need to be in place for NBS programs to be successful.

Enhancing GABAergic Transmission Improves Locomotion in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.Publié le 22 03 2019

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of spinal motor neurons resulting in variable degrees of muscular wasting and weakness. It is caused by a loss-of-function mutation in the survival motor neuron (SMN1) gene. Caenorhabditis elegans mutants lacking SMN recapitulate several aspects of the disease including impaired movement and shorted life span. We examined whether genes previously implicated in life span extension conferred benefits to C. elegans lacking SMN. We find that reducing daf-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this C. elegans model of SMA. The locomotor dysfunction in C. elegans lacking SMN correlated with structural and functional abnormalities in GABAergic neuromuscular junctions (NMJs). Moreover, we demonstrated that reduction in daf-2 signaling reversed these abnormalities. Remarkably, enhancing GABAergic neurotransmission alone was able to correct the locomotor dysfunction. Our work indicated that an imbalance of excitatory/inhibitory activity within motor circuits and underlies motor system dysfunction in this SMA model. Interventions aimed at restoring the balance of excitatory/inhibitory activity in motor circuits could be of benefit to individuals with SMA.

Amyotrophic lateral sclerosis of long clinical course clinically presenting with progressive muscular atrophy.Publié le 22 03 2019

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.

Physicians' attitudes when faced with life-threatening events in children with severe neurological disabilities.Publié le 22 03 2019

PURPOSE: Children with severe neurological disabilities are at an increased risk of acute, life-threatening events. We assessed physicians' attitudes when making decisions in these situations.
METHODS: We surveyed physicians in pediatric intensive care, neurology, and rehabilitation units in Swiss hospitals. The questionnaire explored participants' attitudes toward life-threatening situations in two scenarios: a child with profound intellectual and multiple disabilities (PIMD) and an infant with spinal muscular atrophy (SMA) type I.
RESULTS: The participation rate was 55% (52/95). There was a consensus favoring non-invasive ventilation and comfort care as well as avoiding tracheostomy and invasive ventilation. For the child with PIMD, 61% of participants opposed cardiopulmonary resuscitation (CPR), 51% for the child with SMA. Physicians with over 20 years of experience were significantly more opposed to providing CPR than less experienced colleagues.
CONCLUSIONS: Physicians held different views, influenced by personal factors. This highlights the importance of standardizing multidisciplinary processes toward approaching these complex situations.

Antisense oligonucleotides selectively suppress target RNA in nociceptive neurons of the pain system and can ameliorate mechanical pain.Publié le 22 03 2019

There is an urgent need for better treatments for chronic pain, which affects more than 1 billion people worldwide. Antisense oligonucleotides (ASOs) have proven successful in treating children with spinal muscular atrophy, a severe infantile neurological disorder, and several ASOs are currently being tested in clinical trials for various neurological disorders. Here, we characterize the pharmacodynamic activity of ASOs in spinal cord and dorsal root ganglia (DRG), key tissues for pain signaling. We demonstrate that activity of ASOs lasts up to 2 months after a single intrathecal bolus dose. Interestingly, comparison of subcutaneous, intracerebroventricular, and intrathecal administration shows that DRGs are targetable by systemic and central delivery of ASOs, while target reduction in the spinal cord is achieved only after direct central delivery. Upon detailed characterization of ASO activity in individual cell populations in DRG, we observe robust target suppression in all neuronal populations, thereby establishing that ASOs are effective in the cell populations involved in pain propagation. Furthermore, we confirm that ASOs are selective and do not modulate basal pain sensation. We also demonstrate that ASOs targeting the sodium channel Nav1.7 induce sustained analgesia up to 4 weeks. Taken together, our findings support the idea that ASOs possess the required pharmacodynamic properties, along with a long duration of action beneficial for treating pain.

Is there hope for spinal muscular atrophy synthetic pharmacotherapy?Publié le 21 03 2019

PMID: 30892979 [PubMed - as supplied by publisher]

Exercise biology of neuromuscular disorders.Publié le 21 03 2019

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.

Plecanatide, Nusinersen, and Obeticholic acid.Publié le 21 03 2019

PMID: 28506401 [PubMed - indexed for MEDLINE]

Rewriting the (tran)script: Application to spinal muscular atrophy.Publié le 19 03 2019

Targeting RNA drastically expands our target space to therapeutically modulate numerous cellular processes implicated in human diseases. Of particular interest, drugging pre-mRNA splicing appears a very viable strategy; to control levels of splicing product by promoting the inclusion or exclusion of exons. After describing the concept of "splicing modulation", this chapter will cover the outstanding progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of spinal muscular atrophy using two therapeutic modalities: splice switching oligonucleotides and small molecules. This review discusses the vital but feasible requirement for such drugs to deliver selectivity, and critical safety aspects are highlighted. Transformational medicines such as those developed to treat SMA are likely just the beginning of this story.

Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1.Publié le 18 03 2019

INTRODUCTION: Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1.
METHODS: Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of???4 points in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches.
RESULTS: Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI)?=?4.1-12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR)?=?1.2, 95% CI?1.1-1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI?2.0-3.6) and RR was 1.6 (95% CI?1.4-1.9). For improvement in motor function, NNT was 3.5 (95% CI?2.6-5.3) and RR was 1.4 (95% CI?1.2-1.6). For milestone achievements, the NNTs were 1.4 (95% CI?1.1-1.9), 1.5 (95% CI?1.1-2.5), and 1.2 (95% CI?1.0-1.5); RRs 4.2 (95% CI?2.6-6.7), 7.8 (95% CI?3.6-17.0), and 11.2 (95% CI?5.1-24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach.
CONCLUSION: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones.

Systemic nature of spinal muscular atrophy revealed by studying insurance claims.Publié le 15 03 2019

OBJECTIVE: We investigated the presence of non-neuromuscular phenotypes in patients affected by Spinal Muscular Atrophy (SMA), a disorder caused by a mutation in the Survival of Motor Neuron (SMN) gene, and whether these phenotypes may be clinically detectable prior to clinical signs of neuromuscular degeneration and therefore independent of muscle weakness.
METHODS: We utilized a de-identified database of insurance claims to explore the health of 1,038 SMA patients compared to controls. Two analyses were performed: (1) claims from the entire insurance coverage window; and (2) for SMA patients, claims prior to diagnosis of any neuromuscular disease or evidence of major neuromuscular degeneration to increase the chance that phenotypes could be attributed directly to reduced SMN levels. Logistic regression was used to determine whether phenotypes were diagnosed at significantly different rates between SMA patients and controls and to obtain covariate-adjusted odds ratios.
RESULTS: Results from the entire coverage window revealed a broad spectrum of phenotypes that are differentially diagnosed in SMA subjects compared to controls. Moreover, data from SMA patients prior to their first clinical signs of neuromuscular degeneration revealed numerous non-neuromuscular phenotypes including defects within the cardiovascular, gastrointestinal, metabolic, reproductive, and skeletal systems. Furthermore, our data provide evidence of a potential ordering of disease progression beginning with these non-neuromuscular phenotypes.
CONCLUSIONS: Our data point to a direct relationship between early, detectable non-neuromuscular symptoms and SMN deficiency. Our findings are particularly important for evaluating the efficacy of SMN-increasing therapies for SMA, comparing the effectiveness of local versus systemically delivered therapeutics, and determining the optimal therapeutic treatment window prior to irreversible neuromuscular damage.

Neurocalcin Delta Knockout Impairs Adult Neurogenesis Whereas Half Reduction Is Not Pathological.Publié le 12 03 2019

Neurocalcin delta (NCALD) is a brain-enriched neuronal calcium sensor and its reduction acts protective against spinal muscular atrophy (SMA). However, the physiological function of NCALD and implications of NCALD reduction are still elusive. Here, we analyzed the ubiquitous Ncald knockout in homozygous (Ncald KO/KO) and heterozygous (Ncald KO/WT) mice to unravel the physiological role of NCALD in the brain and to study whether 50% NCALD reduction is a safe option for SMA therapy. We found that Ncald KO/KO but not Ncald KO/WT mice exhibit significant changes in the hippocampal morphology, likely due to impaired generation and migration of newborn neurons in the dentate gyrus (DG). To understand the mechanism behind, we studied the NCALD interactome and identified mitogen-activated protein kinase kinase kinase 10 (MAP3K10) as a novel NCALD interacting partner. MAP3K10 is an upstream activating kinase of c-Jun N-terminal kinase (JNK), which regulates adult neurogenesis. Strikingly, the JNK activation was significantly upregulated in the Ncald KO/KO brains. Contrary, neither adult neurogenesis nor JNK activation were altered by heterozygous Ncald deletion. Taken together, our study identifies a novel link between NCALD and adult neurogenesis in the hippocampus, possibly via a MAP3K10-JNK pathway and emphasizes the safety of using NCALD reduction as a therapeutic option for SMA.

Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems.Publié le 08 03 2019

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons and muscle atrophy. The disease is mainly caused by low level of the survival motor neuron (SMN) protein, which is coded by two genes, namely SMN1 and SMN2, but leads to selective spinal motor neuron degeneration when SMN1 gene is deleted or mutated. Previous reports have shown that SMN-protein-deficient astrocytes are abnormally abundant in the spinal cords of SMA model mice. However, the mechanism of the SMN- deficient astrocyte abnormality remains unclear. The purpose of this study is to identify the cellular signaling pathways associated with the SMN-deficient astrocyte abnormality and propose a candidate therapy tool that modulates signaling. In the present study, we found that the astrocyte density was increased around the central canal of the spinal cord in a mouse SMA model and we identified the dysregulation of Notch signaling which is a known mechanism that regulates astrocyte differentiation and proliferation, in the spinal cord in both early and late stages of SMA pathogenesis. Moreover, pharmacological inhibition of Notch signaling improved the motor functional deficits in SMA model mice. These findings indicate that dysregulated Notch signaling may be an underlying cause of SMA pathology.

Effect of new modalities of treatment on physicians management plan for patients with spinal muscular atrophy.Publié le 08 03 2019

OBJECTIVE: To determine physicians` attitudes and stated practice in the management of patients with spinal muscular atrophy (SMA). We also aimed to explore their knowledge about consensus statement for standard of care in SMA and the role of new treatment modalities in changing the method of practice in the management of these cases.
METHODS: This is a quantitative observational cross-sectional study, conducted from February to May 2017 among physicians who manage SMA patients in Kingdom of Saudi Arabia. The study cohort included pediatric neurologists, adult neurologists, and physicians of other sub-specialties who manage SMA patients. We used online and paper-based questionnaires.
RESULTS: Half of the 169 participants were aware of the consensus guidelines for the care of SMA patients. With regard to the newly released Nursinersen treatment protocol for SMA-diagnosed patients, half of the participants were uncertain, and the other half were hesitant about its outcomes. Junior physicians tended to be significantly more inclined to reverse the do-not-resuscitate (DNR) status of an SMA-diagnosed child than more senior physicians.
CONCLUSION: Our results indicate the existence of wide differences in physician practice with children of SMA disease. Our data demonstrate a need for increased awareness of consensus guidelines and further awareness about the physician`s role in the variability of care for children with SMA.

The New Paradigms in Clinical Research: From Early Access Programs to the Novel Therapeutic Approaches for Unmet Medical Needs.Publié le 01 03 2019

Despite several innovative medicines gaining worldwide approval in recent years, there are still therapeutic areas for which unsatisfied therapeutic needs persist. For example, high unmet clinical need was observed in patients diagnosed with type 2 diabetes mellitus and hemophilia, as well as in specific age groups, such as the pediatric population. Given the urgent need to improve the therapy of clinical conditions for which unmet clinical need is established, clinical testing, and approval of new medicines are increasingly being carried out through accelerated authorization procedures. Starting from 1992, the Food and Drug Administration and the European Medicines Agency have supported the so-called Early Access Programs (EAPs). Such procedures, which can be based on incomplete clinical data, allow an accelerated marketing authorization for innovative medicines. The growth in pharmaceutical research has also resulted in the development of novel therapeutic approaches, such as biotech drugs and advanced therapy medicinal products, including new monoclonal antibodies for the treatment of asthma, antisense oligonucleotides for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy, and new anticancer drugs that act on genetic biomarkers rather than any specific type of cancer. Even though EAPs and novel therapeutic approaches have brought huge benefits for public health, their implementation is limited by several challenges, including the high risk of safety-related label changes for medicines authorized through the accelerated procedure, the high costs, and the reimbursement and access concerns. In this context, regulatory agencies should provide the best conditions for the implementation of the described new tools.

Resolution of skin necrosis after nusinersen treatment in an infant with spinal muscular atrophy.Publié le 28 02 2019

PMID: 30811610 [PubMed - as supplied by publisher]

Development, Implementation, and Use of a Neurology Therapeutics Committee.Publié le 26 02 2019

Innovative therapeutics are transforming care of children with previously untreatable neurological disorders. However, there are challenges in the use of new therapies: the medicine may not be effective in all patients, administration may not be tolerated, and matching therapy choice to patient is complex. Finally, costs are high, which imposes financial burdens on insurance companies, families, and the health-care system. Our objective was to address challenges for clinical implementation of the new therapeutics. We sought to develop a process that would be personalized for patient and disease, encourage appropriate use of a therapeutic agent while mitigating pressure on a clinician to prescribe the therapy in all instances, and assist third-party payers in approving therapeutic use based on safety and efficacy. We report our creation of a Neurology Therapeutics Committee for pediatric patients. We review the committee's mechanisms, describe its use and report outcomes, and suggest the Neurology Therapeutics Committee's broader applicability.

Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis.Publié le 24 02 2019

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder classified into four types based on the age of onset of the disease. Early onset is correlated with a higher mortality rate, mainly due to respiratory complications. Valproic acid (VPA) is a histone deacetylase (HDAC) inhibitor that has shown positive results on SMA both in experimental and cohort studies.
OBJECTIVES: This systematic review and meta-analysis aimed to investigate the efficacy and safety of VPA in patients with SMA.
METHODS: Eleven databases were systematically searched on 30 May 2017 for clinical trials that reported the efficacy and safety of VPA in SMA patients. The primary outcome was the efficacy of VPA in terms of gross motor function and expression of both full-length spinal motor neuron (SMN) gene (FL-SMN) and exon 7-lacking SMN. The secondary outcome was the safety of VPA in terms of reported adverse effects. The protocol was registered at PROSPERO (CRD42017067203).
RESULTS: Five of the ten included studies were used in the meta-analysis (n?=?126). The overall effect estimate, comparing pre- and post-VPA treatment, regardless of carnitine co-administration and design of the studies, showed significant improvement in gross motor function (standard mean difference [SMD]?=?0.302, 95% confidence interval [CI] 0.048-0.556, P?=?0.02) using the Hammersmith Functional Motor Scale (HFMS), Modified Hammersmith Functional Motor Scale (MHFMS), and MHFMS-Extend, with no significant heterogeneity. Similarly, in non-randomized controlled studies, the results indicated that there was a significant improvement detected (SMD?=?0.335, 95% CI 0.041-0.628, P?=?0.025), with no significant heterogeneity. Meanwhile, our results suggest that there was no significant improvement in treatment with co-administered carnitine (SMD?=?0.28, 95% CI -?0.02 to 0.581, P?=?0.067). No significant differences were found between pre- and post-VPA treatment co-administered with carnitine, in terms of the change in FL-SMN and exon 7-lacking SMN. Qualitative synthesis showed that other motor functions were not improved, while respiratory function test results were contradictory. Regarding the safety of the treatment, a double-blind, randomized, placebo-controlled trial reported no statistically significant differences for adverse events (AEs) between groups. Moreover, most of the included studies reported no serious AEs related to VPA use, although weight gain, gastrointestinal symptoms and respiratory symptoms were notable problems.
CONCLUSIONS: Our study suggests that VPA treatment results in an improvement in gross motor functions for SMA patients, but not in other assessments of motor function or, possibly, in respiratory function. Furthermore, VPA appears to be a relatively safe drug, although treatment may be associated with a wide range of AEs (including body weight increase, fatigue, fever, flu-like symptoms, irritability, and pain). Double-blind, randomized, controlled trials are required to confirm these findings.

Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development.Publié le 23 02 2019

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are the two most common motoneuron disorders, which share typical pathological hallmarks while remaining genetically distinct. Indeed, SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene whilst ALS, albeit being mostly sporadic, can also be caused by mutations within genes, including superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS), TAR DNA-binding protein 43 (TDP-43) and chromosome 9 open reading frame 72 (C9ORF72). However, it has come to light that these two diseases may be more interlinked than previously thought. Indeed, it has recently been found that FUS directly interacts with an Smn-containing complex, mutant SOD1 perturbs Smn localization, Smn depletion aggravates disease progression of ALS mice, overexpression of SMN in ALS mice significantly improves their phenotype and lifespan, and duplications of SMN1 have been linked to sporadic ALS. Beyond genetic interactions, accumulating evidence further suggests that both diseases share common pathological identities such as intrinsic muscle defects, neuroinflammation, immune organ dysfunction, metabolic perturbations, defects in neuron excitability and selective motoneuron vulnerability. Identifying common molecular effectors that mediate shared pathologies in SMA and ALS would allow for the development of therapeutic strategies and targeted gene therapies that could potentially alleviate symptoms and be equally beneficial in both disorders. In the present review, we will examine our current knowledge of pathogenic commonalities between SMA and ALS, and discuss how furthering this understanding can lead to the establishment of novel therapeutic approaches with wide-reaching impact on multiple motoneuron diseases.

Value-Based Pricing for Emerging Gene Therapies: The Economic Case for a Higher Cost-Effectiveness Threshold.Publié le 21 02 2019

While one-time gene replacement therapies may offer transformative innovation for the management of ultrarare, health-catastrophic diseases, they also pose challenges to the current U.S. health care system. Historically, the United States and other countries have demonstrated a willingness to support higher prices for health gains in rare diseases. However, payers may be ill-prepared to address reimbursement based on single administrations associated with gene therapies. As yet, there is no consensus on how to appropriately reward gene therapy innovation. The purpose of this article is to characterize challenges for traditional approaches to assessing the value of one-time gene replacement therapies and to provide a health economic rationale for a higher value-based cost-effectiveness threshold (CET). There is a general recognition that ultrarare, health-catastrophic conditions should be judged against a higher CET. The Institute for Clinical and Economic Review in the United States has discussed a range of up to $500K per quality-adjusted life-year (QALY) gained for ultrarare diseases, and the National Institute for Health and Care Excellence in the United Kingdom has described a variable threshold up to £300,000 per QALY depending on the magnitude of the health gains. In practice, health technology assessment decision makers often make comparisons to "benchmarks" to justify both standard and extraordinary CETs. We briefly review and present a list of relevant benchmarks. We also sketch out how a broader concept of value could provide the basis for higher CETs for some ultrarare diseases. This approach is outlined by the recent International Society for Pharmacoeconomics and Outcomes Research Special Task Force on Value Assessment Frameworks. In addition to the QALY gains, other elements of value related to uncertainty may also be important. They include insurance value, severity of disease, real option value, value of hope, and equity. A gene therapy currently in development for the treatment of spinal muscular atrophy (SMA) provides an exemplar for discussing the issues that accompany one-time gene replacement therapies. It is imperative that we find a consensus on how to appropriately reward value created by these gene therapies to incentivize appropriate risk taking and investments by their developers-a higher CET would, by economic logic, support a higher value-based price. If consensus on appropriate rewards cannot be found for safe and effective gene therapies for diseases such as SMA with clear criticality and unmet need, it will be even more difficult to do so for diseases where the value provided is less apparent. DISCLOSURES: Funding for the writing of this article was provided by AveXis Pharmaceuticals, which reviewed the manuscript and contributed feedback during manuscript development. The authors had final editorial control. Jackson and Paul are employees of MME, a biopharmaceutical consulting firm that received funding from AveXis for work on this project. Jackson and Paul report consulting fees from AveXis and numerous other biopharmaceutical companies outside of this project. Garrison reports consulting fees from AveXis for work on this project and advisory/consultancy fees from BioMarin, Roche, Novartis, and Pfizer unrelated to this project. Kenston is a former employee of AveXis and reports consulting fees from AveXis for this project and for other projects outside of this work.

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.Publié le 19 02 2019

PURPOSE: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system.
METHODS: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced.
RESULTS: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER?=?AUD$22/DALY).
CONCLUSION: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases.Publié le 15 02 2019

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Making sense of antisense oligonucleotides: A narrative review.Publié le 13 02 2019

Synthetic nucleic acid sequences that bind to ribonucleic acid (RNA) through Watson-Crick base pairing are known as antisense oligonucleotides (ASOs) because they are complementary to "sense strand" nucleic acids. ASOs bind to selected sequences of RNA and regulate the expression of genes by several mechanisms depending on their chemical properties and targets. They can be used to restore deficient protein expression, reduce the expression of a toxic protein, modify functional effects of proteins, or reduce toxicity of mutant proteins. Two ASOs were approved by the U.S. Food and Drug Administration in 2016: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy. Clinical trials in amyotrophic lateral sclerosis and familial amyloid polyneuropathy are ongoing. We review the chemistry, pharmacology, and mechanisms of action of ASOs, preclinical data, and clinical trials in neuromuscular diseases and discuss some ethical, regulatory, and policy considerations in the clinical development and use of ASOs. Muscle Nerve 57: 356-370, 2018.

Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy.Publié le 09 02 2019

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that causes progressive muscle weakness and is the leading genetic cause of infant mortality worldwide. SMA is caused by the loss of survival motor neuron 1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. Although SMN2 maintains the same coding sequence, this gene cannot compensate for the loss of SMN1 because of a single silent nucleotide difference in SMN2 exon 7. SMN2 primarily produces an alternatively spliced isoform lacking exon 7, which is critical for protein function. SMN2 is an important disease modifier that makes for an excellent target for therapeutic intervention because all SMA patients retain SMN2. Therefore, compounds and small molecules that can increase SMN2 exon 7 inclusion, transcription and SMN protein stability have great potential for SMA therapeutics. Previously, we performed a high throughput screen and established a class of compounds that increase SMN protein in various cellular contexts. In this study, a novel compound was identified that increased SMN protein levels in vivo and ameliorated the disease phenotype in severe and intermediate mouse models of SMA.

Technological advances and changing indications for lumbar puncture in neurological disorders.Publié le 09 02 2019

Technological advances have changed the indications for and the way in which lumbar puncture is done. Suspected CNS infection remains the most common indication for lumbar puncture, but new molecular techniques have broadened CSF analysis indications, such as the determination of neuronal autoantibodies in autoimmune encephalitis. New screening techniques have increased sensitvity for pathogen detection and can be used to identify pathogens that were previously unknown to cause CNS infections. Evidence suggests that potential treatments for neurodegenerative diseases, such as Alzheimer's disease, will rely on early detection of the disease with the use of CSF biomarkers. In addition to being used as a diagnostic tool, lumbar puncture can also be used to administer intrathecal treatments as shown by studies of antisense oligonucleotides in patients with spinal muscular atrophy. Lumbar puncture is generally a safe procedure but complications can occur, ranging from minor (eg, back pain) to potentially devastating (eg, cerebral herniation). Evidence that an atraumatic needle tip design reduces complications of lumbar puncture is compelling, and reinforces the need to change clinical practice.

[Respiratory care in spinal muscular atrophy in the new therapeutic era].Publié le 07 02 2019

Spinal muscular atrophy (SMA) is the first inherited cause of mortality in infants, with four subtypes: SMA0 prenatal onset, SMA1 babies less than 3 months non sitters, SMA2 sitters and SMA3 walkers. Pneumonia and respiratory insufficiency are the most severe complications. Informed parental de cisions are relevant. Respiratory management includes cough assistance, prevention of lung under development due to chest deformity, prompt treatment of respiratory infections, hypoventilation, swallow problems, gastro esophageal reflux and malnutrition. In view of the FDA and EMA approval of the nonsense oligonucleotides nusinersen, the first specific treatment for SMA and the future with gene therapy and others under development, we need to optimize preventive respiratory manage ment with the new standard of care.

Transspinal delivery of drugs by transdermal patch back-of-neck for Alzheimer's disease: a new route of administration.Publié le 06 02 2019

NSAIDs may prevent Alzheimer's disease (AD) but have failed as a treatment, possibly because only 1-2% of an oral NSAID dose reaches the brain. This minuscule dose is enough to have a preventative effect on Alzheimer's disease but not to treat it. We propose a new route of administration for drugs to treat AD: transspinal delivery by transdermal patch over the back-of-neck/cervical spine. The drug would diffuse from the patch through the intervertebral spaces, penetrate the dura, enter the CSF, and reach the brain. For example, diclofenac from a transdermal patch over the back of neck should readily penetrate the dura mater to reach the CSF and brain; since the analgesic ziconotide, and antisense molecules for treating spinal muscular atrophy in children and Huntington's disease, are delivered intrathecally and readily enter the brain. In addition to NSAIDs, an anticancer drug, paclitaxel, has considerable potential as an AD treatment. Paclitaxel is administered IV. But the blood-brain penetration of paclitaxel is poor and paclitaxel has systemic side effects such as anemia, leukopenia, peripheral neuropathy, etc. A high dose of paclitaxel might be administered to the brain by transdermal patch over the back of the neck/cervical spine while avoiding the systemic side effects. A transdermal patch over the cervical spine could revolutionize the drug therapy of AD, and probably other neurodegenerative/neuropsychiatric diseases as well.

Cost Effectiveness of Nusinersen in the Treatment of Patients with Infantile-Onset and Later-Onset Spinal Muscular Atrophy in Sweden.Publié le 05 02 2019

BACKGROUND: Spinal muscular atrophy is a rare neuromuscular disorder with a spectrum of severity related to age at onset and the number of SMN2 gene copies. Infantile-onset (? 6 months of age) is the most severe spinal muscular atrophy and is the leading monogenetic cause of infant mortality; patients with later-onset (> 6 months of age) spinal muscular atrophy can survive into adulthood. Nusinersen is a new treatment for spinal muscular atrophy.
OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of nusinersen for the treatment of patients with infantile-onset spinal muscular atrophy and later-onset spinal muscular atrophy in Sweden.
METHODS: One Markov cohort health-state transition model was developed for each population. The infantile-onset and later-onset models were based on the efficacy results from the ENDEAR phase III trial and the CHERISH phase III trial, respectively. The cost effectiveness of nusinersen in both models was compared with standard of care in Sweden.
RESULTS: For a time horizon of 40 years in the infantile-onset model and 80 years in the later-onset model, treatment with nusinersen resulted in 3.86 and 9.54 patient incremental quality-adjusted life-years and 0.02 and 2.39 caregiver incremental quality-adjusted life-years and an incremental cost of 21.9 and 38.0 million SEK (Swedish krona), respectively. These results translated into incremental cost-effectiveness ratios (including caregiver quality-adjusted life-years) of 5.64 million SEK (€551,300) and 3.19 million SEK (€311,800) per quality-adjusted life-year gained in the infantile-onset model and later-onset model, respectively.
CONCLUSIONS: Treatment with nusinersen resulted in overall survival and quality-adjusted life-year benefits but with incremental costs above 21 million SEK (€2 million) [mainly associated with maintenance treatment with nusinersen over a patient's lifespan]. Nusinersen was not cost effective when using a willingness-to-pay threshold of 2 million SEK (€195,600), which has been considered in a recent discussion by the Dental and Pharmaceutical Benefits Agency as a reasonable threshold for rare disease. Nonetheless, nusinersen gained reimbursement in Sweden in 2017 for paediatric patients (below 18 years old) with spinal muscular atrophy type I-IIIa.

Psychological well-being in adults with spinal muscular atrophy: the contribution of participation and psychological needs.Publié le 01 02 2019

PURPOSE: Patients with spinal muscular atrophy (SMA) suffer from slowly progressive weakness of axial, respiratory and proximal muscles, leading to restrictions in activity and participation. This study aims to investigate patients' level of psychological well-being, using the International Classification of Functioning model and self-determination theory as theoretical frameworks.
MATERIALS AND METHODS: In this cross-sectional study, adults with SMA were invited to complete a questionnaire. Instruments to assess psychological well-being included the Satisfaction with Life Scale, the Rosenberg Self-Esteem Scale and the Positive and Negative Affect Scale. Hierarchical lineal regression analyses were performed to investigate the contribution of participation (International Classification of Functioning model) and satisfaction of the need for autonomy, competence and relatedness (self-determination theory) to well-being.
RESULTS: Ninety-two respondents (67%) returned the questionnaire. Levels of psychological well-being were comparable to that of healthy reference samples. Well-being was unrelated to sociodemographic variables or illness characteristics. By contrast, well-being was closely related to respondents' satisfaction with participation, and their sense of autonomy, competence and relatedness.
CONCLUSIONS: This study illustrates the relevance of psychological needs for understanding well-being of individuals with SMA. Supporting patients in meeting their psychological needs should become an objective of person-centred care for this population. Implications for rehabilitation Spinal muscular atrophy is a rare inherited disease, characterized by slowly progressive muscle weakness. Psychological well-being, including satisfaction with life, self-esteem and emotional functioning of adults with spinal muscular atrophy appears very comparable with that of healthy reference samples. In line with the International Classification of Functioning framework, well-being in adults with spinal muscular atrophy may be improved by increasing their (satisfaction with) participation. Moreover, clinical assessment and management should focus on optimizing patients' satisfaction with their basic psychological needs (autonomy, competence, relatedness), as this is strongly related to indices of psychological well-being.

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy.Publié le 30 01 2019

PMID: 28794153 [PubMed - indexed for MEDLINE]

Rebuttal From Dr Panitch.Publié le 29 01 2019

PMID: 27989615 [PubMed - indexed for MEDLINE]

Rebuttal From Dr Bach.Publié le 29 01 2019

PMID: 27989613 [PubMed - indexed for MEDLINE]

Revised Upper Limb Module for Spinal Muscular Atrophy: 12 month changes.Publié le 25 01 2019

INTRODUCTION: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3.
METHODS: Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module.
RESULTS: The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p=0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients.
DISCUSSION: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. This article is protected by copyright. All rights reserved.

SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy.Publié le 23 01 2019

BACKGROUND: Survival and quality of life for patients affected by spinal muscular atrophy (SMA) are thought to have improved over the last decade due to changes in care. In addition, targeted treatments for SMA have been developed based on a better understanding of the molecular pathology. In 2016 and 2017, nusinersen was the first drug to be approved for treatment of all types of SMA in the United States and in Europe based on well-controlled clinical trials in a small subgroup of pediatric SMA patients. Systems are required to monitor treated and untreated SMA patients in a real-life environment to optimize treatment and care, and to provide outcome data to regulators, payers, and the SMA community.
METHODS: Within SMArtCARE, we conduct a prospective, multicenter non-randomized registration and outcome study. SMArtCARE collects longitudinal data on all available SMA patients independent of their actual treatment regime as disease-specific SMA registry. For this purpose, we provide an online platform for SMA patients seen by health-care providers in Germany, Austria and Switzerland. All data are collected during routine patient visits. Items for data collection are aligned with the international consensus for SMA registries. Data analysis is carried out independent of commercial partners.
CONCLUSION: A prospective monitoring of all SMA patients will lead to a better understanding of the natural history of SMA and the influence of drug treatment. This is crucial to improve the care of SMA patients. Further, we will establish a network for neuromuscular centers to share experience with SMA patients and to promote research projects on SMA.
TRIAL REGISTRATION: German Clinical Trials Register ("Deutsches Register klinischer Studien") DRKS00012699. Registered 09 August 2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012699 .

Novel challenges in spinal muscular atrophy - How to screen and whom to treat?Publié le 19 01 2019

In recent years, disease-modifying and life-prolonging therapies for spinal muscular atrophy (SMA) have been developed. However, patients are currently diagnosed with significant delay and therapies are often administered in advanced stages of motor neuron degeneration, showing limited effects. Methods to identify children in presymptomatic stages are currently evaluated in newborn screening programs. Yet, not all children develop symptoms shortly after birth raising the question whom to treat and when to initiate therapy. Finally, monitoring disease progression becomes essential to individualize management. Here, we review the literature on screening approaches, strategies to predict disease severity, and biomarkers to monitor therapy.

Parents' Experiences of Information and Decision Making in the Care of Their Child With Severe Spinal Muscular Atrophy: A Population Survey.Publié le 16 01 2019

OBJECTIVE:: This study aims to assess the experiences and wishes of parents of children with severe spinal muscular atrophy regarding information and decision-making throughout the course of the illness.
STUDY DESIGN:: A full population survey, conducted in 2015, among parents of children with severe spinal muscular atrophy who were born in Denmark between January 1, 2003, and December 31, 2013. We used a study-specific questionnaire with items about experiences and wishes concerning the provision of information about diagnosis, treatment, and end-of-life care.
RESULTS:: Among the 47 parents that were identified, 34 parents of 21 children participated. Eleven of them were nonbereaved and 23 were bereaved parents. All parents stated that health care staff did not take any decisions without informing them. A proportion of parents indicated that they were not informed about what spinal muscular atrophy entails (32%), possible treatment options (18%), or the fact that their child would have a short life (26%) or that death was imminent (57%). Most of the bereaved parents who had wishes concerning how and where their child would pass away had their wishes fulfilled.
CONCLUSIONS:: The study showed that health care staff did not take treatment decisions without parents being informed. However, there is room for improvement concerning information about what spinal muscular atrophy entails, treatment options, and prognosis. Possibilities of palliative care and advance care planning should be investigated for these parents, their child, and health care staff.

[S2 Alar-Iliac Screws in Fixation and Correction of Combined Neuromuscular Spinal and Pelvic Deformities].Publié le 15 01 2019

PURPOSE OF THE STUDY Neuromuscular deformities of the spine represent surgically uneasy to solve problems as well as serious handicaps causing sitting instability, pressure ulcers as well as pain. The aim of our study is to conduct a retrospective clinical analysis of the results of surgical correction of these deformities. This paper presents the use of a recent technique of sacral-alar-iliac (S2AI) screws and its comparison with other techniques of pelvic stabilisation. MATERIAL AND METHODS The group of 41 patients treated surgically with S2AI screws technique and transpedicular or hybrid instrumentation of the spine consisted of patients with the primary diagnosis of muscular dysthrophy, spinal muscular atrophy, cerebral palsy and some other neuromuscular diseases. The results of pelvic obliquity correction and scoliotic correction in combined neuromuscular deformities of the spine and pelvis were analysed. The technique of S2AI screws implantation and the possibility of their free-hand technique implementation were presented. RESULTS In the followed-up group of patients an average correction of pelvic obliquity by 81% (from 29.1 degrees before the operation to 5.6 degrees after the operation) was reported. On average, 74% correction of scoliotic spine deformity was achieved (from 83.3 degrees before the operation to 22.5 degrees after the operation). In both the cases neither a significant loss of correction at the minimum one-year follow-up nor any serious complications associated with grappling of pelvic fixation were observed. DISCUSSION The S2AI screws offer at least the same stability and ability of correction as iliac screws and at the same time they provide significantly better results compared with the older methods of pelvic fixation such as the Galvestone technique. With a good knowledge of the surgical technique and anatomical aspects this technique can be applied in the form of a free-hand technique. Navigation as well as robotic techniques can help with the accurate positioning of the S2AI screw. Transfixation of sacroiliacal syndesmosis in patients with a neuromuscular handicap does not lead to deterioration of their mobility. CONCLUSIONS Simultaneous stabilisation of spine and pelvis makes it possible to achieve a good quality correction of the deformity and good clinical results over a long period of time. It allows for stability of the sitting position of the patients and improves the quality of their lives. Nowadays, the S2AI screws are considered to be biomechanically the best quality pelvic fixation, eliminating subcutaneous prominence of the instrumentation and reducing the risk of skin decubitus. Key words:neuromuscular deformity, sacral-alar-iliac screw, pelvic obliquity, stabilization, scoliosis.

Treating Disease at the RNA Level with Oligonucleotides.Publié le 12 01 2019

PMID: 30601736 [PubMed - indexed for MEDLINE]

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron.Publié le 10 01 2019

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMN?7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMN?7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMN?7S270A, but not wild-type (WT) SMN?7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers.

[Spinal muscular atrophy treated with nusinersen].Publié le 09 01 2019

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, which causes degeneration of peripheral nerves and muscles. It usually presents in childhood due to an insufficient level of survival motor neuron protein. This is a case series of three children, who had SMA type 1 or 2 and were treated with nusinersen from the age of five months, 16 months, and five years, respectively. At one-year follow-up, all children had improved motor function, but the child, who was treated from the age of five months, had more pronounced motor improvements than the other children. In conclusion, nusinersen seems to improve motor development in SMA, and an early treatment start is crucial.

[Treatment evaluation in patients with 5q-associated spinal muscular atrophy : Real-world experience].Publié le 09 01 2019

Spinal muscular atrophy (SMA) is a progressive autosomal recessive neurodegenerative disease with an incidence of 1:10,000 live births. With a deeper understanding of the molecular basis of SMA in the past two decades, a major focus of therapeutic development has been on increasing the proportion of functionally capable SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene. Since June 2017, the antisense oligonucleotide nusinersen/Spinraza® (Biogen GmbH, Ismaning, Germany) has been approved for 5qSMA treatment. Nusinersen modifies premessenger RNA splicing of exon 7, leading to stable SMN protein expression and for the first time an effective disease-modifying treatment is available. In several controlled trials nusinersen showed a favorable benefit-risk profile along with clinically relevant improvements in motor function. The efficacy was most pronounced in presymptomatic patients, which underlines the necessity for a newborn screening program and is the key to start efficient treatment prior to motor neuron death. The repeated intrathecal administration of nusinersen is associated with practical challenges, in particular for patients with severe scoliosis or after spinal straightening surgery. As the vast majority of SMA patients were outside previous study populations regarding age and disease duration, experts complained about a lack of data on efficacy and safety beyond childhood. To fill these gaps a systematic data collection has been initiated by the SMArtCARE initiative, aiming at collecting comprehensive data in the clinical routine, regardless of the patients' individual treatment regimen.

[Non-invasive positive pressure ventilation during the management of severe spinal muscular atrophy type I].Publié le 03 01 2019

Patients with spinal muscular atrophy type ? (SMA ?) with the onset before the age of 3 months are considered as severe form of SMA ? (severe SMA ?) and have poor prognosis. Here, we report the efficacy of non-invasive positive pressure ventilation (NPPV) in a patient with severe SMA ?. She was born with generalized hypotonia and feeding difficulties, and had SMN1 gene mutations (the deletion of exons 7 and 8). At 1 month of age, she was intubated because of respiratory failure due to a respiratory tract infection, and extubation proved difficult. Her parents decided that NPPV and a mechanical in-exsufflator (MI-E) should be used for respiratory management rather than a tracheotomy. The NPPV improved her peripheral coldness, cold sweats, chest wall movement, and heart rate and enabled her to sleep well. At 1 year and 2 months, chest computed tomography revealed mild pneumonia and did not show any atelectasis. The NPPV facilitated discharge, and the patient had a good quality of life (QOL) from the point of view of voice production, the ability to move easily, the simplicity of bathing, and the low level of discomfort she experienced. However, she suffered repeated episodes of aspiration pneumonia and airway obstruction (by sputum) after 11 months of age. Thereafter, she required continuous NPPV and high-span inspiratory positive airway pressure (21 cmH2O). At 1 year and 4 months, she died of respiratory failure at home. As her bulbar weakness worsened, respiratory management with NPPV became difficult. However, the long-term use of NPPV together with high-span positive inspiratory pressure plus positive end-expiratory pressure, and a high-pressure MI-E at an early age might improve respiratory management outcomes and patient prognosis. In our case, NPPV was effective at improving ventilation and preventing atelectasis and helped to provide the patient with a good QOL.

Perspectives on Spinraza (Nusinersen) Treatment Study: Views of Individuals and Parents of Children Diagnosed with Spinal Muscular Atrophy.Publié le 31 12 2018

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disorder characterized by muscle loss. In December 2016 the FDA approved the first and only treatment drug for SMA: Spinraza (nusinersen). Despite excitement and optimism, there are no published data on the perceptions of individuals with SMA and their families about the benefits, risks, and challenges associated with treatment.
OBJECTIVE: This qualitative interview study sought to characterize the perspectives of patients/families with SMA who did not want, or were unsure about, receiving this new innovative treatment for a previously untreatable and often fatal condition.
METHODS: Individuals and families were recruited via advertisements on Facebook groups related to SMA and through the Stanford Neuromuscular Contact Registry. Participants completed a demographic questionnaire and participated in a semi-structured interview via voice conferencing. Interview questions focused on: 1) experiences with SMA, 2) opinions about Spinraza treatment, and 3) factors considered in decisions regarding treatment.
RESULTS: Thirteen people were interviewed: ten adults with SMA (ages 27- 48, nine with Type II) and three parents of minor children with SMA (one each of Types I, II and III). Qualitative content analysis identified a range of opinions about Spinraza treatment: five were uninterested (2 adults, 3 parents), four adults were still deciding whether to pursue treatment, three adults were interested or in the process of pursuing treatment, and one adult was currently receiving the drug after overcoming significant reluctance. Participants described several key factors influencing their treatment decisions, including: concerns about risk factors and side effects, high cost, insurance coverage, time involvement, and lack of data about efficacy. Participants reported learning about most of these factors through parent/patient testimonials on SMA-specific social media groups.
CONCLUSIONS: Participants reported basing decisions about pursuing Spinraza on a variety of practical and value-based considerations. They described carefully weighing the perceived potential benefits and risks of treatment through the lens of their current quality of life and prognosis. These findings suggest that providers should be aware that some patients and parents, especially those with Types II-IV, may approach treatment decisions differently than parents of children with SMA I. Informed treatment decisions can be supported through: 1) the collection and dissemination of better data on Spinraza treatment in these populations; 2) clear communication about risks, side effects and eligibility; 3) improved access to payment and treatment facilities; and 4) facilitation of discussions between providers and patients/families about identity and disability in the context of goals of care and other life and support challenges.

Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol.Publié le 30 12 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron (SMN1) gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (SMN2). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating SMN2 levels.
METHODS: We have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4?mg of salbutamol or placebo/three times a day. Molecular tests were SMN2 copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design.
RESULTS: Thirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in SMN2 full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients.
CONCLUSIONS: Our data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: SMN transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying SMN2levels.
TRIAL REGISTRATION NUMBER: EudraCT no. 2007-001088-32.

Gene Therapy for Spinal Muscular Atrophy: An Emerging Treatment Option for a Devastating Disease.Publié le 25 12 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that, in most cases, involves homozygous deletion of the SMN1 gene. This causes a deficiency in survival motor neuron (SMN) protein, which plays a critical role in motor neuron development. SMA has a range of phenotype expression resulting in variable age of symptom onset, maximum motor strength achieved, and survival. Without intervention, infants with a more severe form of the disease (type 1 SMA) die before 2 years of age. Although it is rare, SMA is the most common fatal inherited disease of infancy, and until recently, treatment was primarily supportive. In 2016, a new agent, nusinersen, was approved by the FDA. Other treatments are in development, including a gene therapy, AVXS-101. These treatments are not only improving the lives of patients with SMA and their families, they are changing the disease phenotype. They have the greatest benefit when given early in the disease course.
OBJECTIVES: To discuss current knowledge about SMA, provide clinical evidence for available and emerging treatment options, and present approaches for adding new therapies to hospital/health system formularies to ensure timely access to newly approved therapies for SMA.
SUMMARY: Advances in clinical care have significantly extended the lives of individuals with SMA, and research into the genetic mechanisms leading to disease have revealed strategies for intervention that target the underlying cause of SMA. Nusinersen is now on the market, and other treatment options, such as AVXS-101, may soon be approved. This article provides an overview of SMA and the genetic mechanisms leading to SMN deficiency, then describes how new and emerging treatments work to overcome this deficiency and prevent associated nerve damage and disability. In addition, we discuss steps for incorporating AVXS-101 into hospital/health system formularies, along with barriers and concerns that may delay access, based in part on lessons learned with nusinersen.

Perceived Fatigue in Spinal Muscular Atrophy: A Pilot Study.Publié le 20 12 2018

BACKGROUND: Fatigue is a common complaint in spinal muscular atrophy (SMA). Fatigability is well described in ambulatory SMA but the relationship to perceived fatigue has not been evaluated. Understanding this relationship has proven challenging for most disorders.
OBJECTIVE: To assess the relationship of perceived fatigue to fatigability, function, and quality of life in SMA.
METHODS: Thirty-two participants with SMA (21.9% type 2, 78.1% type 3) were recruited. Perceived fatigue and fatigability, function, and quality of life were assessed using standardized questionnaires and assessments. Associations were analyzed using Pearson correlation coefficients (p?=?0.05). Also, the effects of age, type, and ambulatory status were determined on perceived fatigue.
RESULTS: All SMA participants reported fatigue. Perceived fatigue was not associated with function, quality of life, or fatigability in ambulatory SMA patients. Neither age, type, nor ambulatory status influenced perceived fatigue.
CONCLUSIONS: Perceived fatigue can be quantified in SMA. Interestingly, perceived fatigue did not correlate with fatigability or function, suggesting that cognitive, homeostatic, or psychologic factors may be more relevant as co-morbid factors. Clinical trials targeting perceived fatigue in SMA should focus on these patient-reported assessments. A multilevel approach is required to separate the various mechanisms involved in perceived fatigue.

Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy.Publié le 15 12 2018

BACKGROUND: Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy.
METHODS: Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function.
RESULTS: All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range?=?0, 7.6), with a mean length of stay/hospitalization of 6.7 (range?=?3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently.
CONCLUSIONS: AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy.
TRIAL REGISTRATION: ClinicalTrials.gov number, NCT02122952.

Overexpression of SMN2 Gene in Motoneuron-Like Cells Differentiated from Adipose-Derived Mesenchymal Stem Cells by Ponasterone A.Publié le 12 12 2018

Cell therapy and stem cell transplantation strategies have provided potential therapeutic approaches for the treatment of neurological disorders. Adipose-derived mesenchymal stem cells (ADMSCs) are abundant adult stem cells with low immunogenicity, which can be used for allogeneic cell replacement therapies. Differentiation of ADMSCs into acetylcholine-secreting motoneurons (MNs) is a promising treatment for MN diseases, such as spinal muscular atrophy (SMA), which is associated with the level of SMN1 gene expression. The SMN2 gene plays an important role in MN disorders, as it can somewhat compensate for the lack of SMN1 expression in SMA patients. Although the differentiation potential of ADMSCs into MNs has been previously established, overexpression of SMN2 gene in a shorter period with a longer survival has yet to be elucidated. Ponasterone A (PNA), an ecdysteroid hormone activating the PI3K/Akt pathway, was studied as a new steroid to promote SMN2 overexpression in MNs differentiated from ADMSCs. After induction with retinoic acid, sonic hedgehog, forskolin, and PNA, MN phenotypes were differentiated from ADMSCs, and immunochemical staining, specific for ?-tubulin, neuron-specific enolase, and choline acetyltransferase, was performed. Also, the results of real-time PCR assay indicated nestin, Pax6, Nkx2.2, Hb9, Olig2, and SMN2 expression in the differentiated cells. After 2 weeks of treatment, cultures supplemented with PNA showed a longer survival and a 1.2-fold increase in the expression of SMN2 (an overall 5.6-fold increase; *P???0.05), as confirmed by the Western blot analysis. The PNA treatment increased the levels of ChAT, Isl1, Hb9, and Nkx2 expression in MN-like cells. Our findings highlight the role of PNA in the upregulation of SMN2 genes from MSC-derived MN-like cells, which may serve as a potential candidate in cellular therapy for SMA patients.

Motor Unit Number Index (MUNIX) of hand muscles is a disease biomarker for adult spinal muscular atrophy.Publié le 12 12 2018

OBJECTIVE: There is still insufficient knowledge about natural history in adult spinal muscular atrophy, thus valid markers for treatment and disease monitoring are urgently needed.
METHODS: We studied hand muscle innervation pattern of 38 adult genetically confirmed 5q spinal muscular atrophy (SMA) patients by the motor unit number index (MUNIX) method. Data were compared to healthy controls and amyotrophic lateral sclerosis (ALS) patients and systematically correlated to typical disease-relevant scores and other clinical as well as demographic characteristics.
RESULTS: Denervation of hand muscles in adult SMA was not evenly distributed. By calculation of the MUNIX ratios, we identified a specific hand muscle wasting pattern for SMA which is different to the split hand in ALS. Furthermore, MUNIX parameters strongly correlated with established disease course parameters independent of disease stages.
CONCLUSION: We found a pathophysiological remarkable denervation pattern of hand muscles, a 'reversed split hand'. MUNIX of single hand muscles correlated well with disease severity and thus represents an easily available biomarker for adult SMA.
SIGNIFICANCE: Our data show the power of the MUNIX method as a biomarker for upcoming questions in adult SMA.

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes.Publié le 12 12 2018

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5' splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.

Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs.Publié le 08 12 2018

Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues.

Camptocormia Induced by a Dopaminergic Agonist.Publié le 28 11 2018

Camptocormia, a condition that involves the abnormal flexion of the trunk and results in a forward-bending posture, is relatively common during the course of Parkinson disease (PD). Despite this, there is ongoing controversy concerning its mechanisms and no consensus regarding the underlying etiology. This report demonstrates a case in which a dopaminergic agonist (DA) was implicated in the onset of camptocormia episodes in a non-PD patient who developed camptocormia after the start of DA treatment. Over a course of 8 years, the patient experienced intermittent camptocormia, which resulted in multiple falls. After cessation of the DA, the patient showed decreased camptocormia symptoms. This case report suggests that clinicians should consider the possibility of DA-induced camptocormia in patients with PD and non-PD patients receiving DA treatments, and serves to caution clinicians regarding the administration of DAs.

Pharmacoeconomic Review Report: Nusinersen (Spinraza): (Biogen Canada Inc.): Indication: Treatment of patients with 5q SMAPublié le 28 11 2018

Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death. It is characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness. The most common form of SMA, 5q SMA, makes up over 95% of all cases and is an autosomal recessive disorder caused by homozygous deletion or deletion and mutation of the alleles of the survival motor neuron 1 (SMN1) gene. SMA is a rare disease and estimates of its incidence and prevalence vary between studies. The incidence of SMA is often cited as being approximately 10 in 100,000 live births. Four clinical subtypes of SMA are described; SMA type I makes about 60% of SMA diagnoses where patients show symptoms before 6 months of age, never achieve the motor milestone of sitting unsupported, and generally do not survive past two years of age due to respiratory failure; SMA type II achieve the milestone of sitting unsupported, but never walk independently. Symptoms generally appear between 6 to 18 months after birth and most patients will survive past the age of 25, with life expectancy improved by aggressive supportive care; SMA type III makes up about 10% to 20% of SMA cases3 and presents between 18 months of age and adulthood. These patients are able to walk independently at some point in their life and typically have a normal life expectancy; SMA type IV constitutes very small proportion of SMA cases, has an adult onset SMA, and is the mildest form of the disease. Although muscle weakness is present, these patients retain the ability to walk, have a normal life expectancy, and do not suffer from respiratory or nutritional issues. Nusinersen (Spinraza) is a solution for intrathecal injection, indicated for the treatment of 5q spinal muscular atrophy (SMA). It is available as a single use solution in a 5mL vial size (12 mg) administered intrathecal by lumbar puncture. The recommended dose is: initial treatment with 4 loading doses, with the first 3 loading doses administered at 14-day intervals (day 0, day 14, and day 28), and a final loading dose approximately 30 days after the third loading dose (day 63); maintenance treatment is 12 mg every 4 months. The marketed price of $118,000 per 5mL vial, the annual cost of treatment with nusinersen ranges from $354,000 for maintenance treatment (3 doses) to $708,000 in the 1st year (6 doses). The manufacturer’s listing request is as per the Health Canada indication. The manufacturer submitted three cost-utility analyses for SMA type I, II and II. Each analysis was based on a Markov state-transition model comparing nusinersen with current standard of care (or real world care [RWC] which includes supportive symptomatic treatment of respiratory, nutritional, and orthopedic function decline) - for patients with q5 SMA.

Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy.Publié le 28 11 2018

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of ?-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.

Clinical Review Report: Nusinersen (Spinraza): (Biogen Canada Inc.): Indication: Treatment of patients with 5q SMAPublié le 27 11 2018

Spinal muscular atrophy (SMA) is a severe neuromuscular disease and is the leading genetic cause of infant death. It is characterized by the degeneration of alpha motor neurons in the anterior horn of the spinal cord, leading to progressive muscle weakness. Neurological studies indicate that the disease causes a rapid and irreversible degeneration of motor neurons. The rate of motor neuron degeneration has been reported to plateau with time. The most common form of SMA, 5q SMA, makes up more than 95% of all cases and is an autosomal recessive disorder caused by homozygous deletion or deletion and mutation of the alleles of the survival motor neuron 1 (SMN1) gene. While deletion or mutation of the SMN1 gene results in survival motor neuron (SMN) protein deficiency (which is essential for the development of motor neurons), the survival motor neuron 2 (SMN2) gene produces a relatively small amount of functional SMN protein and SMN2 copy number modulates the severity of the disease. SMA is a rare disease and estimates of its incidence and prevalence vary between studies. The incidence of SMA is often cited as being approximately 10 in 100,000 live births. Incidence and prevalence estimates in Canada are not well described in the literature. However, the manufacturer of nusinersen provided Canadian figures of an annualized estimate of new cases of SMA in Canada at 37.2 new cases per year. Four clinical subtypes of SMA are described. SMA type I makes up about 60% of SMA diagnoses where patients show symptoms before 6 months of age, never achieve the motor milestone of sitting unsupported, and generally do not survive past two years of age due to respiratory failure. Patients with SMA type II achieve the milestone of sitting unsupported, but never walk independently. Symptoms generally appear between 6 to 18 months after birth. Most patients will survive past the age of 25, with life expectancy improved by aggressive supportive care. SMA type III makes up about 10% to 20% of SMA cases and presents between 18 months of age and early adulthood. These patients are able to walk independently at some point in their life and typically have a normal life expectancy. SMA type IV constitutes a very small proportion of SMA cases, has an adult onset, and is the mildest form of the disease. Although muscle weakness is present, these patients retain the ability to walk, have a normal life expectancy, and do not suffer from respiratory or nutritional issues.

Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients.Publié le 22 11 2018

Spinal muscular atrophy is a genetic motor neuron disease that leads to progressive muscular atrophy and muscle weakness. In December 2016, the Food and Drug Administration, and in June 2017, the European Medicines Agency approved the antisense oligonucleotide nusinersen for treatment of spinal muscular atrophy. Nusinersen has to be repeatedly administered intrathecally. Due to the clinical features of SMA, the application of the ASO by lumbar puncture can be challenging in symptomatic patients considering the frequently observed scoliosis, previous spine fusion surgeries, joint contractures, and respiratory insufficiency. To evaluate safety and feasibility of the intrathecal treatment in adolescent and adult SMA type 2 and 3 patients, we analyzed 93 lumbar punctures, monitored number of lumbar puncture attempts, duration of the procedure, injection site, and needle length. Oxygen saturation during the intervention, medication for sedation and local anesthesia, adverse events related to lumbar punctures, and macroscopic analysis of CSF were recorded. Moreover, we analyzed the use of CT-scans for performing lumbar punctures and its associated radiation exposure. Performing lumbar puncture for the intrathecal administration of nusinersen in adolescent and adult patients with later-onset SMA is feasible and safe, even in patients with complex spinal anatomies and respiratory insufficiency. To guarantee the quality of the procedure, we recommend establishing an experienced interdisciplinary team consisting of neurologists and/or neuropediatricians, anesthesiologists, orthopedic surgeons, and/or neuroradiologists.

10th Young Faculty Meeting, 6th June 2017.Publié le 18 11 2018

PMID: 30188297 [PubMed - indexed for MEDLINE]

Onabotulinum Toxin A Injections Into the Salivary Glands for Spinal Muscle Atrophy Type I: A Prospective Case Series of 4 Patients.Publié le 16 11 2018

OBJECTIVE: The aim of the study was to investigate the safety and efficacy of onabotulinum toxin A injection to the salivary glands under ultrasound guidance for the treatment of sialorrhea in patients with spinal muscular atrophy type I.
DESIGN: Prospective case series with four patients with spinal muscular atrophy type I who received onabotulinum toxin A injection to parotid and submandibular glands for sialorrhea as part of clinical care. All four patients received validated surveys for measuring drooling, including objective measures of number of bib changes, and number of mouth wipes before injection and 4-6 wks after injection. Research was limited to survey completion. Scales included the Drooling Severity and Frequency Scale and the Drooling Impact Scale as well as a new scale used in our clinic, the Posterior Drooling Scales looking at coughing/choking and number of aspiration pneumonias.
RESULTS: There were no adverse events. All four patients showed clinically significant improvements. The improvement in drooling using the Drooling Impact Scale was statistically significant (paired t test, t = 3.243, P = 0.048). All patients improved with number of mouth wipes.
CONCLUSION: Ultrasound-guided onabotulinum toxin A injections to the salivary glands may be a safe and effective method of decreasing drooling in patients with spinal muscular atrophy type I.

Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care.Publié le 16 11 2018

Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA.

Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1.Publié le 12 11 2018

Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2?years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1.

Upper camptocormia in Parkinson's disease reversed by bilateral subthalamic deep brain stimulation.Publié le 10 11 2018

PMID: 28233683 [PubMed - indexed for MEDLINE]

Discovery of small molecule splicing modulators of survival motor neuron-2 (SMN2) for the treatment of Spinal Muscular Atrophy (SMA).Publié le 09 11 2018

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists, however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070 / branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multi-parameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

The role of sleep diagnostics and non-invasive ventilation in children with spinal muscular atrophy.Publié le 07 11 2018

Spinal muscular atrophy (SMA) is a degenerative motor neurone disorder causing progressive muscular weakness. Without assisted ventilation or novel therapies, most children with SMA type 1 die before the second year of life due to respiratory failure as the respiratory muscles and bulbar function are severely affected. Active respiratory treatment (mechanically assisted cough, invasive or non-invasive ventilation) has improved survival significantly in recent decades, but often at the cost of becoming ventilator dependent. The advent of a new oligonucleotide based therapy (Nusinersen) has created new optimism for improving motor function. However, the long-term effect on respiratory function is unclear and non-invasive respiratory support will remain an important part of medical management in patients with SMA. This review summarises the existing knowledge about sleep-disordered breathing and respiratory failure in patients with SMA, especially type 1, as well as the evidence of improved outcome and survival in patients treated with non-invasive or invasive ventilation. Practical considerations and ethical concerns are delineated with discussion on how these may be affected by the advent of new therapies such as Nusinersen.

Long-term non-invasive ventilation therapies in children: A scoping review.Publié le 06 11 2018

Long-term non-invasive ventilation (NIV) is a common modality of breathing support used for a range of sleep and respiratory disorders. The aim of this scoping review was to provide a summary of the literature relevant to long-term NIV use in children. We used systematic methodology to identify 11,581 studies with final inclusion of 289. We identified 76 terms referring to NIV; the most common term was NIV (22%). Study design characteristics were most often single center (84%), observational (63%), and retrospective (54%). NIV use was reported for 73 medical conditions with obstructive sleep apnea and spinal muscular atrophy as the most common conditions. Descriptive data, including NIV incidence (61%) and patient characteristics (51%), were most commonly reported. Outcomes from sleep studies were reported in 27% of studies followed by outcomes on reduction in respiratory morbidity in 19%. Adverse events and adherence were reported in 20% and 26% of articles respectively. Authors reported positive conclusions for 73% of articles. Long-term use of NIV has been documented in a large variety of pediatric patient groups with studies of lower methodological quality. While there are considerable data for the most common conditions, there are fewer data to support NIV use for many additional conditions.

Nusinersen (Spinraza) for spinal muscular atrophy.Publié le 06 11 2018

PMID: 28323809 [PubMed - indexed for MEDLINE]

New Frontiers in the Treatment of Spinal Muscular Atrophy.Publié le 31 10 2018

PMID: 30376223 [PubMed - in process]

Kan man patentere solen?Publié le 31 10 2018

PMID: 29663751 [PubMed - indexed for MEDLINE]

Postural Disorders and Antiparkinsonian Treatments in Parkinson Disease: An Exploratory Case-Control Study.Publié le 30 10 2018

OBJECTIVE: The aim of this study was to evaluate the relationship between antiparkinsonian treatments, especially dopamine agonist (DAs) and the development of postural disorders in patients with Parkinson's disease (PD).
METHODS: We performed an exploratory case-control study. Cases were PD patients with camptocormia, Pisa syndrome, or anterocollis. Control subjects were PD patients without postural disorders matched by sex and age. Demographic and clinical data including pharmacologic treatments history were collected retrospectively. Characteristics of cases and control subjects were compared using parametric and nonparametric tests accordingly, and logistic regression models were used to analyze correlations.
RESULTS: We included 63 patients with PD and postural disorders and 63 control subjects. Cases were more exposed to DAs (74.60% vs 58.73%, P = 0.05) and amantadine (30.16% vs 7.94%, P < 0.05) than control subjects. Cases showed longer disease duration (7.63 ± 7.83 vs 4.27 ± 3.87 years, P < 0.05), higher Hoehn and Yahr stage (2.83 ± 0.80 vs 2.15 ± 0.73, P < 0.05), higher Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score (29.61 ± 1.39 vs 20.76 ± 10.94, P = 0.05), and more dyslipidemia (28.57% vs 12.70%, P < 0.05) than control subjects, as well as lower prevalence of depression (46.03% vs 28.57%, P < 0.05). We found no clinical predictors for the development of postural disorders after multivariable adjusted regression.
CONCLUSIONS: Our results suggest a possible association between the use of DAs and amantadine and the development of postural disorders in PD and suggest potential risk factors including advanced disease and more severe motor symptoms. These results support the need of a cautious use of these medications in patients with advanced disease due to the possibility of increasing the risk-benefit ratio.

Human Cardiac Gene Therapy.Publié le 27 10 2018

In the past 10 years, there has been tremendous progress made in the field of gene therapy. Effective treatments of Leber congenital amaurosis, hemophilia, and spinal muscular atrophy have been largely based on the efficiency and safety of adeno-associated vectors. Myocardial gene therapy has been tested in patients with heart failure using adeno-associated vectors with no safety concerns but lacking clinical improvements. Cardiac gene therapy is adapting to the new developments in vectors, delivery systems, targets, and clinical end points and is poised for success in the near future.

Physiological Roles of Metallothioneins in Central Nervous System Diseases.Publié le 27 10 2018

Metallothioneins (MTs) are small-molecular weight metal-binding proteins involved in the maintenance of tissue structure, efficient metal metabolism, and metal detoxification and have an antioxidative effect. Moreover, MTs are expressed as four isoforms, and there are no known patterns in their localization with various effects. According to recent studies, MTs affect central nervous system (CNS) diseases, and many reports suggest that each isoform of MT has a protective effect against disease. Notably, MTs are involved in regions of diseases related to unmet medical needs, and MTs affect intractable neurological diseases, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). This review specifically focuses on MT-related ocular diseases, cerebral ischemia, psychological disorders, ALS, and SMA. Each of these diseases has a separate cause, but the conditions are related to MTs. To understand the physiological roles of MTs in CNS diseases, we reviewed the current literature on the complex interactions between each MT, pathological conditions, and perspectives. We also discuss current evidence on the expression and function of MTs for diagnosis and new therapeutic strategies.

Five-Year Follow-Up and Outcomes of Noninvasive Ventilation in Subjects With Neuromuscular Diseases.Publié le 24 10 2018

INTRODUCTION: The purpose of this study was to investigate the 5-year outcomes of noninvasive ventilation (NIV) application in different neuromuscular disease (NMD) groups.
METHODS: We categorized 180 subjects who had initiated NIV between March 2001 and August 2009 into 4 groups and followed them for > 5 y. The NIV maintenance rate and average duration, applying time, and forced vital capacity (FVC) were investigated at the time NIV was initiated and 5 y after NIV initiation in each group.
RESULTS: In subjects with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and spinal muscular atrophy (SMA)-congenital myopathy, the 5-year subjects who continued to use NIV over time were 22.5%, 89.4%, and 91.3%, respectively, and the average NIV maintenance durations were 21.53 ± 19.26 months, 55.22 ± 11.47 months, and 57.48 ± 8.34 months, respectively (P < .001). Median daily applying time changed from 8.0 h to 24.0 h (P < .001), from 8.0 h to 12.0 h (P < .001), and from 8.0 h to 9.0 h (P = .11) in subjects with ALS, DMD, and SMA-congenital myopathy, respectively. FVC decreased significantly after 5 y except in the group with combined SMA-congenital myopathy.
CONCLUSIONS: NIV was tolerated long-term without significant increases in daily application time for most subjects with NMD. However, in individuals with ALS, development of severe bulbar symptoms can risk maintaining NIV.

Successful use of extracorporeal membrane oxygenation in a child with obstructive shock due to massive bilateral pulmonary embolism.Publié le 24 10 2018

BACKGROUND: Acute massive pulmonary embolism (PE) is a very rare condition in children. We report the successful use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) as a lifesaving modality in a child with acute massive PE.
CASE PRESENTATION: A nine-year-old female with spinal muscular atrophy type 1, chronic respiratory failure with tracheostomy and ventilator dependence presented with tachypnea and hypoxia. She had recent coiling of her pulmonary arterio-venous malformation. A chest computerized tomography scan showed massive bilateral PE. Urgent catheter-directed thrombolysis failed. She was placed on VA-ECMO with stabilization of hemodynamics. She underwent surgical thrombo-embolectomy followed by weaning of ECMO support.
DISCUSSION: The use of VA ECMO supported the cardio-respiratory status and perfusion to facilitate surgical embolectomy.

Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice.Publié le 18 10 2018

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), muscular atrophy, and weakness. SMN2 is the centromeric duplication of the SMN gene, whose numbers of copies determine the intracellular levels of SMN protein and define the disease onset and severity. It has been demonstrated that elevating SMN levels can be an important strategy in treating SMA and can be achieved by several mechanisms, including promotion of protein stability. SMN protein is a direct target of the calcium-dependent protease calpain and induces its proteolytic cleavage in muscle cells. In this study, we examined the involvement of calpain in SMN regulation on MNs. In vitro experiments showed that calpain activation induces SMN cleavage in CD1 and SMA mouse spinal cord MNs. Additionally, calpain 1 knockdown or inhibition increased SMN level and prevent neurite degeneration in these cells. We examined the effects of calpain inhibition on the phenotype of two severe SMA mouse models. Treatment with the calpain inhibitor, calpeptin, significantly improved the lifespan and motor function of these mice. Our observations show that calpain regulates SMN level in MNs and calpeptin administration improves SMA phenotype demonstrating the potential utility of calpain inhibitors in SMA therapy.

Therapeutic advances in 5q-linked spinal muscular atrophy.Publié le 18 10 2018

Spinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector. These therapeutic perspectives open a new era in the natural history of the disease. In this review, we intend to discuss the most recent and promising therapeutic strategies, with special consideration to the pathogenesis of the disease and the mechanisms of action of such therapies.

Camptocormia as an onset symptom of myasthenia gravis.Publié le 16 10 2018

PMID: 27812759 [PubMed - indexed for MEDLINE]

Evidence in focus: Nusinersen use in spinal muscular atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.Publié le 15 10 2018

OBJECTIVE: To identify the level of evidence for use of nusinersen to treat spinal muscular atrophy (SMA) and review clinical considerations regarding use.
METHODS: The author panel systematically reviewed nusinersen clinical trials for patients with SMA and assigned level of evidence statements based on the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.
RESULTS: Four published clinical trials were identified, 3 of which were rated above Class IV. There is Class III evidence that in infants with homozygous deletions or mutations of SMN1, nusinersen improves the probability of permanent ventilation-free survival at 24 months vs a well-defined historical cohort. There is Class I evidence that in term infants with SMA and 2 copies of SMN2, treatment with nusinersen started in individuals younger than 7 months results in a better motor milestone response and higher rates of event-free survival than sham control. There is Class I evidence that in children aged 2-12 years with SMA symptom onset after 6 months of age, nusinersen results in greater improvement in motor function at 15 months than sham control. Nusinersen was safe and well-tolerated.
CLINICAL CONTEXT: Evidence of efficacy is currently highest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. While approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use.

Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment.Publié le 12 10 2018

The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs. In this review we concentrate on these developments toward the treatment of the neuromuscular diseases Duchenne muscular dystrophy and spinal muscular atrophy toward a platform technology for the enhancement of cellular and in vivo delivery suitable for widespread use as neuromuscular and neurodegenerative ON drugs.

Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy.Publié le 12 10 2018

Background: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) and the first approved drug for the treatment of spinal muscular atrophy (SMA). However, progressive neuromyopathic scoliosis and the presence of spondylodesis can impede lumbar punctures in SMA patients. Our aim was to assess the feasibility and safety of the treatment in adults with SMA.
Methods: For the intrathecal administration of nusinersen, we performed conventional, fluoroscopy-assisted and computer tomography (CT)-guided lumbar punctures in adult patients with type 2 and type 3 SMA. We documented any reported adverse events and performed blood tests.
Results: We treated a total of 28 adult SMA patients (9 patients with SMA type 2 and 19 patients with SMA type 3) aged between 18-61?years with nusinersen. The mean Revised Upper Limb Module (RULM) score at baseline in SMA type 2 and SMA type 3 patients was 9.9 ± 4.6 and 29.5 ± 8.5, respectively. The mean Hammersmith Functional Motor Scale Expanded (HFMSE) score at baseline was 3.1 ± 2.5 and 31.2 ± 18.1, respectively. Half of the SMA type 3 patients were ambulatory at treatment onset. In total, we performed 122 lumbar punctures with 120 successful intrathecal administrations of nusinersen. Lumbar punctures were well tolerated, and no serious adverse events occurred.
Conclusions: Our data demonstrate the feasibility and tolerability of intrathecal treatment with nusinersen in adults with SMA type 2 and type 3. However, treatment can be medically and logistically challenging, particularly in patients with SMA type 2 and in patients with spondylodesis.

Spinal muscular atrophy 5Q - Treatment with nusinersen.Publié le 12 10 2018

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.

A Phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier.Publié le 12 10 2018

AIMS: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry-into-human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers.
METHODS: Part 1 had a randomized, double-blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6-18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two-period cross-over design (n = 8).
RESULTS: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi-phasic decline with a mean terminal half-life of 40-69 hours. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27-55%) of the estimated maximum increase in SMN2 mRNA.
CONCLUSIONS: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing.

The Swedish motor neuron disease quality registry.Publié le 10 10 2018

OBJECTIVE: We set up the Swedish Motor Neuron Disease (MND) Quality Registry to assure early diagnosis and high-quality health care for all MND patients (mainly amyotrophic lateral sclerosis, ALS), and to create a research base by prospectively following the entire MND population in Sweden.
METHODS: Since 2015, the MND Quality Registry continuously collects information about a wide range of clinical measures, biological samples, and quality of life outcomes from all MND patients recruited at the time of MND diagnosis in Sweden and followed at each clinic visit approximately every 12 weeks. The Registry includes an Internet based patient own reporting portal that involves patients in the registration of their current symptoms and health status.
RESULTS: As of 20th January 2017, the MND Quality Registry included 99% of the MND patients of the Stockholm area (N?=?194), consisting mostly of ALS patients (N?=?153, 78.9%), followed by patients labeled as MND due to a neurophysiology finding but not fulfilling the criteria for ALS (N?=?20, 10.3%), primary lateral sclerosis (N?=?13, 6.7%), and progressive spinal muscular atrophy patients (N?=?8, 4.1%). A higher proportion of these patients were women (N?=?100, 52%), and women and men had a similar age at symptoms onset (59 years).
CONCLUSIONS: Main strengths of the MND Quality Registry are its clinical, quantitative, qualitative, and prospective nature, providing the researchers potential means of identifying appropriate candidates for clinical trials and other research projects, as well as assuring to the patients an effective and adequate time spent on-site with the healthcare professionals.

A retrospective cohort study of children with spinal muscular atrophy type 2 receiving anesthesia for intrathecal administration of nusinersen.Publié le 05 10 2018

INTRODUCTION: Spinal muscular atrophy is characterized by loss of motor neurons in the anterior horn of the spinal cord with resultant proximal muscle weakness. Intrathecal nusinersen has revolutionized the treatment of spinal muscular atrophy. We reviewed the perioperative care of 61 anesthetics performed on eight patients with spinal muscular atrophy type 2 who received nusinersen over 30 months in conjunction with nusinersen's phase 3 clinical trials.
METHODS: Anesthesia was induced in all patients with sevoflurane, nitrous oxide, and oxygen (30%) via facemask. A peripheral intravenous line was placed after the loss of consciousness in all but three procedures. General anesthesia was maintained in 58 anesthetics with a propofol infusion at 250-300 ?g/kg/min, while the remainder was maintained with inhalational anesthetics. The airway was managed via facemask or nasal cannula in all but two procedures, in whom a laryngeal mask airway was placed. We analyzed patient demographics, duration of anesthesia and of postanesthesia care unit stay, discharge destination, preprocedure oxygen saturation (SaO2 ), postanesthesia care unit discharge oxygen saturation, and occurrence of unanticipated admission or postdischarge hospitalization.
RESULTS: Eight American Society of Anesthesiologists physical status three patients (3 male: 5 female) with a median age of 4.1 (2.1-7.8) years and median weight of 13.2 (10-24.7) kg, underwent 61 anesthetics for nusinersen administration or sham procedure. There were no intraoperative anesthetic complications of unanticipated cardiovascular instability, major neurologic events, respiratory failure, or death. Anesthesiologists performed 83% of the procedures.
CONCLUSION: Nusinersen has revolutionized the care of patients with spinal muscular atrophy type 2 and anesthesiologists will be involved in its administration. We found that routine anesthetic care was safe and effective.

Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping.Publié le 05 10 2018

Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51® to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza® as a treatment for spinal muscular atrophy (SMA) - highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cases, the identification and specific removal of 'dispensable' exons by exon-skipping ASOs could potentially bypass lethal mutations in other genes and bring clinical benefits to affected individuals carrying amenable mutations. In this review, we discuss the potential of therapeutic alternative splicing, with a particular focus on targeted exon skipping using Duchenne MD as an example, and speculate on new applications for other inherited rare diseases where redundant or dispensable exons may be amenable to exon-skipping ASO intervention as precision medicine.

Motor neurone disease-associated neck pain misdiagnosed as cervical spondylosis: A case report and literature review.Publié le 28 09 2018

BACKGROUND: Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. Although pain as a symptom appears in many patients with MND, it is often misdiagnosed as other diseases when occurs before the onset of weakness. Patients are often assigned to non-neurological departments due to the atypical symptoms, which can lead to diagnostic delay and inappropriate treatment.
OBJECTIVE: To analyze the causes of misdiagnosis and improve the clinician's understanding of neck pain in patients with MND.
METHODS: We reviewed relevant literature and retrospectively reported a misdiagnosis case of MND-associated neck pain.
RESULTS: A case of MND presenting prominently as neck pain was suspected of suffering from cervical spondylosis and wrongly assigned to orthopedic clinic. When eventually being diagnosed as MND, his neck pain was found to be caused by intracranial hypertension (ICH) resulting from hypoxia via insidious respiratory failure through ventilator insufficiency.
CONCLUSION: Careful evaluation of the clinical progression of the symptoms, extensive EMG and nerve conduction study, as well as the establishment of better clinical approach to the diagnosis and higher public awareness allow a reduction of misdiagnosis.

[Spinal muscular atrophy - clinical spectrum and therapy].Publié le 26 09 2018

Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease with an incidence of 1:10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1), and represents the most frequent neurodegenerative disorder in children. With greater understanding of the molecular basis of SMA in the past two decades, a major focus of therapeutic developments has been on increasing the fulllength SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene. Although the SMA research field is rapidly expanding with new therapeutic opportunities, there are still several issues that remain unsolved. The timing of an optimal intervention is not clear, in particular the point at which there is irreversible pathology precluding any meaningful therapeutic response. Early diagnosis will be crucial for therapeutic success; presumably, the clinical outcome will be much better if treatment already starts presymptomatically. Therefore, presymptomatic diagnosis of SMA via a nationwide genetic newborn screening will be key for an efficient therapy prior to motor neuron death.

Putting our best foot forward: Clinical, treatment-based and ethical considerations of nusinersen therapy in Canada for spinal muscular atrophy.Publié le 26 09 2018

Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality. SMA is a spectral disorder and is categorised based on symptom onset and severity. The median life expectancy for infants with SMA presenting before 6 months of age is less than 2 years without respiratory support. To date, there is no cure for SMA. In June 2017, nusinersen was approved in Canada as the first disease-modifying drug for SMA because of its demonstrated benefits on motor function and survival in clinical trials. However, with a price tag of almost 1 million dollars for the first year of therapy, careful clinical, treatment-based and ethical consideration of the principles of (i) best interests; (ii) universality; (iii) portability; (iv) public administration; (v) accessibility; and (vi) comprehensiveness are important guideposts to ensure transparent and equitable allocation of health-care resources for nusinersen and all other future orphan drugs.

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice.Publié le 21 09 2018

Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH2-terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMN?7+/+; Smn-/-), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA.

Pre-emptive awake airway management under dexmedetomidine sedation in a parturient with spinal muscular atrophy type-2.Publié le 21 09 2018

Historically, pregnancy in females with spinal muscular atrophy was contraindicated due to the great risk to the parturient, but with improved management and increased survival more patients are becoming pregnant. We describe the management of a pregnant patient with spinal muscular atrophy type-2, who had severe restrictive lung disease, extensive spinal fusion that precluded neuraxial anesthesia, and chronic respiratory failure on nocturnal Bilevel Positive Airway Pressure. Airway management was further complicated by limited mouth opening and cervical spine ankylosis.

Magnetically Controlled Devices Parallel to the Spine in Children with Spinal Muscular Atrophy.Publié le 20 09 2018

Background: Children with severe spinal deformity frequently are managed with growth-friendly implants. After initial surgery, externally controlled magnetic rods allow spinal deformity correction during growth without further surgical intervention. The ability to lengthen the spine without additional surgical procedures is especially beneficial in high-risk children, such as those with spinal muscular atrophy (SMA). The purpose of the present study was to assess the level of control of spinal deformity in a homogeneous group of patients with SMA who were managed with magnetically controlled implants for 2 years.
Methods: This prospective, nonrandomized study included 21 non-ambulatory children with type-II SMA and progressive scoliosis who were managed bilaterally with a magnetically controlled implant that was inserted parallel to the spine with use of rib-to-pelvis hook fixation. Radiographic measurements of scoliotic curves, kyphosis, lordosis, pelvic obliquity, and spinal length were performed before and after implantation of the magnetically controlled device and during external lengthening. The mean duration of follow-up was 2 years.
Results: The mean main curve of patients without prior vertical expandable prosthetic titanium rib (VEPTR) treatment decreased from 70° before implantation of the magnetically controlled device to 30° after implantation of the device. Correction was maintained during the follow-up period, with a mean curve of 31° at the time of the latest follow-up at 2.2 years. Pelvic obliquity was surgically corrected by 76% (from 17° to 4°) and remained stable during follow-up. Thoracic kyphosis could not be corrected within the follow-up period. Spinal length of children without prior spinal surgery increased by >50 mm immediately after device implantation and steadily increased at a rate of 13.5 mm/yr over the course of treatment. During treatment, 4 general complications occurred and 6 lengthening procedures failed, with 3 patients requiring surgical revision.
Conclusions: Bilateral implantation of an externally controlled magnetic rod with rib-to-pelvis fixation represents a safe and efficient method to control spinal deformity in children with SMA, achieving sufficient and stable curve correction as well as increased spinal length. The complication rate was lower than those that have been described for VEPTR and other growing rod instrumentation strategies.
Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study.Publié le 19 09 2018

BackgroundThe NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1.ObjectiveTo determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS).MethodsTraining was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with 'expert' consensus scores was examined using Pearson's correlation coefficients.ResultsInter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with 'expert' consensus was within predetermined limits (?85%) after training. Evaluator experience with SMA and MFTs did not affect reliability.ConclusionsReliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps.Publié le 18 09 2018

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed.
WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

Prenatal aspects in spinal muscular atrophy: From early detection to early presymptomatic intervention.Publié le 18 09 2018

With the recent advances in spinal muscular atrophy therapies, the complete scenario of standard of care and following up is changing not only in the clinical field with new phenotypes emerging but also with new expectations for patients, caregivers and health providers. The actual evidence indicates that early intervention and treatment is crucial for better response and prognosis. Knowledge of the prenatal and pre-symptomatic postnatal stages of the disease are becoming essential to consider the opportunities of timely diagnosis and to decide the earliest therapeutic intervention.

Rescue of four pediatric patients with severe influenza A (H3N2) in Weifang, China.Publié le 16 09 2018

In this report, we summarize our experience of rescuing four children with severe type A H3N2 influenza from January to February 2017 in Weifang People's Hospital, Shandong Province, China for reference in clinical treatment. Two boys and two girls, ranging in age from 3 months to 6 years, with fever, cough, and asthma, were admitted to the pediatric intensive care unit. All children had severe pulmonary infection with respiratory distress. Three children had myocardial damage, two had liver damage, and one had encephalitis. One child had a history of bronchial asthma and one had severe spinal muscular atrophy. After all four children were admitted to the pediatric intensive care unit, they were provided active and effective organ function support and ventilator-assisted respiration. They were treated with gamma globulin, methylprednisolone, and antibiotics. Three children were treated with anti-influenza drugs and recovered from influenza; one child died even before antiviral treatment intervention on the first day. Definite diagnosis of the cases was through clinical manifestations, supplemented by laboratory tests, such as influenza virus H3N2 rapid antigen detection and nucleic acid detection. Early antiviral therapy, high-dose glucocorticoids and immunoglobulins, and systemic comprehensive rescue might be important for rescuing children with severe influenza A (H3N2).

A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1.Publié le 13 09 2018

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive disease caused by the loss of the ubiquitously expressed IGHMBP2 gene. SMARD1 causes degeneration of alpha-motor neurons, resulting in distal muscle weakness, diaphragm paralysis, and respiratory malfunction. We have reported that delivery of a low dose of AAV9-IGHMBP2 to the CNS results in a significant rescue of the SMARD1 mouse model (nmd). To examine how a delivery route can impact efficacy, a direct comparison of intravenous (IV) and intracerebroventricular (ICV) delivery of AAV9-IGHMBP2 was performed. Using a low-dose, both IV and ICV delivery routes led to a significant extension in survival and increased body weight. Conversely, only ICV-treated animals demonstrated improvements in the hindlimb muscle, neuromuscular junction, and motor function. The hindlimb phenotype of IV-treated mice resembled the untreated nmd mice. We investigated whether the increased survival of IV-treated nmd mice was the result of a positive impact on the cardiac function. Our results revealed that cardiac function and pathology were similarly improved in IV- and ICV-treated mice. We concluded that while IV delivery of a low dose does not improve the hindlimb phenotype and motor function, partial restoration of cardiac performance is sufficient to significantly extend survival.

New Directions for SMA Therapy.Publié le 13 09 2018

Spinal muscular atrophy (SMA) is a severe disorder of motor neurons and the most frequent genetic cause of mortality in childhood, due to respiratory complications. The disease occurs due to mutations in the survival motor neuron 1 (SMN1) gene that leads to a reduction in the SMN protein, causing degeneration of lower motor neurons, muscle weakness and atrophy. Recently, the Food and Drug Administration (FDA) and the European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first disease-modifying treatment for SMA. Encouraging results from SMN1 gene therapy studies have raised hope for other therapeutic approaches that might arise in the coming years. However, nusinersen licensing has created ethical, medical, and financial implications that will need to be addressed. In this review, the history and challenges of the new SMA therapeutic strategies are highlighted.

Use of pediatric Tracheal Stoma Retainer® in a 24-year-old spinal muscular atrophy patient.Publié le 11 09 2018

PMID: 29508482 [PubMed - indexed for MEDLINE]

Innovation for rare diseases and bioethical concerns: A thin thread between medical progress and suffering.Publié le 08 09 2018

With the development of precision medicines based on small molecules, antibodies, RNAs and gene therapy, technological innovation is providing some exciting possibilities to treat the most severe genetic diseases. However, these treatments do not always lead to a cure for the disease, and there are several factors that may hinder their overall success. Patients living during a period of great medical change and innovation may benefit from these technological advances but may also just face failures, both in terms of frustrated hopes as well as suffering. In this article, we are telling the stories of three children with rare and severe disorders, who live in an age of significant medical changes, bearing the burden of difficult scientific and ethical choices. The first two cases that are suffering respectively from severe immunodeficiency and beta thalassemia have already been described in scientific journals, as well as in popular magazines. Although similar when considering the medical challenges, the two cases had opposite outcomes, which resulted in distinct ethical implications. The third case is a baby with spinal muscular atrophy, living at a time of continued innovation in the treatment of the disease. With these cases, we discuss the challenges of providing correct information and proper counseling to families and patients that are making the bumpy journey on the road of medical innovation.

Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice.Publié le 08 09 2018

OBJECTIVES: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene and insufficient functional SMN protein produced by the SMN2 copy gene. Additional genetic protective modifiers such as Plastin 3 (PLS3) can counteract SMA pathology despite insufficient SMN protein. Recently, Spinraza, an SMN antisense oligonucleotide (ASO) that restores full-length SMN2 transcripts, has been FDA- and EMA-approved for SMA therapy. Hence, the availability of biomarkers allowing a reliable monitoring of disease and therapy progression would be of great importance. Our objectives were (i) to analyse the feasibility of SMN and of six SMA biomarkers identified by the BforSMA study in the Taiwanese SMA mouse model, (ii) to analyse the effect of PLS3 overexpression on these biomarkers, and (iii) to assess the impact of low-dose SMN-ASO therapy on the level of SMN and the six biomarkers.
METHODS: At P10 and P21, the level of SMN and six putative biomarkers were compared among SMA, heterozygous and wild type mice, with or without PLS3 overexpression, and with or without presymptomatic low-dose SMN-ASO subcutaneous injection. SMN levels were measured in whole blood by ECL immunoassay and of six SMA putative biomarkers, namely Cartilage Oligomeric Matrix Protein (COMP), Dipeptidyl Peptidase 4 (DPP4), Tetranectin (C-type Lectin Family 3 Member B, CLEC3B), Osteopontin (Secreted Phosphoprotein 1, SPP1), Vitronectin (VTN) and Fetuin A (Alpha 2-HS Glycoprotein, AHSG) in plasma.
RESULTS: SMN levels were significantly discernible between SMA, heterozygous and wild type mice. However, no significant differences were measured upon low-dose SMN-ASO treatment compared to untreated animals. Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the SMA phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier.

[Pharmacological and clinical profile of spinal muscular atrophy (SMA) therapeutic drug nusinersen (Spinraza®)].Publié le 08 09 2018

Nusinersen (Spinraza®) was approved as Japan's first antisense oligonucleotide (ASO) drug for treatment of SMA (spinal muscular atrophy) patients with a deletion or mutation of the survival motor neuron (SMN) 1 gene and ?1 copy of the SMN2 gene. Nuseinersen is a fully modified 2'-O-(2-methoxyethyl) (2'-MOE) ASO designed to bind the SMN2 pre-mRNA and alter splicing, such that a mature mRNA is produced and is translated as full-length SMN protein. In 4 types of mouse SMA disease models, treatment with nusinersen improved the form of the neuromuscular junction, increased myofiber size, improved righting reflex and grip, and prolonged survival. The efficacy of nusinersen was verified in 2 multinational, randomized, double-blind, sham-controlled clinical studies in SMA patients with differing ages of onset and ages (ENDEAR study and CHERISH study), and improvement and maintenance of motor function by nusinersen were demonstrated regardless of the type of SMA. Moreover, both studies showed that greater efficacy may be obtained with early initiation of nusinersen treatment. Therefore, treatment with nusinersen should be started as early as possible to delay or halt progression of the disease and maximize therapeutic effect. As nusinersen is the only ASO currently available for SMA, it will be widely used, therefore we will expect that nusinersen will contribute to improve patients' QOL and reduce the burden of caregivers and the healthcare system by improving motor function of patients with SMA.

Systemic and ICV Injections of Antisense Oligos into SMA Mice and Evaluation.Publié le 02 09 2018

Spinal muscular atrophy (SMA) is the most common genetic cause of infantile death caused by mutations in the SMN1 gene. Nusinersen (Spinraza), an antisense therapy-based drug with the 2'-methoxyethoxy (2'MOE) chemistry approved by the FDA in 2016, brought antisense drugs into the spotlight. Antisense-mediated exon inclusion targeting SMN2 leads to SMN protein expression. Although effective, 2'MOE has weaknesses such as the inability to cross the blood-brain barrier and the high cost of treatment. To investigate new chemistries of antisense oligonucleotides (ASOs), SMA mouse models can serve as an important source. Here we describe methods to test the efficacy of ASOs, such as phosphorodiamidate morpholino oligomers (PMOs), in a severe SMA mouse model.

In Vitro Evaluation of Antisense-Mediated Exon Inclusion for Spinal Muscular Atrophy.Publié le 02 09 2018

Spinal muscular atrophy (SMA), the most common gentic cause of infantile death caused by mutations in the SMN1 gene, presents a unique case in the field of splice modulation therapy, where a gene (or lack of) is responsible for causing the disease phenotype but treatment is not focused around it. Antisense therapy targeting SMN2 which leads to SMN protein expression has been at the forefront of research when it comes to developing a feasible therapy for treating SMA. Recent FDA approval of an antisense-based drug with the 2'-methoxyethoxy (2'MOE) chemistry, called nusinersen (Spinraza), brought antisense drugs into the spotlight. The 2'MOE, although effective, has weaknesses such as the inability to cross the blood-brain barrier and the high cost of treatment. This propelled the research community to investigate new chemistries of antisense oligonucleotides (ASOs) that may be better in both treatment and cost efficiency. Here we describe two types of ASOs, phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNA)-DNA mixmers, being investigated as potential treatments for SMA, and methods used to test their efficacy, including quantitative RT-PCR, Western blotting, and immunofluorescence staining to detect SMN in nuclear gems/Cajal bodies, in type I SMA patient fibroblast cell lines.

Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion.Publié le 02 09 2018

Antisense-mediated exon skipping and exon inclusion have proven to be powerful tools for treating neuromuscular diseases. The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016. Exon skipping uses short DNA-like molecules called antisense oligonucleotides (AONs) to correct the disrupted reading frame, allowing the production of functional quasi-dystrophin proteins, and ameliorate the progression of the disease. Exon inclusion for SMA employs an AON targeting an intronic splice silencer site to include an exon which is otherwise spliced out. Recently, these strategies have also been explored in many other genetic disorders, including dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy; MM, limb-girdle muscular dystrophy type 2B; LGMD2B, and distal myopathy with anterior tibial onset; DMAT), laminin ?2 chain (merosin)-deficient congenital muscular dystrophy (MDC1A), sarcoglycanopathy (e.g., limb-girdle muscular dystrophy type 2C; LGMD2C), and Fukuyama congenital muscular dystrophy (FCMD). A major challenge in exon skipping and exon inclusion is the difficulty in designing effective AONs. The mechanism of mRNA splicing is highly complex, and the efficacy of AONs is often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter.

Nusinersen in the Treatment of Spinal Muscular Atrophy.Publié le 02 09 2018

Spinal muscular atrophy (SMA) is one of the most common genetic causes of infantile death arising due to mutations in the SMN1 gene and the subsequent loss of motor neurons. With the discovery of the intronic splicing silencer N1 (ISS-N1) as a potential target for antisense therapy, several antisense oligonucleotides (ASOs) are being developed to include exon 7 in the final mRNA transcript of the SMN2 gene and thereby increasing the production of spinal motor neuron (SMN) proteins. Nusinersen (spinraza), a modified 2'-O-methoxyethyl (MOE) antisense oligonucleotide is the first drug to be approved by Food and Drug Agency (FDA) in December of 2016. Here we briefly review the pharmacological relevance of the drug, clinical trials, toxicity, and future directions following the approval of nusinersen.

Recent Advances and Clinical Applications of Exon Inclusion for Spinal Muscular Atrophy.Publié le 02 09 2018

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in SMN1 that stops production of SMN (survival of motor neuron) protein. Insufficient levels of SMN results in the loss of motor neurons, which causes muscle weakness, respiratory distress, and paralysis. A nearly identical gene (SMN2) contains a C-to-T transition which excludes exon 7 from 90% of the mature mRNA transcripts, leading to unstable proteins which are targeted for degradation. Although SMN2 cannot fully compensate for a loss of SMN1 due to only 10% functional mRNA produced, the discovery of the intronic splicing silencer (ISS-N1) opened a doorway for therapy. By blocking its function with antisense oligonucleotides manipulated for high specificity and efficiency, exon 7 can be included to produce full-length mRNA, which then compensates for the loss of SMN1. Nusinersen (Spinraza), the first FDA-approved antisense oligonucleotide drug targeting SMA, was designed based on this concept and clinical studies have demonstrated a dramatic improvement in patients. Novel chemistries including phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNAs), as well as peptide conjugates such as Pip that facilitate accurate targeting to the central nervous system, are explored to increase the efficiency of exon 7 inclusion in the appropriate tissues to ameliorate the SMA phenotype. Due to the rapid advancement of treatments for SMA following the discovery of ISS-N1, the future of SMA treatment is highly promising.

Invention and Early History of Exon Skipping and Splice Modulation.Publié le 02 09 2018

Since its discovery in 1977, much has been known about RNA splicing and how it plays a central role in human development, function, and, notably, disease. Defects in RNA splicing account for at least 10% of all genetic disorders, with the number expected to increase as more information is uncovered on the contribution of noncoding genomic regions to disease. Splice modulation through the use of antisense oligonucleotides (AOs) has emerged as a promising avenue for the treatment of these disorders. In fact, two splice-switching AOs have recently obtained approval from the US Food and Drug Administration: eteplirsen (Exondys 51) for Duchenne muscular dystrophy, and nusinersen (Spinraza) for spinal muscular atrophy. These work by exon skipping and exon inclusion, respectively. In this chapter, we discuss the early development of AO-based splice modulation therapy-its invention, first applications, and its evolution into the approach we are now familiar with. We give a more extensive history of exon skipping in particular, as it is the splice modulation approach given the most focus in this book.

[Innovative therapeutic approaches for hereditary neuromuscular diseases].Publié le 02 09 2018

Advances in the understanding of the genetic mechanisms and pathophysiology of neuromuscular diseases have recently led to the development of new, innovative and often mutation-specific therapeutic approaches. Methods used include splicing modification by antisense oligonucleotides, read-through of premature stopcodons, use of viral vectors to introduce genetic information, or optimizing the effectiveness of enzyme replacement therapies. The first drugs have already been approved for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. For other diseases, such as myotubular myopathy, myotonic dystrophy, facioscapulohumeral muscular dystrophy and Pompe disease, new promising approaches are in preclinical or clinical development. As these are rare diseases with a broad spectrum of clinical severity, drug approval is often based on a limited amount of evidence. Therefore, systematic follow-up in the postmarketing period is particularly important to assess the safety and efficacy of these new and often high-priced orphan drugs.

Ultrasound-guided cervical puncture for nusinersen administration in adolescents.Publié le 02 09 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive disease affecting motor neurons and is the most common genetic cause of death in infants. Intrathecal nusinersen is the only therapy approved by the U.S. Food and Drug Administration for SMA. Deformities and spinal instrumentation from orthopedic surgeries are common in children with SMA, complicating traditional intrathecal access for nusinersen delivery. Cervical punctures are routinely performed in adults for cervical myelograms and should be considered for children with SMA as a viable form of intrathecal access.
OBJECTIVE: This retrospective study assessed technical feasibility and complications of ultrasound-guided cervical puncture for nusinersen administration.
MATERIALS AND METHODS: We reviewed 14 consecutive ultrasound-guided cervical punctures for nusinersen administration with local anesthesia. We reviewed technical success and complications.
RESULTS: All procedures were technically successful. There were no major complications. Two minor complications included headaches that resolved by observation within 24 h after the procedure.
CONCLUSION: Our series describes a successful novel method of ultrasound-guided cervical spine access for intrathecal administration of nusinersen, adding to the armamentarium of procedures for delivering nusinersen to adolescents with challenging lumbar spine access caused by scoliosis and spinal instrumentation. This technique has the advantages of real-time ultrasound guidance and potential avoidance of general anesthesia in children.

A potential biomarker strategy to monitor treatment response in spinal muscular atrophy.Publié le 31 08 2018

PMID: 30158561 [PubMed - as supplied by publisher]

Nusinersen in spinal muscular atrophy type 1 patients older than 7 months: A cohort study.Publié le 31 08 2018

OBJECTIVE: To evaluate the safety and clinical efficacy of nusinersen in patients with spinal muscular atrophy type 1 (SMA1) older than 7 months.
METHODS: Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32).
RESULTS: We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene.
CONCLUSIONS: Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

Essay On Being A Doctor: Mirrors.Publié le 28 08 2018

Through the generosity of Charles R. Millikan, D. Min., vice president for Spiritual Care and Values Integration, an annual award competition was established at Houston Methodist Hospital among the resident staff. To enter the writing competition, residents must submit a poem or essay of 1,000 words or less on the topic, "On Being a Doctor." A committee of seven was selected from Houston Methodist Hospital Education Institute to establish the judging criteria and select the winning entries. The following is the second-place winning entry for 2017; the third-place entry will be published in the next issue of this journal.

A blended psychosocial support program for partners of patients with amyotrophic lateral sclerosis and progressive muscular atrophy: protocol of a randomized controlled trial.Publié le 28 08 2018

BACKGROUND: Informal caregivers of patients with Amyotrophic Lateral Sclerosis (ALS) or Progressive Muscular Atrophy (PMA) face stressful demands due to severe impairments and prospect of early death of the patients they care for. Caregivers often experience feelings of psychological distress and caregiver burden, but supportive interventions are lacking. The objective of this study is to investigate the effectiveness of a psychosocial support program aimed at enhancing feelings of control over caregiving tasks and reducing psychological distress. This support program is based on an existing program for adult partners of people with cancer and is adapted to meet the needs of ALS caregivers.
METHODS: This study is a randomized controlled trial using a wait-list control design. One hundred and forty caregiver-patient dyads, recruited from a nationwide database and through the website of the Dutch ALS Center, will be either randomized to a support program or a wait-list control group. The blended intervention is based on Acceptance and Commitment Therapy and consists of 1 face-to-face contact, 6 online guided modules and 1 telephone contact. The intervention can be worked through in 8 weeks. The effectiveness and the participants' satisfaction with the intervention will be evaluated using a mixed method design. Caregivers and patients will be asked to fill in questionnaires on 4 occasions during the study: baseline, 3 months, 6 months and 9 months. The main study outcome is the psychological distress of the caregiver assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes are caregiver burden, caregiver quality of life, quality of life of the patient and psychological distress of the patient. Group differences in primary and secondary outcomes at 6 months will be compared with linear mixed model analysis. In a subgroup of caregivers we will explore experiences with the support program through semi-structured interviews. Usage of the online modules will be logged.
DISCUSSION: The study will provide insights into the effectiveness of a blended psychosocial support program on psychological distress of caregivers of patients with ALS or PMA, as well as into indirect relations with patients' wellbeing.
TRIAL REGISTRATION: Netherlands Trial Registry NTR5734 , registered 28 March 2016.

Inhibition of autophagy delays motoneuron degeneration and extends lifespan in a mouse model of spinal muscular atrophy.Publié le 28 08 2018

Spinal muscular atrophy (SMA) is a recessive autosomal neuromuscular disease, due to homozygous mutations or deletions in the telomeric survival motoneuron gene 1 (SMN1). SMA is characterized by motor impairment, muscle atrophy, and premature death following motor neuron (MN) degeneration. Emerging evidence suggests that dysregulation of autophagy contributes to MN degeneration. We here investigated the role of autophagy in the SMNdelta7 mouse model of SMA II (intermediate form of the disease) which leads to motor impairment by postnatal day 5 (P5) and to death by P13. We first showed by immunoblots that Beclin 1 and LC3-II expression levels increased in the lumbar spinal cord of the SMA pups. Electron microscopy and immunofluorescence studies confirmed that autophagic markers were enhanced in the ventral horn of SMA pups. To clarify the role of autophagy, we administered intracerebroventricularly (at P3) either an autophagy inhibitor (3-methyladenine, 3-MA), or an autophagy inducer (rapamycin) in SMA pups. Motor behavior was assessed daily with different tests: tail suspension, righting reflex, and hindlimb suspension tests. 3-MA significantly improved motor performance, extended the lifespan, and delayed MN death in lumbar spinal cord (10372.36?±?2716 MNs) compared to control-group (5148.38?±?94 MNs). Inhibition of autophagy by 3-MA suppressed autophagosome formation, reduced the apoptotic activation (cleaved caspase-3 and Bcl2) and the appearance of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive neurons, underlining that apoptosis and autophagy pathways are intricately intertwined. Therefore, autophagy is likely involved in MN death in SMA II, suggesting that it might represent a promising target for delaying the progression of SMA in humans as well.

Preliminary Safety and Tolerability of a Novel Subcutaneous Intrathecal Catheter System for Repeated Outpatient Dosing of Nusinersen to Children and Adults With Spinal Muscular Atrophy.Publié le 23 08 2018

BACKGROUND: Many patients with spinal muscular atrophy (SMA) who might benefit from intrathecal antisense oligonucleotide (nusinersen) therapy have scoliosis or spinal fusion that precludes safe drug delivery. To circumvent spinal pathology, we designed a novel subcutaneous intrathecal catheter (SIC) system by connecting an intrathecal catheter to an implantable infusion port.
METHODS: Device safety and tolerability were tested in 10 SMA patients (age, 5.4 to 30.5?y; 80% with 3 copies of SMN2); each received 3 sequential doses of nusinersen (n=30 doses). Pretreatment disease burden was evaluated using the Revised Hammersmith Scale, dynamometry, National Institutes of Health pegboard, pulmonary function testing, electromyography, and 2 health-related quality of life tools.
RESULTS: Device implantation took ?2 hours and was well tolerated. All outpatient nusinersen doses were successfully administered via SIC within 20 minutes on the first attempt, and required no regional or systemic analgesia, cognitive distraction, ultrasound guidance, respiratory precautions, or sedation. Cerebrospinal fluid withdrawn from the SIC had normal levels of glucose and protein; cerebrospinal fluid white blood cells were slightly elevated in 2 (22%) of 9 specimens (median, 1?cell/µL; range, 0 to 12?cells/µL) and red blood cells were detected in 7 (78%) specimens (median, 4; range, 0 to 2930?cells/µL).
DISCUSSION: Preliminary observations reveal the SIC to be relatively safe and well tolerated in SMA patients with advanced disease and spinal fusion. The SIC warrants further study and, if proven effective in larger trials of longer duration, could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Subthalamic deep brain stimulation and trunk posture in Parkinson's disease.Publié le 23 08 2018

OBJECTIVES: We sought to assess the efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD)-associated trunk posture abnormalities retrospectively analyzing data from 101 patients reporting mild-to-severe trunk posture abnormalities of a cohort of 216 PD patients treated with STN-DBS at our center.
METHODS: Abnormal trunk posture was rated on a scale of 0 (normal) to 4 (marked flexion with an extreme abnormality of posture) as per the grading score reported in the Unified Parkinson's Disease Rating Scale. The independent effect of STN-DBS on trunk posture was assessed comparing Medication-Off (presurgery) vs Stimulation-On/Medication-Off (post-surgery). The combined effect of STN-DBS plus levodopa was evaluated comparing Medication-On (presurgery) vs Stimulation-On/Medication-On (post-surgery). Analyses were conducted considering both the entire cohort of patients and the subgroup with camptocormia (CMC) and Pisa syndrome (PS).
RESULTS: The independent effect of STN-DBS resulted in a 41.4% improvement in abnormal trunk posture severity (P < .001), with 78.2% of patients (n = 79) reporting an improvement of at least 1 point. The combined effect of STN-DBS and levodopa resulted in a 30.9% improvement (P = .061), with 54.5% of patients (n = 55) reporting an improvement of at least 1 point. The subanalysis of patients with CMC (n = 23) and PS (n = 5) showed a 42.7% improvement in abnormal posture severity when considering the independent effect of STN-DBS (P < .001) and 30.5% when considering the combined effect of STN-DBS and levodopa (P < .001).
CONCLUSIONS: STN-DBS may have the potential for improving posture in patients with advanced PD.

Future avenues for therapy development for spinal muscular atrophy.Publié le 21 08 2018

PMID: 30124076 [PubMed - as supplied by publisher]

Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2.Publié le 21 08 2018

INTRODUCTION: The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2.
PATIENTS: The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19?months, the son was unable to walk at age 3?years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5?years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression.
INVESTIGATIONS AND RESULTS: Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family.
DISCUSSION: BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA.

Preconditioning and Cellular Engineering to Increase the Survival of Transplanted Neural Stem Cells for Motor Neuron Disease Therapy.Publié le 19 08 2018

Despite the extensive research effort that has been made in the field, motor neuron diseases, namely, amyotrophic lateral sclerosis and spinal muscular atrophies, still represent an overwhelming cause of morbidity and mortality worldwide. Exogenous neural stem cell-based transplantation approaches have been investigated as multifaceted strategies to both protect and repair upper and lower motor neurons from degeneration and inflammation. Transplanted neural stem cells (NSCs) exert their beneficial effects not only through the replacement of damaged cells but also via bystander immunomodulatory and neurotrophic actions. Notwithstanding these promising findings, the clinical translatability of such techniques is jeopardized by the limited engraftment success and survival of transplanted cells within the hostile disease microenvironment. To overcome this obstacle, different methods to enhance graft survival, stability, and therapeutic potential have been developed, including environmental stress preconditioning, biopolymers scaffolds, and genetic engineering. In this review, we discuss current engineering techniques aimed at the exploitation of the migratory, proliferative, and secretive capacity of NSCs and their relevance for the therapeutic arsenal against motor neuron disorders and other neurological disorders.

Surgical treatment of spinal disorders in Parkinson's disease.Publié le 19 08 2018

PURPOSE: Most patients suffering from Parkinson's disease (PD) exhibit alterations in the posture, which can in several cases give rise to spine deformities, both in the sagittal and the coronal plane. In addition, degenerative disorders of the spine frequently associated to PD, such as spinal stenosis and sagittal instability, can further impact the quality of life of the patient. In recent years, spine surgery has been increasingly performed, with mixed results. The aim of this narrative review is to analyze the spinal disorders associated to PD, and the current evidence about their surgical treatment.
METHODS: Narrative review.
RESULTS: Camptocormia, i.e., a pronounced flexible forward bending of the trunk with 7% prevalence, is the most reported sagittal disorder of the spine. Pisa syndrome and scoliosis are both common and frequently associated. Disorders to the spinopelvic alignment were not widely investigated, but a tendency toward a lower ability of PD patients to compensate the sagittal malalignment with respect to non-PD elderly subjects with imbalance seems to emerge. Spine surgery in PD patients showed high rates of complications and re-operations.
CONCLUSIONS: Disorders of the posture and spinal alignment, both in the sagittal and in the coronal planes, are common in PD patients, and have a major impact on the quality of life. Outcomes of spine surgery are generally not satisfactory, likely mostly due to muscle dystonia and poor bone quality. Knowledge in this field needs to be consolidated by further clinical and basic science studies. These slides can be retrieved under Electronic Supplementary Material.

Do Perineuronal Net Elements Contribute to Pathophysiology of Spinal Muscular Atrophy? In Vitro and Transcriptomics Insights.Publié le 16 08 2018

Spinal muscular atrophy (SMA) is one of the most common childhood onset neurodegenerative disorders in global health whereby novel biomarkers and therapeutic targets are sorely needed. SMA is an autosomal recessive genetic disorder resulting in degeneration of ?-motor neurons in the brain stem and spinal cord that leads to mortality in infants worldwide. In majority of the patients, SMA is caused by homozygous deletion of the SMN1 gene. The clinical spectrum of the SMA displays, however, large person-to-person variations where the underlying mechanisms are poorly understood. We report in this study transcriptomics insights gleaned from patients with the severe type I (GM03813 and GM09677) and the mild type III. Pathway enrichment and functional analysis showed that especially extracellular matrix (ECM), synapse organization, and ECM receptor interaction pathways were affected. Among the neural ECM components, hyaluronan and proteoglycan link protein (HAPLN1), which is a key triggering molecule of the perineuronal net (PNN), was significantly downregulated in type I fibroblasts compared to type III. PNN is a specialized form of neural ECM around the neuronal cell bodies and dendrites in the central nervous system. In addition, we evaluated the PNN expression in vitro in a model established by SMN silencing in the PC12 rat pheochromocytoma cell line which can be differentiated into neurons with nerve growth factor treatment. In this neuronal in vitro model, we found that HAPLN1 showed a significant 50% decrease. Our results describe the association between PNN elements, especially HAPLN1, and SMA pathophysiology for the first time. These observations collectively inform future translational research on SMA for discovery of novel molecular targets for diagnostics and precision medicine innovation.

Evaluation of the role of an antioxidant gene in NSC-34 motor neuron-like cells as a model of a motor neuron disease.Publié le 16 08 2018

BACKGROUND: Spinal muscular atrophy is a rare genetic disease, which primarily affects motor neurons and predominantly occurs in children. To date, alternatives for the treatment of the disease have been controversial. Spinal muscular atrophy has a multi-factorial etiology, with mitochondrial oxidative stress considered as the crucial pathogenic mechanism. To determine the mechanisms underlying the loss of motor neurons, NSC-34 motor neuron-like cells are often used as an in vitro model of spinal muscular atrophy. As Plastin 3 (PLS3) has been demonstrated as a modifier of spinal muscular atrophy, the aim of the current study was to evaluate the neuroprotective effect of plastin 3 in NSC-34 cells.
MATERIALS AND METHODS: Plastin 3 was overexpressed in human embryonic kidney 293T cells and NSC-34 cells via lentiviral transduction. NSC-34 cells transduced with a lentiviral vector carrying the gene for LacZ ?-galactosidase served as a control. Oxidative stress was then induced by depriving cells of serum, and the protective effect of plastin 3 was assessed using a cellular reactive oxygen species detection assay.
RESULTS: While plastin 3 was successfully overexpressed in human embryonic kidney 293T cells and NSC-34 cells, upregulation of this protein did not significantly decrease oxidative stress in serum-deprived NSC-34 cells relative to controls.
CONCLUSIONS: Plastin 3 overexpression in NSC-34 cells did not elicit an antioxidative effect following serum deprivation.

Spinraza-a rare disease success story.Publié le 14 08 2018

PMID: 28963567 [PubMed - indexed for MEDLINE]

Gene Therapy, more than ever-a new vision for the journal.Publié le 14 08 2018

PMID: 28963565 [PubMed - indexed for MEDLINE]

Spinraza-the patient perspective.Publié le 14 08 2018

PMID: 28880018 [PubMed - indexed for MEDLINE]

Gene therapy for neurological disorders: progress and prospects.Publié le 13 08 2018

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Incidence of infantile spinal muscular atrophy on Shikoku Island of Japan.Publié le 13 08 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by homozygous mutations in the SMN1 gene. SMA has long been known to be the most common genetic cause of infant mortality. However, there have been no reports on the epidemiology of infantile SMA (types 1 and 2) based on genetic testing in Japan. In this study, we estimated the incidence of infantile SMA on Shikoku Island, which is a main island of Japan and consists of four prefectures: Ehime, Kagawa, Tokushima and Kochi.
METHODS: A questionnaire was sent to 91 hospitals on Shikoku Island to investigate the number of SMA infants born from 2011 to 2015. A second questionnaire was then sent to confirm the diagnoses of SMA based on clinical and genetic features.
RESULTS: Responses were received from all of the hospitals, and four patients were diagnosed with infantile SMA among 147,950 live births. We estimated the incidence of infantile SMA patients as 2.7 per 100,000 live births (95% confidence interval, 0.1-5.4). A comparison of the four prefectures indicated that the incidence of infantile SMA was significantly higher in Ehime Prefecture than in the other three prefectures; 5.6 per 100,000 live births (95% confidence interval, -0.7 to 11.9) in Ehime Prefecture and 1.1 per 100,000 live births (95% confidence interval, -1.0 to 3.1) in the other prefectures.
CONCLUSION: We estimated the incidence of infantile SMA in an isolated area of Japan. For more precise determination of the incidence of infantile SMA, further studies that include neonatal screening will be needed.

Gene therapy rescues newborns with spinal muscular atrophy.Publié le 07 08 2018

PMID: 30080825 [PubMed - in process]

Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial).Publié le 01 08 2018

INTRODUCTION: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.
METHODS AND ANALYSIS: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1?week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2?mg/kg/day to the maximum dose of 6?mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.
ETHICS AND DISSEMINATION: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Manual Feeding Device Experiences of People With a Neurodisability.Publié le 01 08 2018

OBJECTIVE: Neurological bilateral upper limb weakness can result in self-feeding difficulties and reliance on care providers. Mealtimes become time consuming and frustrating. In this exploratory inquiry, we examined the experiences of users of a feeding device.
METHOD: Semistructured interviews were either conducted by telephone or administered via email to explore quality of life, changes to independence, benefits and limitations, and psychological impact of the equipment.
RESULTS: Thematic analysis gave rise to five themes: independence and positivity, emotions, impact on family and social life, equipment functionality, and motivation.
CONCLUSION: This exploratory inquiry has contributed new qualitative evidence to the knowledge and understanding of users' experiences of a manual feeding device. Users reported that the need for assistance was reduced and that their quality of life, independence, and freedom improved. Time and resources savings for the family, care providers, and staff appeared to result in a more equal relationship between user and care provider.

Amyotrophic lateral sclerosis: the complex path to precision medicine.Publié le 30 07 2018

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the corticomotorneuronal network responsible for voluntary movement. There are well-established clinical, genetic and pathological overlaps between ALS and frontotemporal dementia (FTD), which together constitute the 'TDP-43 proteinopathies'. An ever-expanding list of genes in which mutation leads to typical ALS have implicated abnormalities in RNA processing, protein homoeostasis and axonal transport. How these apparently distinct pathways converge to cause the characteristic clinical syndrome of ALS remains unclear. Although there are major gaps in our understanding of the essential nature of ALS pathophysiology, the identification of genetic causes in up to 15% of ALS patients, coupled with advances in biotechnology and biomarker research provide a foundation for approaches to treatment based on 'precision medicine', and even prevention of the disease in pre-symptomatic mutation carriers in the future. Currently, multidisciplinary care remains the bedrock of management and this is increasingly being put onto an evidence-based footing.

Symptom management and psychological support for families are the cornerstones of end-of-life care for children with spinal muscular atrophy type 1.Publié le 28 07 2018

AIM: This study described end-of-life care for children affected by spinal muscular atrophy type 1 (SMA1), which is characterised by progressive muscle weakness and develops in the first six months of life.
METHODS: We retrospectively analysed 17 children (13 boys) who attended the University of Padua's paediatric palliative care centre in Italy from March 2000 to March 2015. All the children received supportive care without proactive respiratory intervention to prolong survival.
RESULTS: The median age at admission was 3.57 months, and the median age at death was 6.80 months. The most frequent symptoms were dyspnoea and pain. In the last 72 hours of life, 15/17 children required more intense doses of morphine and, or, benzodiazepines for intractable dyspnoea and pain, but deep palliative sedation was not needed. Airway suction to manage secretions and nasogastric tubes was required in all cases. The place of death was previously planned by the parents in all cases - home, hospital or hospice - and 15/17 deaths occurred in that place. We also interviewed 16 of the 17 parents after their child died.
CONCLUSION: Our study found that symptom management and psychological support for families were the cornerstones of end-of-life care for children with SMA1.

Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study.Publié le 27 07 2018

Spinal muscular atrophy (SMA) is a monogenic disorder caused by loss of function mutations in the survival motor neuron 1 gene, which results in a broad range of disease severity, from neonatal to adult onset. There is currently a concerted effort to define the natural history of the disease and develop outcome measures that accurately capture its complexity. As several therapeutic strategies are currently under investigation and both the FDA and EMA have recently approved the first medical treatment for SMA, there is a critical need to identify the right association of responsive outcome measures and biomarkers for individual patient follow-up. As an approved treatment becomes available, untreated patients will soon become rare, further intensifying the need for a rapid, prospective and longitudinal study of the natural history of SMA Type 2 and 3. Here we present the baseline assessments of 81 patients aged 2 to 30 years of which 19 are non-sitter SMA Type 2, 34 are sitter SMA Type 2, 9 non-ambulant SMA Type 3 and 19 ambulant SMA Type 3. Collecting these data at nine sites in France, Germany and Belgium established the feasibility of gathering consistent data from numerous and demanding assessments in a multicenter SMA study. Most assessments discriminated between the four groups well. This included the Motor Function Measure (MFM), pulmonary function testing, strength, electroneuromyography, muscle imaging and workspace volume. Additionally, all of the assessments showed good correlation with the MFM score. As the untreated patient population decreases, having reliable and valid multi-site data will be imperative for recruitment in clinical trials. The pending two-year study results will evaluate the sensitivity of the studied outcomes and biomarkers to disease progression.
TRIAL REGISTRATION: ClinicalTrials.gov (NCT02391831).

A Semi-mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy.Publié le 26 07 2018

A pharmacokinetic (PK) model was developed for Nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for Spinal Muscular Atrophy. The model was built with data from 92 non-human primates following intrathecal doses (0.3-7mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain and pons. The estimated volumes were 13.6, 937, 4.5, 53.8 and 2.11 mL, respectively. Global sensitivity analysis demonstrated that the CSF-to-plasma drug distribution rate (0.09 hr-1 ) is a major determinant of the maximum nusinersen concentration in central nervous system tissues. Physiological age- and body weight-based allometric scaling was then implemented with exponent values of -0.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric Phase I PK profiles. The developed model can be employed to guide the design of clinical trials with ASOs. This article is protected by copyright. All rights reserved.

Intrathecal administration of Nusinersen in type 1 SMA: successful psychological program in a single Italian center.Publié le 26 07 2018

Nusinersen is the first approved drug to treat spinal muscular atrophy (SMA). Its periodic intrathecal delivery may cause psychological burden in infants and in their parents. We report our experience during expanded access program (EAP) for type 1 SMA in a single Italian center. Because of the occurrence of stress emotional states, anxious reactions and fear before, during, and after lumbar puncture (LP), a specific psychological intervention was implemented based on regulation of emotions, anticipatory expectations, and post-event attributions. Activities included the use of fairy tales, distraction, music play through listening preferred cartoon themes in the youngest children, and contextual games and solution of fun riddle quizzes in the oldest ones. State anxiety greatly reduced in children and their parents. Treatment of psychological aspects should therefore become an integral part of health care in SMA infants and children during Nusinersen treatment.

Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA).Publié le 26 07 2018

SMA is an inherited disease that leads to loss of motor function and ambulation and a reduced life expectancy. We have been working to develop orally administrated, systemically distributed small molecules to increase levels of functional SMN protein. Compound 2 was the first SMN2 splicing modifier tested in clinical trials in healthy volunteers and SMA patients. It was safe and well tolerated and increased SMN protein levels up to 2-fold in patients. Nevertheless, its development was stopped as a precautionary measure because retinal toxicity was observed in cynomolgus monkeys after chronic daily oral dosing (39 weeks) at exposures in excess of those investigated in patients. Herein, we describe the discovery of 1 (risdiplam, RG7916, RO7034067) that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is undergoing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages with SMA.

Acid ceramidase deficiency: Farber disease and SMA-PME.Publié le 23 07 2018

Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.

Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis.Publié le 23 07 2018

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS.
RECENT FINDINGS: The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno-associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS.
SUMMARY: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.

Nusinersen: A Review in 5q Spinal Muscular Atrophy.Publié le 23 07 2018

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder most commonly caused by a deletion or mutation in the survival motor neuron 1 (SMN1) gene, which leads to insufficient levels of survival motor neuron (SMN) protein. In such patients, SMN protein production relies on the SMN2 gene. Nusinersen (Spinraza®) is a modified antisense oligonucleotide (ASO) approved in several countries worldwide, including the USA, Japan and those of the EU, for the treatment of 5q SMA. It binds to a specific site in the intron downstream of exon 7 on the SMN2 pre-messenger ribonucleic acid (pre-mRNA), modulating the splicing of SMN2 mRNA and thus increasing the production of SMN protein. In multinational phase III studies, nusinersen (administered intrathecally) provided significant improvements in motor function in patients with infantile- and later-onset 5q SMA compared with a sham procedure. It was also associated with significant improvements in event-free survival and overall survival in patients with infantile-onset 5q SMA, with preliminary data from an ongoing multinational phase II study suggesting a potential clinical benefit with early intervention (i.e. before symptom onset) with nusinersen. Preliminary subgroup data from a phase III extension study suggested continued improvements in motor function with longer-term therapy. Nusinersen demonstrated a favourable safety profile in clinical studies in symptomatic and presymptomatic patients, with no safety concerns due to nusinersen exposure. In conclusion, although studies in presymptomatic patients and over the long term in symptomatic patients are ongoing, current evidence indicates that nusinersen modifies 5q SMA and has a favourable safety profile and, thus, is a valuable treatment for this patient population.

A comprehensive institutional overview of intrathecal nusinersen injections for spinal muscular atrophy.Publié le 20 07 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder resulting in progressive muscle weakness. In December 2016, the U.S. Food and Drug Administration approved the first treatment for SMA, a drug named nusinersen (Spinraza) that is administered intrathecally. However many children with SMA have neuromuscular scoliosis or spinal instrumentation resulting in challenging intrathecal access. Therefore alternative routes must be considered in these complex patients.
OBJECTIVE: To investigate routes of drug access, we reviewed our institutional experience of administering intrathecal nusinersen in all children with spinal muscular atrophy regardless of spinal anatomy or instrumentation.
MATERIALS AND METHODS: We reviewed children with SMA who were referred for intrathecal nusinersen injections from March to December 2017 at our institution. In select children with spinal hardware, spinal imaging was requested to facilitate pre-procedure planning. Standard equipment for intrathecal injections was utilized. All children were followed up by their referring neurologist.
RESULTS: A total of 104 intrathecal nusinersen injections were performed in 26 children with 100% technical success. Sixty procedures were performed without pre-procedural imaging and via standard interspinous technique. The remaining 44 procedures were performed in 11 complex (i.e. neuromuscular scoliosis or spinal instrumentation) patients requiring pre-procedural imaging for planning purposes. Nineteen of the 44 complex procedures were performed via standard interspinous technique from L2 to S1. Twenty-two of the 44 complex procedures were performed using a neural-foraminal approach from L3 to L5. Three of the 44 complex procedures were performed via cervical puncture technique. There were no immediate or long-term complications but there was one child with short-term complications of meningismus and back pain at the injection site.
CONCLUSION: Although we achieved 100% technical success in intrathecal nusinersen administration, our practices evolved during the course of this study. As a result of our early experience we developed an algorithm to assist in promoting safe and effective nusinersen administration in children with spinal muscular atrophy regardless of SMA type, abnormal spinal anatomy and complex spinal instrumentation.

Different profiles of upper limb function in four types of neuromuscular disorders.Publié le 20 07 2018

The aim of this research was to study impairments, activity limitations and participation restrictions due to upper limb involvement in people with four different types of neuromuscular disorders (NMD) - FacioScapuloHumeral Dystrophy (FSHD), Limb-Girdle Muscular Dystrophy (LGMD), Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD) - and to investigate whether common or different profiles could be identified. Total of 267 respondents with NMD from the Netherlands answered a set of questionnaires covering upper limb impairments (pain and stiffness), activity limitations and participation restrictions. Pain was most often reported by persons with FSHD. Problems in the FSHD group were mainly characterized by relatively high scores for pain and stiffness and low scores for activity limitations. People with LGMD reported also low scores for activity limitations. Conversely, people with SMA and DMD experienced in general relatively low scores for pain and stiffness and high scores for activity limitations. Although people with FSHD and LGMD had relatively few activity limitations, all NMD groups experienced restrictions when participating in social activities. Our results indicate specific profiles of upper limb function in different types of NMD. While the profile observed in persons with FSHD seems to reflect overuse, the profile seen in persons with DMD and SMA is suspicious of disuse, each requiring a specific rehabilitation strategy.

Nusinersen: A Treatment for Spinal Muscular Atrophy.Publié le 17 07 2018

OBJECTIVE: To review the efficacy and safety of nusinersen (Spinraza) in the treatment of spinal muscular atrophy (SMA).
DATA SOURCES: An English-language literature search of PubMed and MEDLINE (1946 to June 2018) was performed using the terms nusinersen, ISIS-SMN (Rx), and spinal muscular atrophy. Manufacturer prescribing information, abstracts, article bibliographies, and clinicaltrials.gov data were incorporated for additional materials.
STUDY SELECTION/DATA EXTRACTION: All clinical trials of nusinersen were identified and analyzed in the review.
DATA SYNTHESIS: Nusinersen is the first drug therapy approved for the treatment of SMA. It is a novel modified antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency. Nusinersen has been studied for safety, pharmacokinetics, and efficacy in both open-label and randomized controlled trials. The studies show improvement in motor function across SMA of all types. The most common adverse effects were respiratory tract infections, headache, back pain, constipation, and post-lumbar puncture syndrome. Relevance to Patient Care and Clinical Practice: Based on phase III trial data, nusinersen produced positive changes in the clinical course of patients with SMA. The acquisition and administration of nusinersen present a number of challenges in clinical practice. Its intrathecal delivery and costly price tag must be recognized.
CONCLUSION: Nusinersen is safe and effective in patients with SMA. It was well tolerated across all studied age groups.

Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy.Publié le 15 07 2018

OBJECTIVE: To report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access.
BACKGROUND: SMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration-approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen.
METHOD: Retrospective chart review.
RESULTS: Intrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.
CONCLUSION: Cervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure.

Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain.Publié le 11 07 2018

The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self-complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases.

Insights into the Pharmaceuticals and Mechanisms of Neurological Orphan Diseases: Current Status and Future Expectations.Publié le 08 07 2018

Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ?6% - 10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes. This review debates current progress in chemical genetics, and how a variety of compounds and reaction mechanisms can be used to study and ultimately treat rare genetic diseases. We focus here on a study involving Amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Spinal muscular atrophy (SMA) and Familial Amyloid Polyneuropathy (FAP), approaching different treatment methods and the reaction mechanisms of several compounds, trying to elucidate new routes capable of assisting in the treatment profile.

CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis.Publié le 04 07 2018

Autosomal recessive spinal muscular atrophy (SMA), the leading genetic cause of infant lethality, is caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. SMA disease severity inversely correlates with the number of SMN2 copies, which in contrast to SMN1, mainly produce aberrantly spliced transcripts. Recently, the first SMA therapy based on antisense oligonucleotides correcting SMN2 splicing, namely SPINRAZATM, has been approved. Nevertheless, in type I SMA-affected individuals-representing 60% of SMA patients-the elevated SMN level may still be insufficient to restore motor neuron function lifelong. Plastin 3 (PLS3) and neurocalcin delta (NCALD) are two SMN-independent protective modifiers identified in humans and proved to be effective across various SMA animal models. Both PLS3 overexpression and NCALD downregulation protect against SMA by restoring impaired endocytosis; however, the exact mechanism of this protection is largely unknown. Here, we identified calcineurin-like EF-hand protein 1 (CHP1) as a novel PLS3 interacting protein using a yeast-two-hybrid screen. Co-immunoprecipitation and pull-down assays confirmed a direct interaction between CHP1 and PLS3. Although CHP1 is ubiquitously present, it is particularly abundant in the central nervous system and at SMA-relevant sites including motor neuron growth cones and neuromuscular junctions. Strikingly, we found elevated CHP1 levels in SMA mice. Congruently, CHP1 downregulation restored impaired axonal growth in Smn-depleted NSC34 motor neuron-like cells, SMA zebrafish and primary murine SMA motor neurons. Most importantly, subcutaneous injection of low-dose SMN antisense oligonucleotide in pre-symptomatic mice doubled the survival rate of severely-affected SMA mice, while additional CHP1 reduction by genetic modification prolonged survival further by 1.6-fold. Moreover, CHP1 reduction further ameliorated SMA disease hallmarks including electrophysiological defects, smaller neuromuscular junction size, impaired maturity of neuromuscular junctions and smaller muscle fibre size compared to low-dose SMN antisense oligonucleotide alone. In NSC34 cells, Chp1 knockdown tripled macropinocytosis whereas clathrin-mediated endocytosis remained unaffected. Importantly, Chp1 knockdown restored macropinocytosis in Smn-depleted cells by elevating calcineurin phosphatase activity. CHP1 is an inhibitor of calcineurin, which collectively dephosphorylates proteins involved in endocytosis, and is therefore crucial in synaptic vesicle endocytosis. Indeed, we found marked hyperphosphorylation of dynamin 1 in SMA motor neurons, which was restored to control level by the heterozygous Chp1 mutant allele. Taken together, we show that CHP1 is a novel SMA modifier that directly interacts with PLS3, and that CHP1 reduction ameliorates SMA pathology by counteracting impaired endocytosis. Most importantly, we demonstrate that CHP1 reduction is a promising SMN-independent therapeutic target for a combinatorial SMA therapy.

[Clinical diagnosis and management of cervical spondylotic amyotrophy].Publié le 04 07 2018

Objective: To investigate the clinical characteristics and surgical treatment of cervical spondylotic amyotrophy. Methods: Thirteen patients(13 man) with proximal (10) and distal(3) cervical spondylotic amyotrophy between November 2014 and September 2016 were included in this study. The average age of the patients was 55 (range, 47-66) years. The sex, age, clinical course, type of amyotrophy, lesion segment and postdecompression improvement in muscle power were reviewed. Results: Of 13 cervical spondylotic amyotrophy patients, 9 were performed on with cervical disectomy, 2 were performed on with cervical posterior operation, 2 remainding patients received nonoperative treatment. Cervical spondylotic amyotrophy patients were followed up 6-22 (average 10.6) months, muscle power of 4 patients (all proximal-type)were improved completely (the average recovery time were 4.4 months), muscle power of 6 patients were improved uncompletely, 1 patients failed to improve, the 2 remainding patients received nonoperative treatment had no change. Conclusion: Cervical spondylotic amyotrophy as a rare type of cervical spondylotic disorder, It should distinguish cervical spondylotic amyotrophy from amyotrophic lateral sclerosis, especially in the early stage of amyotrophic lateral sclerosis. A surgical treatment is recommended as the first line of proximal-type CSA, especially those with serious compression. It is important that clinicians should be aware that distal-type CSA had a poor results, resulting in a lower lower satisfaction, especially those with no, or insignificant, sensory disturbance.

[A survivor of Hodgkin lymphoma manifesting dropped head syndrome as a late-onset complication of radiotherapy: a case report].Publié le 29 06 2018

We report the case of a 50-year-old female survivor of Hodgkin lymphoma (HL), who developed dropped head syndrome (DHS). The patient was diagnosed with HL at 20 years of age, and underwent chemo-radiotherapy, which led to complete remission. Undergoing supplemental therapy for post-radiation hypothyroidism, she had twin babies. She noticed white stains on her neck at the age of 30, and the decolored area gradually expanded. Sixteen years after the radiotherapy (RT), her posterior neck muscle strength began to decline. She had to make considerable efforts to keep her neck straight, and came to experience a severe pain in the neck and shoulders. The patient visited our department due to DHS at the age of 50. She had leukoderma, muscle weakness, and muscle atrophy in the neck and para-spinal region, which were consistent with the area of RT. The strength was preserved in the other parts of the muscle, including the proximal upper limbs. Sensory nerve disorder was not detected. The serum creatine kinase level was slightly elevated. Cervical spine or cervical cord disease that can cause DHS was not detected by MRI examination. The MRI and CT images revealed marked atrophy in the posterior neck and para-spinal muscles. The electromyogram revealed myopathic changes, and the cause of her DHS was diagnosed as radiation-induced myopathy. DHS is a well-known late-onset radiation injury, and Japanese cases have been reported in elderly persons with laryngeal or lung cancer. However, there have been no Japanese case reports of radiation-induced DHS due to RT against HL in younger persons. The patient had visited several clinics and hospitals before she came to our hospital, but RT-induced DHS had been overlooked. Greater recognition and consideration is required for DHS as one of the various issues arising after long passage of HL survivors.

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression.Publié le 28 06 2018

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ? 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

Targeting TGF? Signaling to Address Fibrosis Using Antisense Oligonucleotides.Publié le 28 06 2018

Fibrosis results from the excessive accumulation of extracellular matrix in chronically injured tissue. The fibrotic process is governed by crosstalk between many signaling pathways. The search for an effective treatment is further complicated by the fact that there is a degree of tissue-specificity in the pathways involved, although the process is not completely understood for all tissues. A plethora of drugs have shown promise in pre-clinical models, which is not always borne out translationally in clinical trial. With the recent approvals of two antisense oligonucleotides for the treatment of the genetic diseases Duchenne muscular dystrophy and spinal muscular atrophy, we explore here the potential of antisense oligonucleotides to knockdown the expression of pro-fibrotic proteins. We give an overview of the generalized fibrotic process, concentrating on key players and highlight where antisense oligonucleotides have been used effectively in cellular and animal models of different fibrotic conditions. Consideration is given to the advantages antisense oligonucleotides would have as an anti-fibrotic therapy alongside factors that would need to be addressed to improve efficacy. A prospective outlook for the development of antisense oligonucleotides to target fibrosis is outlined.

Mathematical Disease Progression Modeling in Type 2/3 Spinal Muscular Atrophy.Publié le 28 06 2018

Introduction We propose a mathematical model to empirically describe spinal muscular atrophy (SMA) progression assessed by the three domains of the motor function measure (MFM) scale. The model implements development and deterioration of muscle function. Methods Nonlinear mixed-effects modeling was applied to data from two observational and one prospective clinical efficacy study comprising in total 190 healthy subjects and 277 Type 2/3 SMA patients. Results The model evidenced correlations between parameters for different MFM domains. Slower development in MFM domain D1 was associated with faster deterioration for MFM domains D2 and D3. Discussion The model describes all individual data well, although sparseness and variability of observational data prevented numerically stable estimation of parameters. Treatment duration in clinical studies was too limited to determine a proper drug effect model that could differentiate between symptomatic and disease modifying effect. This article is protected by copyright. All rights reserved.

Being Yourself and Thinking About the Future in People With Motor Neuron Disease: A Grounded Theory of Self-care Processes.Publié le 28 06 2018

INTRODUCTION: Self-care is a crucial aspect in the management of people with motor neuron disease (MND). Nurses and healthcare professionals must know the processes used by patients in performing self-care to identify problems and help them. Decision-making processes, self-understanding, and political and social support influence the self-care process in chronic diseases. Little is known about the self-care process in MND.
OBJECTIVE: The aim of this study was to gain insight on the self-care processes in people with MND.
METHOD: A grounded theory method was chosen for this study. Data from interviews were gathered, and a simultaneous comparative analysis was conducted to identify categories and codes.
RESULTS: Twenty-one people with spinal muscular atrophy and amyotrophic lateral sclerosis participated in the study. Five categories were identified as grounded in the data. The process starts from "being yourself in the care," and it develops thanks to "growing and changing" and with a "thinking about the future" approach. "Family role" and "you and who helps you" categories affect the process itself.
CONCLUSION: The self-care process in people with MND is not seen in a daily perspective but changes with the evolution of the disease. For the growing patients with MND, changing, accepting and controlling the disease while deciding autonomously are the foundations of the process.

Molecular Therapies for Muscular Dystrophies.Publié le 23 06 2018

PURPOSE OF REVIEW: To construct a framework to understand the different molecular interventions for muscular dystrophy.
RECENT FINDINGS: The recent approval of antisense oligonucleotides treatment for Duchenne muscular dystrophy and spinal muscular atrophy and current clinical trials using recombinant adeno-associated virus for the treatment of those diseases suggests that we are at a tipping point where we are able to treat and potentially cure muscular dystrophies. Understanding the basic molecular pathogenesis of muscular dystrophies and the molecular biology of the treatment allows for critical evaluation of the proposed therapies.

Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function.Publié le 22 06 2018

PURPOSE: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures.
METHODS: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded.
RESULTS: A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive.
CONCLUSIONS: Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

Onabotulinumtoxin-A injections into the salivary glands for spinal muscle atrophy type I: A prospective case series of four patients.Publié le 20 06 2018

OBJECTIVE: To investigate the safety and efficacy of Onabotulinum Toxin-A (BTX-A) injection to the salivary glands under ultrasound guidance for the treatment of sialorrhea in patients with spinal muscular atrophy type I (SMA I).
DESIGN: Prospective case series with four patients with SMA I who received BTX-A injection to parotid and submandibular glands for sialorrhea as part of clinical care. All four patients received validated surveys for measuring drooling, including objective measures of number of bib changes, and number of mouth wipes before injection and 4-6 weeks after injection. Research was limited to survey completion. Scales included the Drooling Severity and Frequency Scale and the Drooling Impact Scale as well as a new scale used in our clinic, the Posterior Drooling Scales looking at coughing/choking and number of aspiration pneumonias.
RESULTS: There were no adverse events. All four patients showed clinically significant improvements. The improvement in drooling using the DIS was statistically significant (Paired-t test, t=3.243, P=0.048). All patients improved with number of mouth wipes.
CONCLUSION: Ultrasound guided BTX-A injections to the salivary glands may be a safe and effective method of decreasing drooling in patients with SMA I.

Carbon nanofiber-based multiplexed immunosensor for the detection of survival motor neuron 1, cystic fibrosis transmembrane conductance regulator and Duchenne Muscular Dystrophy proteins.Publié le 12 06 2018

Simultaneous and point-of-care detection of multiple protein biomarkers has significant impact on patient care. Spinal Muscular Atrophy (SMA), Cystic Fibrosis (CF) and Duchenne Muscular Dystrophy (DMD) are well known progressive hereditary disorders associated with increased morbidity as well as mortality. Therefore, rapid detection of biomarkers specific for these three disorders in newborns offers new opportunities for early diagnosis, delaying symptoms and effective treatment. Here, we report the development of a disposable carbon nanofiber (CNF)-based electrochemical immunosensor for simultaneous detection of survival motor neuron 1 (SMN1), cystic fibrosis transmembrane conductance regulator (CFTR) and DMD proteins. The CNF-modified array electrodes were first functionalized by electroreduction of carboxyphenyl diazonium salt. Then, the immunosensor was fabricated by the covalent immobilization of the three antibodies on the working electrodes of the array sensor via carbodiimide (EDC/NHS) chemistry. Simultaneous detection of CFTR, DMD and SMN1 was achieved with high sensitivity and detection limits of 0.9?pg/ml, 0.7?pg/ml and 0.74?pg/ml, respectively. The multiplexed immunosensor has also shown strong selectivity against non-specific proteins. Moreover, high recovery percentage was obtained when the immunosensor was applied in spiked whole blood samples. This voltammetric immunosensor offers cost effective, easy to use, rapid and high throughput potential screening method for these three hereditary disorders using only few drops of blood.

[Nusinersen in the treatment of spinal muscular atrophy].Publié le 12 06 2018

Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages.

Weight-Loss Cognitive-Behavioural Treatment and Essential Amino Acid Supplementation in a Patient with Spinal Muscular Atrophy and Obesity.Publié le 12 06 2018

Spinal muscular atrophy is a genetic neuromuscular disease characterised by muscle atrophy, hypotonia, weakness, and progressive paralysis. Usually, these patients display increased fat mass deposition and reductions in fat-free mass and resting energy expenditure-an unfavourable condition that facilitates the development of obesity. However, weight management of these patients remains poorly described. Hence, the aim of this case report was to describe the clinical presentation and weight management of a 31-year-old male patient with spinal muscular atrophy type III, class I obesity, and metabolic syndrome treated for 1 year by means of a personalised multistep cognitive-behavioural treatment for obesity. The treatment produced a weight loss of 7.2?kg (7.1%), which was associated with a marked improvement in both the patient's self-reported general conditions and obesity-related cardiometabolic profile, and no adverse effects in terms of spinal muscular atrophy (i.e., reductions in fat-free mass or resting energy expenditure).

Evaluator Training and Reliability for SMA Global Nusinersen Trials1.Publié le 06 06 2018

BACKGROUND: Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes.
METHODS: Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability.
RESULTS: Inter and intra-rater reliability were both excellent. Intraclass correlation coefficients (ICC) ranged between 0.906-0.994 across initial training meetings and 0.824-0.996 across annual retraining meetings. This was similar for CHOP INTEND (ICC = 0.824-0.951), HFMSE (ICC = 0.981-0.996), and RULM (ICC = 0.966-0.990). Intra-rater reliability for the CHOP INTEND, HFMSE, and RULM were ICC = 0.895 (95% CI: 0.852-0.926; n = 116), ICC = 0.959 (95% CI: 0.942-0.971; n = 125), and ICC = 0.948 (95% CI: 0.927-0.963; n = 126) respectively.
CONCLUSIONS: Rigorous evaluator training ensures reliability of assessment of subjects with spinal muscular atrophy (SMA) in multicenter international trials.

Update on Standard Operating Procedures in Preclinical Research for DMD and SMA Report of TREAT-NMD Alliance Workshop, Schiphol Airport, 26 April 2015, The Netherlands.Publié le 06 06 2018

A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies.

Designing Effective Antisense Oligonucleotides for Exon Skipping.Publié le 06 06 2018

During the past 10 years, antisense oligonucleotide-mediated exon skipping and splice modulation have proven to be powerful tools for correction of mRNA splicing in genetic diseases. In 2016, the US Food and Drug Administration (FDA)-approved Exondys 51 (eteplirsen) and Spinraza (nusinersen), the first exon skipping and exon inclusion drugs, to treat patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively. The exon skipping of DMD mRNA aims to restore the disrupted reading frame using antisense oligonucleotides (AONs), allowing the production of truncated but partly functional dystrophin proteins, and slow down the progression of the disease. This approach has also been explored in several other genetic disorders, including laminin ?2 chain-deficient congenital muscular dystrophy, dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy and limb-girdle muscular dystrophy type 2B), sarcoglycanopathy (limb-girdle muscular dystrophy type 2C), and Fukuyama congenital muscular dystrophy. Antisense-mediated exon skipping is also a powerful tool to examine the function of genes and exons. A significant challenge in exon skipping is how to design effective AONs. The mechanism of mRNA splicing is highly complex with many factors involved. The selection of target sites, the length of AONs, the AON chemistry, and the melting temperature versus the RNA strand play important roles. A cocktail of AONs can be employed to skip multiples exons. In this chapter, we discuss the design of effective AONs for exon skipping.

A Camptocormia Case Treated With Electroconvulsive Therapy.Publié le 05 06 2018

PMID: 27668941 [PubMed - indexed for MEDLINE]

Antisense Oligonucleotide-Mediated Terminal Intron Retention of the SMN2 Transcript.Publié le 03 06 2018

The severe childhood disease spinal muscular atrophy (SMA) arises from the homozygous loss of the survival motor neuron 1 gene (SMN1). A homologous gene potentially encoding an identical protein, SMN2 can partially compensate for the loss of SMN1; however, the exclusion of a critical exon in the coding region during mRNA maturation results in insufficient levels of functional protein. The rate of transcription is known to influence the alternative splicing of gene transcripts, with a fast transcription rate correlating to an increase in alternative splicing. Conversely, a slower transcription rate is more likely to result in the inclusion of all exons in the transcript. Targeting SMN2 with antisense oligonucleotides to influence the processing of terminal exon 8 could be a way to slow transcription and induce the inclusion of exon 7. Interestingly, following oligomer treatment of SMA patient fibroblasts, we observed the inclusion of exon 7, as well as intron 7, in the transcript. Because the normal termination codon is located in exon 7, this exon/intron 7-SMN2 transcript should encode the normal protein and only carry a longer 3' UTR. Further studies showed the extra 3' UTR length contained a number of regulatory motifs that modify transcript and protein regulation, leading to translational repression of SMN. Although unlikely to provide therapeutic benefit for SMA patients, this novel technique for gene regulation could provide another avenue for the repression of undesirable gene expression in a variety of other diseases.

Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model.Publié le 02 06 2018

Spinal muscular atrophy (SMA) is an intractable disease characterized by a progressive loss of spinal motor neurons, which leads to skeletal muscle weakness and atrophy. Currently, there are no curative agents for SMA, although it is understood to be caused by reduced levels of survival motor neuron (SMN) protein. Additionally, why reduced SMN protein level results in selective apoptosis in spinal motor neurons is still not understood. Our purpose in this study was to evaluate the therapeutic potential of edaravone, a free radical scavenger, by using induced pluripotent stem cells from an SMA patient (SMA-iPSCs) and to address oxidative stress-induced apoptosis in spinal motor neurons. We first found that edaravone could improve impaired neural development of SMA-iPSCs-derived spinal motor neurons with limited effect on nuclear SMN protein expression. Furthermore, edaravone inhibited the generation of reactive oxygen species and mitochondrial reactive oxygen species upregulated in SMA-iPSCs-derived spinal motor neurons, and reversed oxidative-stress induced apoptosis. In this study, we suggest that oxidative stress might be partly the reason for selective apoptosis in spinal motor neurons in SMA pathology, and that oxidative stress-induced apoptosis might be the therapeutic target of SMA.

Antisense oligonucleotides in neurological disorders.Publié le 02 06 2018

The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD, myotonic dystrophies, Huntington's disease, amyotrophic lateral sclerosis and Alzheimer's disease.

A Half-Century History of Applications of Antisense Oligonucleotides in Medicine, Agriculture and Forestry: We Should Continue the Journey.Publié le 31 05 2018

Antisense oligonucleotides (ASO), short single-stranded polymers based on DNA or RNA chemistries and synthesized in vitro, regulate gene expression by binding in a sequence-specific manner to an RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense and nucleic acid nanotechnologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. Today the majority of ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake. This review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the elaboration of unmodified insect-specific DNA insecticides and RNA preparations in the areas of agriculture and forestry, a relatively new branch of ASO that allows circumvention of the use of non-selective chemical insecticides. When considering the variety of successful ASO modifications with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.

Small-Molecule Screening for Genetic Diseases.Publié le 29 05 2018

The genetic determinants of many diseases, including monogenic diseases and cancers, have been identified; nevertheless, targeted therapy remains elusive for most. High-throughput screening (HTS) of small molecules, including high-content analysis (HCA), has been an important technology for the discovery of molecular tools and new therapeutics. HTS can be based on modulation of a known disease target (called reverse chemical genetics) or modulation of a disease-associated mechanism or phenotype (forward chemical genetics). Prominent target-based successes include modulators of transthyretin, used to treat transthyretin amyloidoses, and the BCR-ABL kinase inhibitor Gleevec, used to treat chronic myelogenous leukemia. Phenotypic screening successes include modulators of cystic fibrosis transmembrane conductance regulator, splicing correctors for spinal muscular atrophy, and histone deacetylase inhibitors for cancer. Synthetic lethal screening, in which chemotherapeutics are screened for efficacy against specific genetic backgrounds, is a promising approach that merges phenotype and target. In this article, we introduce HTS technology and highlight its contributions to the discovery of drugs and probes for monogenic diseases and cancer. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy.Publié le 28 05 2018

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by deleterious variants in SMN1 that lead to a marked decrease in survival motor neuron (SMN) protein expression. Humans have a second SMN gene (SMN2) that is almost identical to SMN1. However, due to alternative splicing the majority of SMN2 mRNA is translated into a truncated, unstable protein that is quickly degraded. Because the presence of SMN2 provides a unique opportunity for therapy development in SMA patients, the mechanisms that regulate SMN2 splicing and mRNA expression have been elucidated in great detail. In contrast, how much SMN protein is produced at different developmental time points and in different tissues remains under-characterised. In this study, we addressed this issue by determining SMN protein expression levels at three developmental time points across six different mouse tissues and in two distinct mouse models of SMA ('severe' Taiwanese and 'intermediate' Smn2B/- mice). We found that, in healthy control mice, SMN protein expression was significantly influenced by both age and tissue type. When comparing mouse models of SMA, we found that, despite being transcribed from genetically different alleles, control SMN levels were relatively similar. In contrast, the degree of SMN depletion between tissues in SMA varied substantially over time and between the two models. These findings offer an explanation for the differential vulnerability of tissues and organs observed in SMA and further our understanding of the systemic and temporal requirements for SMN with direct relevance for developing effective therapies for SMA.

The progress of AAV-mediated gene therapy in neuromuscular disorders.Publié le 28 05 2018

INTRODUCTION: The well-defined genetic causes and monogenetic nature of many neuromuscular disorders, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), present gene therapy as a prominent therapeutic approach. The novel variants of adeno-associated virus (AAV) can achieve satisfactory transduction efficiency of exogenous genes through the central nervous system and body-wide in skeletal muscle. Areas covered: In this review, we summarize the strategies of AAV gene therapy that are currently under preclinical and clinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on diseases such as DMD and SMA. In addition to gene replacement strategy, we provide an overview of other approaches such as AAV-mediated RNA therapy and gene editing in the treatment of muscular dystrophies. Expert opinion: AAV gene therapy has achieved striking therapeutic efficacy in clinical trials in infants with SMA. Promising results have also come from the preclinical studies in small and large animal models of DMD and several clinical trials are now on the way. This strategy shows great potential as a therapy for various neuromuscular disorders. Further studies are still required to confirm its long-term safety and improve the efficacy.

Glial Activation and Central Synapse Loss, but Not Motoneuron Degeneration, Are Prevented by the Sigma-1 Receptor Agonist PRE-084 in the Smn2B/- Mouse Model of Spinal Muscular Atrophy.Publié le 17 05 2018

Spinal muscular atrophy (SMA) is characterized by the loss of ?-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn2B/- mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn2B/- mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn2B/- animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2B/- mice. These effects were also observed in a severe SMA model, the SMN?7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice.

Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice.Publié le 09 05 2018

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn-/-;SMN2 and Smn2B/- mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling.

Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases.Publié le 04 05 2018

Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO) can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations.

Recent therapeutic developments in spinal muscular atrophyPublié le 02 05 2018

Proximal spinal muscular atrophy (SMA) is an inherited neurodegenerative disease with a heterogeneous clinical phenotype. Although there is no cure for SMA, several strategies are currently being developed. In this review, we summarize the ongoing clinical trials and molecular mechanisms of successful approaches to SMA treatment.

Mechanistic studies of a small-molecule modulator of SMN2 splicing.Publié le 02 05 2018

RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the SMN2 gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing. Chemical proteomic and genomic techniques reveal that SMN-C2 directly binds to the AGGAAG motif on exon 7 of the SMN2 pre-mRNA, and promotes a conformational change in two to three unpaired nucleotides at the junction of intron 6 and exon 7 in both in vitro and in-cell models. This change creates a new functional binding surface that increases binding of the splicing modulators, far upstream element binding protein 1 (FUBP1) and its homolog, KH-type splicing regulatory protein (KHSRP), to the SMN-C2/C3-SMN2 pre-mRNA complex and enhances SMN2 splicing. These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre-mRNA splicing as an approach to the treatment of human disease.

New and developing therapies in spinal muscular atrophy.Publié le 30 04 2018

Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy. The overhaul of the landscape for all those involved in SMA extends to the design of further drug trials and the necessity of multidisciplinary supportive care to potentiate the effects of disease modifying medications. The impact of respiratory complications in SMA is central to management in the current era of emerging novel therapies. These fundamental changes in our knowledge and management approach to those with SMA are explored further in this review.

Comprehensive nutritional and metabolic assessment in patients with spinal muscular atrophy: Opportunity for an individualized approach.Publié le 28 04 2018

Optimal nutrition support is recommended for patients with spinal muscular atrophy (SMA). In a prospective study, we performed comprehensive nutritional assessments with the aim to guide best nutritional strategies for patients with SMA types II and III. We recorded a) anthropometry; b) macro- and micronutrient intakes; c) measured resting energy expenditure by indirect calorimetry; and d) body composition including dual X-ray absorptiometry. We enrolled a cohort of 21 patients aged 3 to 36 years of which 13 were female; 19 had SMA type II and 2 had SMA type III. The body mass index z-score ranged from -3 to 2.4. Forty-five percent of the cohort was either underfed or overfed, based on the difference between actual energy intake and measured resting energy expenditure. Vitamin D, E, K, folate and calcium intakes were low in a majority of the cohort. Forty-five percent of the cohort was either hypometabolic or hypermetabolic. Fat mass index (kg/m2) was significantly higher and lean body mass index (kg/m2) was significantly lower in the study cohort compared to population normalized values. Bone mineral density was low in 13 of 17 patients. In summary, we have described the prevalence of malnutrition, suboptimal feeding and alterations in body composition in children with SMA. A comprehensive nutritional assessment could guide individualized nutrition therapy in this vulnerable population.

Structural basis for the activation of acid ceramidase.Publié le 26 04 2018

Acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes. Abnormal function of aCDase leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer's, diabetes, and cancer. Here, we present crystal structures of mammalian aCDases in both proenzyme and autocleaved forms. In the proenzyme, the catalytic center is buried and protected from solvent. Autocleavage triggers a conformational change exposing a hydrophobic channel leading to the active site. Substrate modeling suggests distinct catalytic mechanisms for substrate hydrolysis versus autocleavage. A hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein, saposin-D. Structural mapping of disease mutations reveals that most would destabilize the protein fold. These results will inform the rational design of aCDase inhibitors and recombinant aCDase for disease therapeutics.

Evaluation of Children with SMA Type 1 Under Treatment with Nusinersen within the Expanded Access Program in Germany.Publié le 25 04 2018

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA.
OBJECTIVE: Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP). In contrast to previous clinical trials, children of different age groups and different stages of the disease were treated with nusinersen.
METHODS: We conducted a prospective, longitudinal data collection of patients treated with nusinersen within the EAP in seven neuromuscular centers in Germany. Standardized assessments including CHOP-INTEND and HINE-2 motor milestones were performed at baseline and 60 and 180 days after start of treatment.
RESULTS: Data from 61 SMA type 1 patients (mean age 21.08 months, range 1-93) were available for analysis. After six months of treatment, 47 children (77.0%) improved by ?4 points in CHOP INTEND score. Mean change in CHOP INTEND score was 9.0±8.0 points. Nineteen patients (31.1%) improved by ?2 points in HINE-2 motor milestones. Regression analysis revealed age at onset of treatment as major determinant of change in CHOP INTEND from baseline.
CONCLUSION: When analyzing a broad spectrum of SMA type 1 patients, many children showed an improvement of motor function after six months of treatment with nusinersen, which is generally not expected within the natural course of the disease. Long-term observation and follow-up of patients with later onset types of SMA are crucial to understand the clinical impact of treatment with nusinersen.

Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice.Publié le 21 04 2018

Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic. Splice-switching antisense oligonucleotides (ASOs) can be effective targeted therapeutics for neurodegenerative diseases, such as nusinersen (Spinraza), an approved drug for spinal muscular atrophy. Using a two-step screen with ASOs targeting IKBKAP exon 20 or the adjoining intronic regions, we identified a lead ASO that fully restored exon 20 splicing in FD patient fibroblasts. We also characterized the corresponding cis-acting regulatory sequences that control exon 20 splicing. When administered into a transgenic FD mouse model, the lead ASO promoted expression of full-length human IKBKAP mRNA and IKAP protein levels in several tissues tested, including the central nervous system. These findings provide insights into the mechanisms of IKBKAP exon 20 recognition, and pre-clinical proof of concept for an ASO-based targeted therapy for FD.

Update on muscle disease.Publié le 21 04 2018

In this article, we highlight some of the most important developments from the last few years in the field of muscle diseases, including new additions to the congenital myasthenic syndromes (CMS) and limb-girdle muscular dystrophies (LGMD), advances in our understanding of the pathophysiology of certain muscle disorders and progress in diagnostics and therapeutics. Unsurprisingly, the most prominent developments have come from the field of genetics, with significant advances in diagnosis and gene therapy giving hope to those with hitherto untreatable conditions.

Effect of Salbutamol on Respiratory Muscle Strength in Spinal Muscular Atrophy.Publié le 14 04 2018

BACKGROUND: Oral salbutamol has shown clinical benefits in spinal muscular atrophy (SMA). We studied its effect on the respiratory muscle strength in children with different types of SMA.
METHODS: Lung and respiratory muscle functions were assessed in children receiving daily oral salbutamol for at least one year. The respiratory data of age-matched SMA II historical control subjects were compared with data of SMA II patients receiving salbutamol.
RESULTS: Seven children (6.4 ± 2.0 years old, range four to ten; one SMA I, five SMA II, and one SMA III) treated with salbutamol (duration 23 ± 8 months) were assessed. Maximal static inspiratory pressure, sniff nasal inspiratory pressure, and slow vital capacity were significantly better in the salbutamol-treated SMA II group compared with control subjects (P < 0.05).
CONCLUSIONS: Long-term oral salbutamol showed benefits in respiratory function in children with SMA and appeared to increase the strength of the inspiratory muscles in a small cohort of SMA II patients.

Modelling Motor Neuron Disease in Fruit Flies: Lessons from Spinal Muscular Atrophy.Publié le 13 04 2018

Motor neuron disease (MND) is characterised by muscle weakness and paralysis downstream of motor neuron degeneration. Genetic factors play a major role in disease pathogenesis and progression. This is best underscored by spinal muscular atrophy (SMA), the most common MND affecting children. Although SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene, partial compensation by the paralogous SMN2 gene and/or genetic modifiers influence age of onset and disease severity. SMA is also the first MND that is treatable thanks to the recent development of a molecular-based therapy. This key milestone was possible following an intense research campaign in which animal models had a starring role. In this review, we specifically focus on the fruit fly Drosophila melanogaster and highlight its sterling contributions aimed at furthering our understanding of SMA pathogenesis. Methods of gene disruption utilised to generate SMA fly models are discussed and ways through which neuromuscular defects have been characterised are elaborated on. A phenotypic overlap with patients and mammalian models, allowed the use of SMA fly models to identify genetic modifiers, hence spurring investigators to discover pathways that are perturbed in disease. Targeting these can potentially lead to complimentary therapies for SMA. The same output is expected from the use of SMA fly models to identify therapeutic compounds that have an ameliorative effect. We believe that lessons gained from SMA will allow researchers to eagerly exploit Drosophila to confirm novel genes linked to MND, reveal disease mechanisms and ultimately identify therapeutics.

[Camptocormia: From diagnosis to treatment].Publié le 13 04 2018

Camptocormia or Bent Spine Syndrome (BSS) is a symptom, often unknown, affecting elderly patients. Camptocormia is a dynamic anteflexion of the trunk occurring during physical exercises or in standing position and reducible in decubitus. It is caused by an impairment of the extensor muscles of the spinal column, either idiopathic or secondary to a muscular or a neurological disease. Its diagnosis is primarily anamnestic and clinical. The use of imaging could highlight a paraver tebral muscular fatty infi l tration with preserved volume in the case of idiopathic disorder and allows exclusion of osteoarticular pathologies. The treatment must be proposed as early as possible, before advanced adipose muscle evolution and significant anteflexion of the trunck. Symptomatic measures apply to primary and secondary forms and include physiotherapy, technical assistances to the walk and equipment by lordosis supporting corsets.

Dose-Dependent Lowering of Mutant Huntingtin Using Antisense Oligonucleotides in Huntington Disease Patients.Publié le 06 04 2018

On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data. This news follows the approval of another therapeutic ASO nusinersen (trade name Spinraza) for a neurological disease, spinal muscular atrophy, by the U.S. Food and Drug Administration and European Medicines Agency, in 2016 and 2017, respectively. Combined, this offers hope for the development of the HTTRx therapy for HD patients.

RNA-Targeted Therapeutics.Publié le 05 04 2018

RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.

Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening.Publié le 05 04 2018

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity.
OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number.
METHODS: A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines.
RESULTS: The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n?=?13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation.
CONCLUSIONS: The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process.

Drugs that made headlines in 2016.Publié le 05 04 2018

PMID: 27923025 [PubMed - indexed for MEDLINE]

[Ethical attitudes of intensive care paediatricians as regards patients with spinal muscular atrophy type 1].Publié le 04 04 2018

INTRODUCTION: Spinal muscular atrophy type 1 (SMA-1) is a progressive and fatal disease that leads to ethical problems for Paediatric professionals. Our objective was to determine the ethical options of Paediatric Intensive Care Unit (PICU) paediatricians as regards a child with SMA-1 and respiratory failure.
MATERIAL AND METHODS: A cross-sectional descriptive study was conducted using an anonymous questionnaire sent to PICUs in Spain (which can be accessed through the Spanish Society of Paediatric Critical Care web page).
RESULTS: Of the 124 responses analysed, 70% were from women, 51% younger than 40 years, 54% from a PICU with more than 10 beds, 69% with prior experience in such cases, and 53% with religious beliefs. In the last patient cared for, most paediatricians opted for non-invasive mechanical ventilation (NIV) and limitation of therapeutic effort (LET) in case of NIV failure. Confronted with a future hypothetical case, half of paediatricians would opt for the same plan (NIV+LET), and 74% would support the family's decision, even in case of disagreement. Age, prior experience and sex were not related to the preferred options. Paediatricians with religious beliefs were less in favour of initial LET. Less than two-thirds (63%) scored the quality of life of a child with SMA-1 and invasive mechanical ventilation as very poor.
CONCLUSIONS: Faced with child with SMA-1 and respiratory failure, most paediatricians are in favour of initiating NIV and LET when such support is insufficient, but they would accept the family's decision, even in case of disagreement.

CIM Journal Club: Gene therapy for spinal muscular atrophy Comment on Mendell et al. N Engl J Med 2017;377:1713-22.Publié le 01 04 2018

In their landmark paper, Mendell et al. show that infants with spinal muscular atrophy (SMA) reached important motor milestones and survived longer when treated with AVXS-101 (AveXis), a viral vector containing DNA encoding the survival of motor neuron protein (SMN). Patients not only crawled, stood and walked independently, but learned to speak. These results are very encouraging for patients with SMA and offer hope for pediatric and adult patients with other types of motor neuron diseases.

GeneReviews®Publié le 30 03 2018

CLINICAL CHARACTERISTICS: The spectrum of ASAH1-related disorders ranges from Farber disease (FD) to spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years.
DIAGNOSIS/TESTING: The diagnosis of an ASAH1-related disorder is established in a proband with suggestive clinical findings by identification of biallelic pathogenic variants in ASAH1 and/or decreased activity of the enzyme acid ceramidase in peripheral blood leukocytes or cultured skin fibroblasts.
MANAGEMENT: Treatment of manifestations is symptomatic and multidisciplinary. For FD: Management may include gastrostomy tube placement, surgical removal of oral and airway granulomas, and treatment of seizures as per standard practice. Hematopoietic stem cell transplantation may be an option in affected individuals who do not have significant neurologic involvement. For SMA-PME: Management may include standard treatment for hearing loss, scoliosis, seizures, and tremor. Weakness can be mitigated with the use of orthotics, wheelchairs, or other assistive devices. Surveillance: For FD: At each visit assess growth with emphasis on feeding and nutritional status; airway, joint mobility, and developmental milestones. For SMA-PME: At each visit monitor growth with emphasis on feeding and nutritional status, pulmonary function, back for evidence of scoliosis, strength, seizure control, functional capacity (e.g., mobility, communication); assess hearing annually.
GENETIC COUNSELING: ASAH1-related disorders are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. Once the ASAH1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible.

Intron-retained transcripts of the spinal muscular atrophy genes, SMN1 and SMN2.Publié le 29 03 2018

BACKGROUND: The SMN genes, SMN1 and SMN2, are highly homologous genes which are related to the development or clinical severity of spinal muscular atrophy. Some alternative splicing patterns of the SMN genes have been well documented. In 2007, an SMN1 transcript with a full sequence of intron 3 was reported as the first intron-retained SMN transcript.
METHODS: Intron-retained SMN transcripts in various cells and tissues were studied using reverse transcription (RT)-PCR. HeLa cells were used for subcellular localization of the transcripts and protein expression analysis with Western blotting.
RESULTS: Two intron-retained SMN transcripts were detected, which contain full sequences of intron 2b or intron 3. These transcripts were produced from SMN1 and SMN2, and ubiquitously expressed in human cells and tissues. Western blotting analysis showed no proteins derived from the intron-retained transcripts. Fractionation analysis showed that these intron-retained transcripts were localized mainly in the nucleus. Contrary to our expectation, the intron-retained transcript levels decreased during the treatment of cycloheximide, an inhibitor of nonsense-mediated decay (NMD), suggesting that they were not targets of NMD.
CONCLUSION: Intron 2b-retained SMN transcript and intron3-retained SMN transcript were ubiquitously expressed in human cells and tissues. The intron-retained transcripts were mainly localized in the nucleus and decreased through non-NMD pathway.

Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide.Publié le 27 03 2018

Spinal muscular atrophy (SMA), the leading genetic disease of children, is caused by low levels of survival motor neuron (SMN) protein. Here, we employ A15/283, an antisense oligonucleotide targeting a deep intronic sequence/structure, to examine the impact of restoration of SMN in a mild SMA mouse model. We show gender-specific amelioration of tail necrosis upon subcutaneous administrations of A15/283 into SMA mice at postnatal days 1 and 3. We also demonstrate that a modest increase in SMN due to early administrations of A15/283 dramatically improves testicular development and spermatogenesis. Our results reveal near total correction of expression of several genes in adult testis upon temporary increase in SMN during early postnatal development. This is the first demonstration of in vivo efficacy of an antisense oligonucleotide targeting a deep intronic sequence/structure. This is also the first report of gender-specific amelioration of SMA pathology upon a modest peripheral increase of SMN.

Nusinersen for spinal muscular atrophy.Publié le 24 03 2018

PMID: 29568328 [PubMed]

Transforaminal Lumbar Puncture: An Alternative Technique in Patients with Challenging Access.Publié le 24 03 2018

Interlaminar lumbar puncture and cervical puncture may not be ideal in all circumstances. Recently, we have used a transforaminal approach in selected situations. Between May 2016 and December 2017, twenty-six transforaminal lumbar punctures were performed in 9 patients (25 CT-guided, 1 fluoroscopy-guided). Seven had spinal muscular atrophy and were referred for intrathecal nusinersen administration. In 2, CT myelography was performed via transforaminal lumbar puncture. The lumbar posterior elements were completely fused in 8, and there was an overlying abscess in 1. The L1-2 level was used in 2; the L2-3 level, in 10; the L3-4 level, in 12; and the L4-5 level, in 2 procedures. Post-lumbar puncture headache was observed on 4 occasions, which resolved without blood patching. One patient felt heat and pain at the injection site that resolved spontaneously within hours. One patient had radicular pain that resolved with conservative treatment. Transforaminal lumbar puncture may become an effective alternative to classic interlaminar lumbar puncture or cervical puncture.

Gait dynamics in Pisa syndrome and Camptocormia: The role of stride length and hip kinematics.Publié le 22 03 2018

This is an observational cross-sectional study evaluating gait dynamics in patients with Parkinson's Disease (PD) and severe postural deformities, PD without axial deviations and healthy subjects. Ten PS individuals with Pisa syndrome (PS) and nine subjects with Camptocormia (CC) performed 3-D Gait Analysis and were evaluated with walking and balance scales. Correlations with clinical and functional scales were investigated. Spatio-temporal and kinematic data were compared to ten PD subjects without postural deformities (PP) and ten healthy matched individuals (CG). Data obtained showed decreased walking velocity, stride and step length in PP, PS and CC groups compared to controls. The correlation analysis showed that stride and step length were associated with reduced functional abilities and disease severity in PS and CC groups. Kinematic data revealed marked reduction in range of movements (ROMs) at all lower-extremity joints in PS group. While, in CC group the main differences were pronounced in hip and knee joints. PS and CC groups presented a more pronounced reduction in hip articular excursion compared to PP subjects, revealing an increased hip flexion pattern during gait cycle. Moreover, the increased hip and knee flexion pattern adversely affected functional performance during walking tests. Results obtained provide evidence that step length, along with stride length, can be proposed as simple and clear indicators of disease severity and reduced functional abilities. The reduction of ROMs at hip joint represented an important mechanism contributing to decreased walking velocity, balance impairment and reduced gait performance in PD patients with postural deformities.

Oligonucleotide therapeutics in neurodegenerative diseases.Publié le 22 03 2018

Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.

Spinal muscular atrophy type I and the dual role of viruses: An interview with Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School.Publié le 22 03 2018

According to Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School and Director of the Spinal Muscular Atrophy (SMA) Program at Boston Children's Hospital in Boston (MA, USA), the diagnosis of SMA type I is clinical and is based on detailed general physical and neurological examinations. SMA type I remains the most common genetic disease resulting in death in infancy and is really devastating for the child, the parents, as well as the medical professionals with the privilege of caring for patients with SMA and their parents. The proposed management options include: i) no respiratory support; ii) non-invasive ventilation; and iii) tracheotomy with mechanical ventilation. Deciding, which option is the best, is indeed a very personal decision. The optimal clinical care should be extremely mindful of parents' wishes and management goals with regard to the quality of life. Since the end of 2016 in the USA, and recently in Europe, there exists the possibility of accessing a novel treatment drug for SMA, namely Nusinersen. This antisense oligonucleotide is administered intrathecally and increases the production of the fully functional SMN protein, thus improving motor function, the quality of life and survival. Among the ongoing clinical trials, oral treatment with RG7916, a small molecule SMN2 splicing modifier, appears to be really promising. Gene therapy using viral vectors is expected to offer an 'one and done' therapy and possibly a cure, if administered early in life, before any symptoms appear. It is really interesting that viruses, which at the moment are the cause of death of children with SMA, if genetically modified, may be used for their treatment.

Plastin 3 Promotes Motor Neuron Axonal Growth and Extends Survival in a Mouse Model of Spinal Muscular Atrophy.Publié le 20 03 2018

Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene (SMN1), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons. Delivery of adeno-associated virus serotype 9 (AAV9) harboring Pls3 cDNA via cisterna magna in SMN?7 mice, a widely used animal model of SMA, led to high neuronal transduction efficiency. PLS3 treatment allowed a small but significant increase of lifespan by 42%. Although there was no improvement of phenotype, this study has demonstrated the potential use of Pls3 as a target for gene therapy, possibly in combination with other disease modifiers.

Nusinersen for SMA: expanded access programme.Publié le 20 03 2018

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1.
METHODS: An Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017. Standard-of-care medical therapy and treatment with intrathecal nusinersen were provided to all patients. Clinical and diagnostic characteristics, molecular genetics, treatment administered, and functional motor outcomes were assessed.
RESULTS: A total of 20 patients with SMA type 1 met the inclusion criteria, of whom 16 consented and received nusinersen treatment. Median time to diagnosis from symptom onset was 5.0 months and was correlated with age of onset (r=0.54, P<0.05). Management shifts included proactive nutritional and pulmonary support in all newly diagnosed patients with increased complexity of decision making. Supplemental nutrition with or without nocturnal non-invasive ventilation was implemented during follow-up in new diagnoses with age of onset <3 months and 2 SMN2 copies.
CONCLUSIONS: The nusinersen EAP highlights difficulties in achieving early diagnosis and/or prevention, the evolution of optimal clinical care in a time of uncertain prognostication, resource implications and ethical issues in clinical practice for SMA type 1. These challenges are broadly relevant to the realisation of all novel therapeutics in neurological disorders.

Adult-onset spinal muscular atrophy: An update.Publié le 20 03 2018

Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials. This report provides a general overview of the clinical features and pathophysiological mechanisms in adult-onset genetic SMA disorders in which the causative gene has been identified (SMN1-related SMA, Kennedy disease, CHCHD10, TRPV4, DYNC1H1 and BICD2). Sporadic lower motor neuron disease, also known as progressive muscular atrophy (PMA), is also discussed. The finding of TDP-43 aggregates in immunohistochemical studies of PMA strongly supports the idea that it is a phenotypic variant of amyotrophic lateral sclerosis (ALS).

Benign focal amyotrophy.Publié le 20 03 2018

Within lower motor neuron diseases, benign focal amyotrophy is a rare syndrome characterized by insidious neurogenic asymmetric atrophy restricted to upper or lower limbs with a good prognosis over time. Described under several terms, the nosology is probably heterogeneous. In juvenile distal upper-limbs forms, specific MRI signs with in particular a compression of the spinal cord by forward displacement of dura, lead to evoke a mechanical process. In other forms, occurring later in the life, affecting proximal part of upper limbs or lower limbs, the physiopathology is still unknown and a focal spinal muscular atrophy is suspected. In this review, we will discuss the clinical, electrophysiological and radiological features of each presentation.

Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.Publié le 18 03 2018

There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle's contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX® and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.

Hirayama disease.Publié le 18 03 2018

PURPOSE: Hirayama disease is an initially progressive disease caused by cervical neck flexion compressing the anterior horns of the lower cervical spinal cord. It is primarily seen in young males of Indian or Asian descent. With increasing dispersion of these populations this condition is increasingly being encountered internationally. This grand round reviews this rare but increasingly recognized condition.
MATERIALS AND METHODS: We present a classic case of a young Indian male with progressive hand and forearm weakness. We discuss the typical clinical presentation, appropriate investigations and management of this condition.
RESULTS: Our patient presented with oblique amyotrophy and underwent a diagnostic flexion MRI scan which revealed anterior translation of the posterior dura with compression of the anterior horns of the lower cervical cord. He has been successfully treated in a cervical collar.
CONCLUSIONS: This case illustrates the typical presentation, diagnostic investigations and treatment of Hirayama syndrome. It is hoped that this review will alert clinicians of this condition and optimize the management of affected individuals.

Effectiveness of spinal cord stimulation for painful camptocormia with Pisa syndrome in Parkinson's disease: a case report.Publié le 14 03 2018

BACKGROUND: Spinal cord stimulation (SCS) has recently been reported to be effective for truncal postural abnormalities such as camptocormia and Pisa syndrome in Parkinson's disease. In this case report, we describe a case of a woman with Parkinson's disease in whom SCS was effective for painful camptocormia with Pisa syndrome.
CASE PRESENTATION: A 65-year-old woman was admitted to our hospital because of painful camptocormia. She had noticed resting tremor in the left upper limb and aprosody at 48 years of age. She was diagnosed as having Parkinson's disease (Hoehn & Yahr stage 1) at 53 years of age. Cabergoline was started during that same year, with subsequent addition of selegiline hydrochloride; the symptoms of parkinsonism disappeared. Wearing-off occurred when she was 57 years old, 3 years after starting carbidopa/levodopa, and truncal postural abnormalities-painful camptocormia with Pisa syndrome to the right-appeared at 58 years of age. These symptoms worsened despite adjustment of her oral medications, and deep brain stimulation (DBS) was performed when she was 60 years old. The truncal postural abnormalities improved after DBS, and she could travel abroad at 61 years of age. However, from 62 years of age, painful camptocormia with Pisa syndrome to the right reappeared. The pain was unsuccessfully treated with oral analgesics, radiofrequency coagulation of the dorsal and medial branches of the lumbar spinal nerve, and lumbar epidural block. Finally, SCS was performed for the pain relief. The pain disappeared immediately after SCS and her posture then gradually improved. Unified Parkinson's Disease Rating Scale score improved from 48 to 34 points and Timed Up and Go Test improved from 15 s to 7 s after SCS.
CONCLUSIONS: This case suggests that SCS may be effective for improving painful truncal postural abnormalities and motor complications of Parkinson's disease. Pain relief or a direct effect on the central nervous system by SCS was considered to explain the alleviation of these symptoms.

Noninvasive airway approaches for acute neuromuscular respiratory failure in emergency departments.Publié le 13 03 2018

Emerging evidence advocates for noninvasive ventilation (NIV) combined with mechanical in-exsufflation (MIE) as a first-line approach for acute respiratory failure (ARF) in patients with neuromuscular disorders (NMD). To date, most NIV studies of ARF in NMD patients have been performed in intensive care units or in hospital settings. However, the utility of using combined NIV/MIE in the emergency department (ED) settings is unclear. We report on the implementation of NIV/MIE in two children with type II spinal muscular atrophy who presented to the ED with ARF. This is the first report on the feasibility and efficacy of combining NIV/MIE in ED settings for pediatric NMD patients with ARF.

Augmenting the SMN Protein to Treat Infantile Spinal Muscular Atrophy.Publié le 09 03 2018

Spinal muscular atrophy (SMA) is a common and oft-fatal pediatric neuromuscular disorder caused by insufficient SMN protein. Now, two clinical trials (Mendell et al., 2017; Finkel et al., 2017) demonstrate that restoring the protein is therapeutic, offering new treatment options and renewed hope to SMA patients.

ASO Therapy: Hope for Genetic Neurological Diseases.Publié le 03 03 2018

PMID: 29383373 [PubMed - indexed for MEDLINE]

Prenatal transplantation of human amniotic fluid stem cells for spinal muscular atrophy.Publié le 02 03 2018

PURPOSE OF REVIEW: To review the current medical and stem-cell therapy for spinal muscular atrophy (SMA) and prenatal transplantation of amniotic fluid stem cells in the future.
RECENT FINDINGS: SMA is an autosomal recessive inheritance of neurodegenerative disease, which is caused of the mutation in survival motor neuron. The severe-type SMA patients usually die from the respiratory failure within 2 years after birth. Recently, researchers had found that 3-methyladenine could inhibit the autophagy and had the capacity to reduce death of the neurons. The first food and drug administration-approved drug to treat SMA, Nusinersen, is a modified antisense oligonucleotide to target intronic splicing silencer N1 just recently launched. Not only medical therapy, but also stem cells including neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells could show the potential to repair the injured tissue and differentiate into neuron cells to rescue the SMA animal models. Human amniotic fluid stem cells (HAFSCs) share the potential of mesenchymal stem cells and could differentiate into tri-lineage-relative cells, which are also having the ability to restore the injured neuro-muscular function. In this review, we further demonstrate the therapeutic effect of using HAFSCs to treat type III SMA prenatally. HAFSCs, similar to other stem cells, could also help the improvement of SMA with even longer survival.
SUMMARY: The concept of prenatal stem-cell therapy preserves the time window to treat disease in utero with much less cell number. Stem cell alone might not be enough to correct or cure the SMA but could be applied as the additional therapy combined with antisense oligonucleotide in the future.

Long-term Non-Invasive Ventilation in Infants: A Systematic Review and Meta-Analysis.Publié le 01 03 2018

Background: The use of long-term non-invasive ventilation (NIV) to treat sleep and breathing disorders in children has increased substantially in the last decade; however, less data exist about its use in infants. Given that infants have distinct sleep and breathing patterns when compared to older children, the outcomes of infants on long-term NIV may differ as well. The aim of this study is to systematically review the use and outcomes of long-term NIV in infants.
Methods: Ovid Medline, Ovid Embase, CINAHL (via EbscoHOST), PubMed, and Wiley Cochrane Library were systematically searched from January 1990 to July 2017. Studies on infants using long-term NIV outside of an acute care setting were included. Data were extracted on study design, population characteristics, and NIV outcomes.
Results: A total of 327 studies were full-text reviewed, with final inclusion of 60. Studies were distributed across airway (40%), neuromuscular (28%), central nervous system (10%), cardio-respiratory (2%), and multiple (20%) disease categories. Of the 18 airway studies reporting on NIV outcomes, 13 (72%) reported improvements in respiratory parameters. Of the 12 neuromuscular studies exclusively on spinal muscular atrophy type 1 (SMA1), six (50%) reported decreased hospitalizations and nine (75%) reported on mortality outcomes. Risk of bias was moderate to serious, and quality of the evidence was low to very low for all studies. Most studies had an observational design with no control group, limiting the potential for a meta-analysis.
Conclusion: The outcomes reported in studies differed by the disease category being studied. Studies on airway conditions showed improvements in respiratory parameters for infants using NIV. Studies on neuromuscular disorder, which were almost exclusively on SMA1, reported decreased hospitalizations and prolonged survival. Overall, it appears that NIV is an effective long-term therapy for infants. However, the high risk of bias and low quality of the available evidence limited strong conclusions.

The Canadian Neuromuscular Disease Registry: Connecting patients to national and international research opportunities.Publié le 01 03 2018

Introduction: Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments.
Methods: In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry.
Results: As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population.
Discussion: The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada's visibility as a competitive location for the conduct of clinical trials for NM therapies.

Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS.Publié le 01 03 2018

To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy.

Intracerebroventricular Delivery in Mice for Motor Neuron Diseases.Publié le 01 03 2018

The use of antisense oligonucleotides to target specific mRNA sequences represents a promising therapeutic strategy for neurological disorders. Recent advances in antisense technology enclose the development of phosphorodiamidate morpholino oligomers (MO), which is one of the best candidates for molecular therapies due to MO's excellent pharmacological profile.Nevertheless, the route of administration of antisense compounds represents a critical issue in the neurological field. Particularly, as regards motor neuron diseases, intracerebroventricular (ICV) injection is undoubtedly the most efficient procedure to directly deliver therapeutic molecules in the central nervous system (CNS). Indeed, we recently demonstrated the outstanding efficacy of the MO antisense approach by its direct administration to CNS of the transgenic mouse models of Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS).Here, we describe methods to perform the ICV delivery of MO in neonatal SMA mice and in adult ALS mice.

Barriers and facilitators to clinical trial participation among parents of children with pediatric neuromuscular disorders.Publié le 26 02 2018

BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials.
METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics. These parents ( N?=?203) completed a questionnaire including assessments of barriers and facilitators to clinical trial participation, parents' interest in trial participation, and their perceptions of others' views about participation in a clinical trial.
RESULTS: Trial interest in participating parents was high (64% combined group). The most highly endorsed barrier to participation was the possibility of receiving placebo, followed by not having enough information on risks and trial procedures. Compared to parents of children with Duchenne or Becker muscular dystrophy, parents of children with spinal muscular atrophy endorsed significantly more information and knowledge barriers. The greatest facilitators of participation were (1) confidence in improving disease understanding and (2) guarantee to receive the treatment after a successful trial. A logistic regression model, ?2 (4, n?=?188)?=?80.64, p?<?.001, indicated that higher perceived barriers and more frequent trial communication by the provider were associated with lower interest, while positive trial perceptions by the child's providers and concordance in trial perceptions among those close to the decision-maker were associated with higher interest.
CONCLUSION: We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents' informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools.

Respiratory complications, management and treatments for neuromuscular disease in children.Publié le 26 02 2018

PURPOSE OF REVIEW: To summarize current literature describing the respiratory complications of neuromuscular disease (NMD) and the effect of respiratory interventions and to explore new gene therapies for patients with NMD.
RECENT FINDINGS: Measurements of respiratory function focus on vital capacity and maximal inspiratory and expiratory pressure and show decline over time. Management of respiratory complications includes lung volume recruitment, mechanical insufflation-exsufflation, chest physiotherapy and assisted ventilation. Lung volume recruitment can slow the progression of lung restriction. New gene-specific therapies for Duchenne muscular dystrophy and spinal muscular atrophy have the potential to preserve respiratory function longitudinally. However, the long-term therapeutic benefit remains unknown.
SUMMARY: Although NMDs are heterogeneous, many lead to progressive muscle weakness that compromises the function of the respiratory system including upper airway tone, cough and secretion clearance and chest wall support. Respiratory therapies augment or support the normal function of these components of the respiratory system. From a respiratory perspective, the new mutation and gene-specific therapies for NMD are likely to confer long-term therapeutic benefit. More sensitive and standard tools to assess respiratory function longitudinally are needed to monitor respiratory complications in children with NMD, particularly the youngest patients.

Disease impact on general well-being and therapeutic expectations of European Type II and Type III spinal muscular atrophy patients.Publié le 23 02 2018

Spinal muscular atrophy (SMA) is a neurodegenerative disorder showing a broad clinical spectrum and no cure to date. To design and select evaluation criteria for the potential assessment of drugs currently being developed, the patient's perspective is critical. A survey, aiming to obtain a view on the current clinical state of European Type II and Type III SMA patients, the impact of this situation on their quality of life and their expectations regarding clinical development, was carried out by SMA-Europe member organizations in July 2015. A questionnaire was set up, translated into 8 European languages and sent out directly via electronic mailing to the targeted SMA patient population by the respective European patient organizations. We were able to collect 822 valid replies in less than two weeks. The questionnaire captured the current abilities of the respondents, their perception of the disease burden which appeared very similar across Europe despite some regional variations in care. According to the great majority of the respondents, stabilization of their current clinical state would represent a therapeutic progress for a compelling majority of the respondents to the questionnaire.

Antisense oligonucleotides and other genetic therapies made simple.Publié le 20 02 2018

Many genetic neurological diseases result from the dysfunction of single proteins. Genetic therapies aim to modify these disease-associated proteins by targeting the RNA and DNA precursors. This review provides a brief overview of the main types of genetic therapies, with a focus on antisense oligonucleotides (ASOs) and RNA interference (RNAi). We use examples of new genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy and familial amyloid polyneuropathy to highlight the different mechanisms of action of ASOs and RNAi.

FDA-Approved Oligonucleotide Therapies in 2017.Publié le 20 02 2018

Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and followed about 15 years ago by siRNAs. During that lengthy period of time, numerous clinical trials have been performed and thousands of trial participants accrued onto studies. Of all the molecules evaluated as of January 2017, the regulatory authorities assessed that six provided clear clinical benefit in rigorously controlled trials. The story of these six is given in this review.

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.Publié le 15 02 2018

Background Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). Methods We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (?3 points), an outcome that indicates improvement in at least two motor skills. Results In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). Conclusions Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).

Increasing Agrin Function Antagonizes Muscle Atrophy and Motor Impairment in Spinal Muscular Atrophy.Publié le 15 02 2018

Spinal muscular atrophy (SMA) is a pediatric genetic disease, characterized by motor neuron (MN) death, leading to progressive muscle weakness, respiratory failure, and, in the most severe cases, to death. Abnormalities at the neuromuscular junction (NMJ) have been reported in SMA, including neurofilament (NF) accumulation at presynaptic terminals, immature and smaller than normal endplates, reduced transmitter release, and, finally, muscle denervation. Here we have studied the role of agrin in SMA?7 mice, the experimental model of SMAII. We observed a 50% reduction in agrin expression levels in quadriceps of P10 SMA mice compared to age-matched WT controls. To counteract such condition, we treated SMA mice from birth onwards with therapeutic agrin biological NT-1654, an active splice variant of agrin retaining synaptogenic properties, which is also resistant to proteolytic cleavage by neurotrypsin. Mice were analyzed for behavior, muscle and NMJ histology, and survival. Motor behavior was significantly improved and survival was extended by treatment of SMA mice with NT-1654. At P10, H/E-stained sections of the quadriceps, a proximal muscle early involved in SMA, showed that NT-1654 treatment strongly prevented the size decrease of muscle fibers. Studies of NMJ morphology on whole-mount diaphragm preparations revealed that NT-1654-treated SMA mice had more mature NMJs and reduced NF accumulation, compared to vehicle-treated SMA mice. We conclude that increasing agrin function in SMA has beneficial outcomes on muscle fibers and NMJs as the agrin biological NT-1654 restores the crosstalk between muscle and MNs, delaying muscular atrophy, improving motor performance and extending survival.

Advances in spinal muscular atrophy therapeutics.Publié le 13 02 2018

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.

Degeneration of the corticofugal tract from the secondary motor area in a Parkinson's disease patient with limb-kinetic apraxia: A case report.Publié le 13 02 2018

RATIONALE: In this case report, we describe a Parkinson's disease (PD) patient with limb-kinetic apraxia (LKA) in whom degeneration of the corticofugal tract (CFT) from the supplementary motor area (SMA) was observed in diffusion tensor tractography (DTT).
PATIENT CONCERNS: A 63-year-old woman presented with a loss of dexterity in both upper extremities, which indicated LKA, and typical PD-related symptoms, including a gait disturbance with a short step, resting tremor in both upper extremities, and rigidity, and these symptoms had been present for 2 years. The F-florinated-N-3-fluoropropyl-2-?-carboxymethoxy-3-?-(4-lodophenyl) nortropane positron emission tomography scanning findings were consistent with PD. Based on the clinical symptoms and imaging findings, we diagnosed the patient with PD. In a coin-rotation test that was used to evaluate the severity of the LKA, the patient's results significantly decreased compared to the results of the normal controls.
DIAGNOSES: The DTT showed that the CFTs from the SMAs in both hemispheres were partially torn and thinned. The fractional anisotropy values and CFT volumes in both SMAs were >2 standard deviations lower than those of the normal controls.
INTERVENTIONS: The patient was treated with an initial dose of 150/37.5?mg/day of levodopa/benserazide, and the dose was gradually increased to 400/100?mg/day.
OUTCOMES: After treatment, although the bradykinesia, rigidity, and resting tremor of the patient significantly decreased, the dexterity of the patient's hands did not improve.
LESSONS: These observations indicated degeneration of the CFTs from the SMAs in both hemispheres in the patient. This degeneration might have, at least in part, contributed to the patient's LKA. The results of this study suggest that CFT degeneration could be one of the pathological mechanisms underlying LKA in patients with PD.

Cell freezing protocol suitable for ATAC-Seq on motor neurons derived from human induced pluripotent stem cells.Publié le 13 02 2018

In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy. We found that while flash-frozen iMNs are not suitable for ATAC-Seq, the assay is successful with slow-cooled cryopreserved cells. Using this method, we were able to isolate high quality, intact nuclei, and we verified that epigenetic results from fresh and cryopreserved iMNs quantitatively agree.

Advances in therapy for spinal muscular atrophy: promises and challenges.Publié le 10 02 2018

Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

Minimally Invasive Surgery for Neuromuscular Scoliosis: Results and Complications in a Series of one hundred Patients.Publié le 09 02 2018

STUDY DESIGN: A retrospective review.
OBJECTIVES: To report the results of an alternative technique using a minimally invasive fusionless surgery. The originality is based on the progressive correction of the deformities with proximal and distal fixation and on the reliability of the pelvic fixation using ilio-sacral screws on osteoporotic bones.
SUMMARY OF BACKGROUND DATA: Spinal deformities are common in neuromuscular diseases. Conventional treatment involves bracing, followed by spinal instrumented fusion. Growing rod techniques are increasingly advocated but have a high rate of complications.
METHODS: The technique relies on a bilateral double rod sliding construct anchored proximally by 4 hooks claws and distally to the pelvis by ilio-sacral screws through a minimally invasive approach.100 patients with neuromuscular scoliosis underwent the same fusionless surgery extended from T1 to the pelvis. The average age at initial surgery was 11+6y. Diagnoses included cerebral palsy (61), spinal muscular atrophy (22), muscular dystrophy (10), and other neurological etiologies (7).Cobb angle and pelvic obliquity were measured before and after initial surgery, and at final follow-up. Complications were reviewed.
RESULTS: At latest follow-up 3+9 y (range 2y - 6+3y), the mean Cobb angle improved from 89° to 35° which corresponds to 61% correction. Mean pelvic obliquity improved from 29° to 5° which corresponds to 83% correction. Mean T1-S1 length increased from 30.02?cm to 37.28?cm. Mean preoperative hyper kyphosis was reduced from 68.44° to 33.29°. Complications occurred in 22 patients including mechanical complications (12) and wound infections (16). No arthrodesis was required at last follow-up.
CONCLUSION: This original fusionless technique is safe and effective, preserving spinal and thoracic growth. It provides a significant correction of spinal deformities and pelvic obliquity with a reduced complications rate. The strength and stability of this modular construct over time allow the avoidance of final arthrodesis.
LEVEL OF EVIDENCE: xxxxThis is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.Publié le 08 02 2018

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.

Development of gene therapies-lessons from nusinersen.Publié le 08 02 2018

The nusinersen development and approval process provide important lessons regarding the pathway to marketing approval for gene therapies. These lessons emphasize rigorous clinical trial design, flexibility in trial design and analysis, a collaborative effort with regular communications between the drug developer and the Food and Drug Administration (FDA), and use of FDA's expedited programs. These lessons are critical to the development of gene therapies for the treatment of serious or life-threatening rare diseases.

Spinal muscular atrophy approval boosts antisense drugs.Publié le 08 02 2018

PMID: 28178250 [PubMed - indexed for MEDLINE]

New quantitative method for evaluation of motor functions applicable to spinal muscular atrophy.Publié le 06 02 2018

OBJECTIVE: The aim of this study was to develop and introduce new method to quantify motor functions of the upper extremity.
METHODS: The movement was recorded using a three-dimensional motion capture system, and the movement trajectory was analyzed using newly developed two indices, which measure precise repeatability and directional smoothness. Our target task was shoulder flexion repeated ten times. We applied our method to a healthy adult without and with a weight, simulating muscle impairment. We also applied our method to assess the efficacy of a drug therapy for amelioration of motor functions in a non-ambulatory patient with spinal muscular atrophy. Movement trajectories before and after thyrotropin-releasing hormone therapy were analyzed.
RESULTS: In the healthy adult, we found the values of both indices increased significantly when holding a weight so that the weight-induced deterioration in motor function was successfully detected. From the efficacy assessment of drug therapy in the patient, the directional smoothness index successfully detected improvements in motor function, which were also clinically observed by the patient's doctors.
CONCLUSION: We have developed a new quantitative evaluation method of motor functions of the upper extremity. Clinical usability of this method is also greatly enhanced by reducing the required number of body-attached markers to only one. This simple but universal approach to quantify motor functions will provide additional insights into the clinical phenotypes of various neuromuscular diseases and developmental disorders.

Increase of HCN current in the aberrant excitability of spinal muscular atrophy.Publié le 03 02 2018

Objective The pathophysiology of spinal muscular atrophy (SMA) is still unclear. Methods The nerve excitability test in SMA patients and a mouse model of SMA was carried out to explore the pathophysiology of nodal and internodal currents, and quantitative PCR, Western blotting and whole-cell patch-clamp recording were used for the identified hypothesis. Results The nerve excitability test in SMA patients showed increased inward rectification in the current-threshold relationship and increased overshoot after hyperpolarizing threshold electrotonus, which indicates increased hyperpolarization-activated cyclic nucleotide-gated (HCN) current; these findings correlated with disease severity. Increased inward rectification in the current-threshold relationship was reproducible in a mouse model of mild SMA and the abnormality preceded the decline of compound motor action potential amplitudes. Furthermore, quantitative PCR of spinal cord tissues and Western blotting of the spinal cord and sciatic nerves showed increased HCN1 and HCN2 expression in the SMA mice, and voltage-clamp recording in dissociated spinal motor neurons from SMA mice also showed increased HCN current density. Treatment with ZD7288, an HCN channel blocker, also reduced early mortality, improved motor function, and restored neuromuscular junction architecture in a mouse model of severe SMA. Interpretation This study shows that increased HCN current underlies the pathophysiology of SMA and can be a novel non-SMN-target for SMA therapy. This article is protected by copyright. All rights reserved.

[Weak respiratory muscles as a first sign of ALS: symptoms may put the physician on the wrong track].Publié le 03 02 2018

BACKGROUND: Patients with decreased exercise tolerance and orthopnoea are often referred to an internist, a cardiologist or a pulmonologist. These symptoms can also be caused by weakness of the respiratory muscles, as an indication of a neuromuscular disease. If these symptoms are not recognized as such, this may result in a delay in timely diagnosis.
CASE DESCRIPTION: An 82-year-old man had suffered from decreased exercise tolerance for 18 months. For the last months he had been sleeping upright and had lost 20 kg in weight. Analyses by the cardiologist and the internist had not led to a definitive diagnosis. He was finally brought to the emergency department with loss of consciousness and hypercapnic respiratory insufficiency. Neurological examination was suggestive of motor neuron disease such as progressive spinal muscular atrophy or amyotrophic lateral sclerosis. The patient died within 24 hours of admission.
CONCLUSION: Patients with symptoms resulting from respiratory muscle weakness are commonly referred to non-neurological specialists, leading to a delay in diagnosis and treatment of an underlying neuromuscular disease.

Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy.Publié le 03 02 2018

The hereditary neurodegenerative disorder spinal muscular atrophy (SMA) is characterized by the loss of spinal cord motor neurons and skeletal muscle atrophy. SMA is caused by mutations of the survival motor neuron (SMN) gene leading to a decrease in SMN protein levels. The SMN deficiency alters nuclear body formation and whether it can contribute to the disease remains unclear. Here we screen a series of small-molecules on SMA patient fibroblasts and identify flunarizine that accumulates SMN into Cajal bodies, the nuclear bodies important for the spliceosomal small nuclear RNA (snRNA)-ribonucleoprotein biogenesis. Using histochemistry, real-time RT-PCR and behavioural analyses in a mouse model of SMA, we show that along with the accumulation of SMN into Cajal bodies of spinal cord motor neurons, flunarizine treatment modulates the relative abundance of specific spliceosomal snRNAs in a tissue-dependent manner and can improve the synaptic connections and survival of spinal cord motor neurons. The treatment also protects skeletal muscles from cell death and atrophy, raises the neuromuscular junction maturation and prolongs life span by as much as 40 percent (p?<?0.001). Our findings provide a functional link between flunarizine and SMA pathology, highlighting the potential benefits of flunarizine in a novel therapeutic perspective against neurodegenerative diseases.

Therapy for Spinal Muscular Atrophy.Publié le 01 02 2018

PMID: 29385371 [PubMed - in process]

Does stabilization of the degenerative lumbar spine itself produce multifidus atrophy?Publié le 01 02 2018

The effect of stabilization of the degenerative segment on changes in the pattern of paraspinal muscle activity was investigated using a previously developed musculoskeletal model. Muscle activity change depending on L4-L5 segment stabilization with and without taking into account the presence of multifidus atrophy according to direct invasion of the back muscle during surgery (MADIBM) was analysed in erect standing and 20° flexed postures. For the stabilization of the degenerative segment, a fusion or non-fusion stabilization with a pedicle-based dynamic stabilization system (PBDS) was applied. During erect standing, fusion generated a 12% reduction in the total multifidus muscle force, while its reduction was 6.6% with PBDS application. The presence of MADIBM produced 23.0% and 22.5% reductions in fusion and with PBDS application, respectively. During 20° flexion, 10.5% and 9.3% reductions were produced for fusion and PBDS application, respectively, and the corresponding values were 23.4% and 23.0%, respectively, in the presence of MADIBM. Increased facet joint contact forces were produced at the non-stabilized levels after stabilization while in erect standing posture. Alterations in muscle activity, which could be regarded as adaptions to altered spinal stability, may generate unexpected secondary problems in the spine.

Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy.Publié le 31 01 2018

Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons, leading to progressive paralysis and premature death in the most severe cases. SMA is caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene, leading to low levels of SMN protein. However, a second SMN gene (SMN2) exists, which can be therapeutically targeted to increase SMN levels. This has recently led to the first disease-modifying therapy for SMA gaining formal approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Spinraza (nusinersen) is a modified antisense oligonucleotide that targets the splicing of SMN2, leading to increased SMN protein levels, capable of improving clinical phenotypes in many patients. In addition to Spinraza, several other therapeutic approaches are currently in various stages of clinical development. These include SMN-dependent small molecule and gene therapy approaches along with SMN-independent strategies, such as general neuroprotective factors and muscle strength-enhancing compounds. For each therapy, we provide detailed information on clinical trial design and pharmacological/safety data where available. Previous clinical studies are also discussed to provide context on SMA clinical trial development and the insights these provided for the design of current studies.

Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an AAV vector expressing human SMN.Publié le 31 01 2018

Neurotropic AAV serotypes such as AAV9 have been demonstrated to transduce spinal alpha motor neurons when administered intravenously at high doses. This observation led to the recent successful application of intravenous AAV9 delivery to treat infants with spinal muscular atrophy (SMA), an inherited deficiency of the survival of motor neuron (SMN) protein characterized by selective death of lower motor neurons. To evaluate the efficiency of motor neuron transduction with an AAV9 variant (AAVhu68) using this approach, we treated three juvenile nonhuman primates (NHPs; age 14 months) and three piglets (age 7-30 days) with an intravenous injection of an AAVhu68 vector carrying a human SMN transgene at a dose similar to that employed in the SMA clinical trial. Administration of 2x1014 genome copies per kilogram body weight resulted in widespread transduction of spinal motor neurons in both species. However, severe toxicity occurred in both NHPs and piglets. All three NHPs exhibited marked transaminase elevations. In two NHPs the transaminase elevations resolved without clinical sequelae, while one NHP developed acute liver failure and shock and was euthanized 4 days after vector injection. Degeneration of dorsal root ganglia (DRG) sensory neurons was also observed, although NHPs exhibited no clinically apparent sensory deficits. There was no correlation between clinical findings and T-cell responses to the vector capsid or transgene product in NHPs. Piglets demonstrated no evidence of hepatic toxicity, but within 14 days of vector injection all three animals exhibited proprioceptive deficits and ataxia which profoundly impaired ambulation and necessitated euthanasia. These clinical findings correlated with more severe DRG sensory neuron lesions than those observed in NHPs. The liver and sensory neuron findings appear to be a direct consequence of AAV transduction independent of an immune response to the capsid or transgene product. The present results and those of another recent study utilizing a different AAV9 variant and transgene indicate that systemic and sensory neuron toxicity may be general properties of intravenous delivery of AAV vectors at high doses irrespective of the capsid serotype or transgene. Preclinical and clinical studies involving high systemic doses of AAV vectors should include careful monitoring for similar toxicities.

The Cross-Sectional Area of Paraspinal Muscles Predicts the Efficacy of Deep Drain Stimulation for Camptocormia.Publié le 31 01 2018

BACKGROUND: Camptocormia, a disturbance of posture, is a well-described clinical feature of PD and other parkinsonian syndromes. Previous reports have shown that DBS of the subthalamic nucleus (STN) or globus pallidus internus is effective in treating camptocormia. However, the efficacy of DBS for camptocormia varies.
OBJECTIVE: To determine a clinical marker for selecting an appropriate therapy for camptocormia, a disabling manifestation of Parkinson's disease (PD) that has a variable response to systemic and local therapies.
METHODS: We obtained pre-operative lumbar magnetic resonance imaging of 14 consecutive PD patients with camptocormia who underwent subthalamic nucleus deep brain stimulation (STN-DBS) in this retrospective-designed study. Lumbar MRI was performed three to six months prior to the operation. We measured the cross-sectional area (CSA) and width of each participant's paraspinal muscles.
RESULTS: Four (28.6%) patients were effective (EF), five (35.7%) were partially effective (PE), and five (35.7%) were non-effective (NE) to STN-DBS. The lumbar paraspinal CSA and width were significantly larger in the EF group than in the PE and NE groups.
CONCLUSIONS: The CSA of paraspinal muscles and erector spinae width can be good predictive markers for improving camptocormia in patients with PD after deep brain stimulation.

Splicing solutions: Companies explore new techniques to fix splicing errors.Publié le 31 01 2018

PMID: 27603128 [PubMed - indexed for MEDLINE]

[Intrathecal Nursinersen Therapy in Children with Spinal Muscular Atrophy and Spinal Deformities].Publié le 30 01 2018

PMID: 29378349 [PubMed - as supplied by publisher]

"Transcriptomics": molecular diagnosis of inborn errors of metabolism via RNA-sequencing.Publié le 27 01 2018

Exome wide sequencing techniques have revolutionized molecular diagnostics in patients with suspected inborn errors of metabolism or neuromuscular disorders. However, the diagnostic yield of 25-60% still leaves a large fraction of individuals without a diagnosis. This indicates a causative role for non-exonic regulatory variants not covered by whole exome sequencing. Here we review how systematic RNA-sequencing analysis (RNA-seq, "transcriptomics") lead to a molecular diagnosis in 10-35% of patients in whom whole exome sequencing failed to do so. Importantly, RNA-sequencing based discoveries cannot only guide molecular diagnosis but might also unravel therapeutic intervention points such as antisense oligonucleotide treatment for splicing defects as recently reported for spinal muscular atrophy.

Describing nutrition in spinal muscular atrophy: A systematic review.Publié le 27 01 2018

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease of variable severity. Progressive muscle wasting and impairment in functional ability in SMA have a profound influence on nutritional outcomes. This systematic review summarises the existing evidence on nutrition in SMA. The search strategy was conducted across five databases in August 2014, and updated in March 2016, using key terms relating to growth, nutrition requirements, dietary intake and nutrition management. Studies were selected for inclusion using a two pass method, and data systematically extracted using standardised forms. Thirty-nine studies met eligibility criteria. Body composition is abnormal in patients with SMA, and feeding and swallowing issues are prevalent among sufferers of SMA types I and II. Nutritional management practices vary internationally. There is a paucity of literature regarding nutrition requirements in SMA, although it appears that energy expenditure may be reduced. Children with SMA require individualised nutritional management in order to address their growth and nutrition requirements. There is an urgent need for larger, coordinated, prospective intervention studies of nutrition in SMA.

Recurrent de novo BICD2 mutation associated with arthrogryposis multiplex congenita and bilateral perisylvian polymicrogyria.Publié le 27 01 2018

Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo. The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1.

Military genomics: a perspective on the successes and challenges of genomic medicine in the Armed Services.Publié le 21 01 2018

We describe the impact genomics has on the health and readiness of the military service member, highlight several examples of the current and future plans for genomic medicine within the military, discuss challenges to implementation and provide recommendations to address some of those challenges.

RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.Publié le 19 01 2018

Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

Effects of Arm Cycling Exercise in Spinal Muscular Atrophy Type II Patients: A Pilot Study.Publié le 13 01 2018

Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels. The active cycling distance and duration of patients significantly improved. Significant changes could not have detected either SMN or IGF1 and IGFBP3 levels in response to exercise. The findings demonstrated that the patients tolerated the exercise protocol and gained a benefit from arm cycling but benefits could not be associated with SMN2 copy number, SMN protein level, IGF1, or IGFBP3 levels.

Investigation of New Morpholino Oligomers to Increase Survival Motor Neuron Protein Levels in Spinal Muscular Atrophy.Publié le 11 01 2018

Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous SMN2 gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype. Here, we optimized this strategy by testing the efficacy of four new MO sequences targeting SMN2. Two out of the four new MO sequences showed better efficacy in terms of SMN protein production both in SMA induced pluripotent stem cells (iPSCs) and SMA?7 mice. Further, the effect was enhanced when different MO sequences were administered in combination. Our data provide an important insight for MO-based treatment for SMA. Optimization of the target sequence and validation of a treatment based on a combination of different MO sequences could support further pre-clinical studies and the progression toward future clinical trials.

Time Is Motor Neuron: Therapeutic Window and Its Correlation with Pathogenetic Mechanisms in Spinal Muscular Atrophy.Publié le 03 01 2018

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of lower motor neurons (MNs) in the spinal cord and brain stem, which results in relentless muscle weakness and wasting, leading to premature death due to respiratory complications. The identification of the specific mutations in the survival motor neuron 1 (SMN1) gene that causes SMA has led to the development of experimental therapeutic strategies to increase SMN protein expression, including antisense oligonucleotides, small molecules, and gene therapy, which have so far shown promising results. The timing of therapeutic intervention is crucial since most of the degeneration in MNs occurs in the first months of life in patients with SMA type 1, which is the most severe and common form of SMA. Nevertheless, a precise temporal window for therapeutic intervention has not yet been identified. Evidence from in vivo studies in mice and large animals suggested that early therapeutic intervention for SMA correlated with better motor performance, longer survival, and, occasionally, rescue of the pathological phenotype. Indeed, the need to compensate for the loss of SMN protein function seemed to diminish during adulthood (even though repair ability after nerve injury remained impaired), suggesting the possibility of tapering the therapy administration late in the disease course. Moreover, recent clinical trials on children afflicted with SMA type 1 have shown a more rapid achievement of motor milestones and diminished disease severity when therapy was administered at an early age and earlier in the disease course. Finally, these results highlight the importance of newborn screening for SMA to facilitate early diagnosis and present the patient with available treatments while they are still in the presymptomatic stage.

Lysine-Less Variants of Spinal Muscular Atrophy SMN and SMN?7 Proteins Are Degraded by the Proteasome Pathway.Publié le 03 01 2018

Spinal muscular atrophy is due to mutations affecting the SMN1 gene coding for the full-length protein (survival motor neuron; SMN) and the SMN2 gene that preferentially generates an exon 7-deleted protein (SMN?7) by alternative splicing. To study SMN and SMN?7 degradation in the cell, we have used tagged versions at the N- (Flag) or C-terminus (V5) of both proteins. Transfection of those constructs into HeLa cells and treatment with cycloheximide showed that those protein constructs were degraded. Proteasomal degradation usually requires prior lysine ubiquitylation. Surprisingly, lysine-less variants of both proteins tagged either at N- (Flag) or C-terminus (V5) were also degraded. The degradation of the endogenous SMN protein, and the protein constructs mentioned above, was mediated by the proteasome, as it was blocked by lactacystin, a specific and irreversible proteasomal inhibitor. The results obtained allowed us to conclude that SMN and SMN?7 proteasomal degradation did not absolutely require internal ubiquitylation nor N-terminal ubiquitylation (prevented by N-terminal tagging). While the above conclusions are firmly supported by the experimental data presented, we discuss and justify the need of deep proteomic techniques for the study of SMN complex components (orphan and bound) turn-over to understand the physiological relevant mechanisms of degradation of SMN and SMN?7 in the cell.

Spinal Muscular Atrophy Type I: Is It Ethical to Standardize Supportive Care Intervention in Clinical Trials?Publié le 03 01 2018

The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial.

Home Mechanical Ventilation: An Overview.Publié le 30 12 2017

Prevalence studies have shown heterogeneous use of home mechanical ventilation in different conditions, with a marked increase in uptake especially in users of noninvasive ventilation. Although randomized controlled trials have examined noninvasive ventilation in acute exacerbations of chronic obstructive pulmonary disease, for weaning from invasive ventilation and for postextubation respiratory failure, the evidence base for long-term noninvasive ventilation and comparisons with invasive ventilation are less well developed. The combination of noninvasive ventilation and cough-assist devices has reduced the indications for tracheotomy ventilation in some situations (e.g., Duchenne muscular dystrophy, spinal muscular atrophy, myopathies, and amyotrophic lateral sclerosis) and has also prolonged survival. Several excellent overviews have been written on the history of home mechanical ventilation and its evolution from negative pressure to positive pressure techniques, including a systematic review of outcomes. This review, instead, will cover recent trials, trends in the field, outcomes, and safety. Because the greatest growth has been in home noninvasive ventilation, this will be the main focus of this article.

Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.Publié le 24 12 2017

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the where, which, what, and when in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience.Publié le 22 12 2017

Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post-lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture-related adverse event frequency was similar to that previously reported in children.

AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials.Publié le 19 12 2017

INTRODUCTION: Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway. Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed. Expert opinion: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction.

The relative frequency of common neuromuscular diagnoses in a reference center.Publié le 15 12 2017

The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests.
OBJECTIVE: To report the relative frequency of common neuromuscular diagnoses in a reference center.
METHODS: A 17-year chart review of patients with suspicion of myopathy.
RESULTS: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%).
CONCLUSION: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications.

More Clinical Mimics of Infant Botulism.Publié le 14 12 2017

OBJECTIVE: To ascertain the actual diagnoses of 76 patients (2005-2015) whose clinical presentations so closely resembled infant botulism that the patients were treated with Human Botulism Immune Globulin Intravenous (BIG-IV; BabyBIG), but whose illnesses subsequently were not laboratory confirmed as infant botulism ("clinical mimics" of infant botulism).
STUDY DESIGN: The California Department of Public Health produces BIG-IV and distributes it nationwide as a public service (ie, not-for-profit) orphan drug to treat patients hospitalized with suspected infant botulism. During the study period, admission records and discharge summaries for all patients treated with BIG-IV but who lacked a laboratory-confirmed diagnosis of infant botulism were collected and abstracted. The patients' discharge diagnoses were identified, categorized, and compared with previously reported clinical mimics categories for 32 patients (1992-2005).
RESULTS: From 2005 to 2015, 76 clinical mimic illnesses were identified. These illnesses were distributed into the 5 categories previously reported of (1) probable infant botulism lacking confirmatory testing (26.3%); (2) spinal muscular atrophy (19.7%); (3) miscellaneous (15.8%); (4) metabolic disorders (11.8%); and (5) other infectious diseases (10.6%). Of the 76 clinical mimic illnesses, 15.8% had no alternate diagnosis established and were therefore categorized as undetermined.
CONCLUSIONS: Over the 23 years 1992-2015, patients presenting with illnesses so clinically similar to infant botulism that they were treated with BIG-IV had actual diagnoses that were distributed into 5 main categories. These categories and their individual components constitute a working bedside differential diagnosis of infant botulism.

Denosumab Treatment of Severe Disuse Osteoporosis in a Boy With Spinal Muscular Atrophy.Publié le 14 12 2017

Denosumab is a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-?B ligand. Denosumab is used in the treatment of postmenopausal osteoporosis and cancer-related bone disorders. There are only very scarce data on denosumab treatment in children. 14-year-old boy with spinal muscular atrophy (SMA) and severe disuse osteoporosis (spinal bone mineral density L1-L4 BMD-6.2SD Z-score) and two prevalent fragility fractures was treated with denosumab. He received 60 mg  subcutaneous injection at the baseline and seven months later. Six months after the initial injection there was a 19% increase in L1-L4 BMD. The injections were well tolerated without any adverse reactions. Calcemia remained stable (2.3-2.4 mmol/L). He was scheduled for the third denosumab injection six months later. Prior to this date, he acquired pneumonia and died due to respiratory failure, which is a frequent cause of death in patients with SMA. There was no relation to the denosumab treatment. In conclusion, one dose of denosumab significantly increased BMD in a child with severe osteoporosis.

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study.Publié le 14 12 2017

OBJECTIVE: To evaluate the prognosis and progression of spinal and bulbar muscular atrophy (SBMA), a rare X-linked motor neuron disorder caused by trinucleotide repeat expansion in the AR (androgen receptor) gene, after long-term androgen suppression with leuprorelin acetate treatment.
METHODS: In the present natural history-controlled study, 36 patients with SBMA treated with leuprorelin acetate for up to 84 months (leuprorelin acetate-treated group; LT group) and 29 patients with SBMA with no specific treatment (non-treated group; NT group) were analysed. Disease progression was evaluated by longitudinal quantitative assessment of motor functioning using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and the modified Norris score. In addition, we selected two major clinical endpoint events, namely the occurrence of pneumonia requiring hospitalisation and death, to evaluate disease prognosis following long-term leuprorelin acetate treatment.
RESULTS: In our analysis of the longitudinal disease progression using the random slope model, we observed a significant difference in the ALSFRS-R total score, the Limb Norris Score, and the Norris Bulbar Score (p=0.005, 0.026 and 0.020, respectively), with the LT group exhibiting a slower per-12-months decline compared with the NT group. As for the event analysis, the prognosis of the LT group was better in comparison to the NT group as for the event-free survival period (p=0.021).
CONCLUSION: Long-term treatment with leuprorelin acetate appears to delay the functional decline and suppress the incidence of pneumonia and death in subjects with SBMA.

Motor milestone assessment of infants with spinal muscular atrophy using the hammersmith infant neurological Exam-Part 2: Experience from a nusinersen clinical study.Publié le 14 12 2017

INTRODUCTION: In this study we examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam-Part 2 (HINE-2) in a phase 2 study of nusinersen.
METHODS: Nineteen SMA infants were assessed using the HINE-2 at baseline (?7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE-2 was feasible, reliable, and sensitive to change.
RESULTS: Motor milestone assessments in SMA infants were feasible using the HINE-2. Baseline test-retest reliability was excellent (R = 0.987; P < 0.0001). SMA infants were extremely low functioning at baseline and the HINE-2 was able to detect changes over time in 16 of 19 infants within all 8 domains. HINE-2 improvements were correlated with changes in other neuromuscular outcome measures.
CONCLUSION: Results support the use of the HINE-2 motor milestone assessment in clinical trials of SMA infants. Muscle Nerve 57: 143-146, 2017.

Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy.Publié le 12 12 2017

The US Food and Drug Administration's December 2016 approval of nusinersen for the treatment of patients with all subtypes of spinal muscular atrophy ushered in a new era for patients with spinal muscular atrophy, their families, and all those involved in their care. The extreme cost of the medication and the complicated logistical requirements for administering nusinersen via lumbar puncture have created practical challenges that raise important ethical considerations. We discuss 6 challenges faced at the institutional level in the United States: cost, limited evidence, informed consent, treatment allocation, fair distribution of responsibilities, and transparency with stakeholders. These challenges must be understood to ensure that patients with spinal muscular atrophy benefit from treatment, are protected from harm, and are treated fairly.

Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model.Publié le 09 12 2017

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive degeneration of spinal-cord motor neurons, leading to atrophy of skeletal muscles. However, accumulating evidence indicates that it is a multi-system disorder, particularly in its severe forms. Several studies delineated structural and functional cardiac abnormalities in SMA patients and mouse models, yet the abnormalities have been primarily attributed to autonomic dysfunction. Here, we show in a severe mouse model that its cardiomyocytes undergo G0/G1 cell-cycle arrest and enhanced apoptosis during postnatal development. Microarray and real-time RT-PCR analyses revealed that a set of genes associated with cell cycle and apoptosis were dysregulated in newborn pups. Of particular interest, the Birc5 gene, which encodes Survivin, an essential protein for heart development, was down-regulated even on pre-symptomatic postnatal day 0. Interestingly, cultured cardiomyocytes depleted of SMN recapitulated the gene expression changes including downregulation of Survivin and abnormal cell-cycle progression; and overexpression of Survivin rescued the cell-cycle defect. Finally, increasing SMN in SMA mice with a therapeutic antisense oligonucleotide improved heart pathology and recovered expression of deregulated genes. Collectively, our data demonstrate that the cardiac malfunction of the severe SMA mouse model is mainly a cell-autonomous defect, caused by widespread gene deregulation in heart tissue, particularly of Birc5, resulting in developmental abnormalities through cell-cycle arrest and apoptosis.

Restoration of SMN expression in mesenchymal stem cells derived from gene-targeted patient-specific iPSCs.Publié le 07 12 2017

Spinal muscular atrophy (SMA) is primarily a neurodegenerative disease caused by the homozygous deletion of the survival motor neuron 1 (SMN1) gene, thereby reducing SMN protein expression. Mesenchymal stem cells (MSCs) have been implicated in the treatment of SMA. In the present study, we overexpressed exogenous SMN1 at the ribosomal DNA (rDNA) locus of induced pluripotent stem cells (iPSCs) generated from a SMA patient using an rDNA-targeting vector. The gene-targeted patient iPSCs differentiated into MSCs (SMN1-MSCs). A 2.1-fold higher expression level of SMN protein was detected in SMN1-MSCs than that detected in MSCs derived from patient iPSCs, and the results of the immunofluorescence analysis showed no difference in the quantity of SMN nuclear structures (gems) between SMN1-MSCs and MSCs derived from normal human iPSCs (h-MSCs). These findings provide a novel strategy for obtaining gene-targeted MSCs for potential clinical applications in autologous cell-based therapy.

Single-center experience with intrathecal administration of Nusinersen in children with spinal muscular atrophy type 1.Publié le 07 12 2017

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder mainly characterized by proximal muscle weakness. There have been enormous advances in therapeutic development with the possibility to influence the clinical course of the disease. Nusinersen is the first approved drug to treat SMA. It is administered intrathecally and acts as splicing modifier of the SMN2 gene.
METHODS: Lumbar punctures were performed using a standardized protocol. To evaluate safety and feasibility of the intrathecal treatment, vital signs and the need for sedation, analgesia or mechanical ventilation during the procedure were monitored. Furthermore, the number of puncture attempts, the injection site and the macroscopic appearance of cerebrospinal fluid were documented.
RESULTS: Treatment with Nusinersen was initiated in 20 children aged from 2 to 50 months. Administration of a local anesthetic cream on the puncture site and a peripheral analgesic led to an adequate pain management. We observed a beneficial distraction through the possibility to watch a movie or listen to music during the procedure. In some cases, an additional sedation was necessary. In patients accustomed to non-invasive ventilation, this was used during lumbar punctures. On average, 1.5 ± 1.0 puncture attempts were performed between L 4/5 and L 2/3. If required, the position of the medullary cone was identified by ultrasound to guarantee a safe puncture above L 3/4.
CONCLUSIONS: Lumbar punctures for intrathecal administration of Nusinersen could be performed without any relevant complications. With the described approach lumbar punctures were tolerated well in all investigated age groups.

Neuromuscular Diseases: Diagnosis and Management.Publié le 04 12 2017

Neuromuscular diseases (NMDs) affect the peripheral nervous system, which includes the motor neurons and sensory neurons; the muscle itself; or the neuromuscular junction. Thus, the term NMDs encompasses a vast array of different syndromes. Some of these syndromes are of direct relevance to paediatric orthopaedic surgeons, either because the presenting manifestation is a functional sign (e.g., toe walking) or deformity (e.g., pes cavus or scoliosis) suggesting a need for orthopaedic attention or because orthopaedic abnormalities requiring treatment develop during the course of a known NMD. The main NMDs relevant to the orthopaedic surgeon are infantile spinal muscular atrophy (a motor neuron disease), peripheral neuropathies (chiefly Charcot-Marie-Tooth disease), congenital muscular dystrophies, progressive muscular dystrophies, and Steinert myotonic dystrophy (or myotonic dystrophy type 1). Muscle weakness is a symptom shared by all these conditions. The paediatric orthopaedic surgeon must be familiar, not only with the musculoskeletal system, but also with many other domains (particularly respiratory and cardiac function and nutrition) that may interfere with the treatment and require pre-operative management. Good knowledge of the natural history of each NMD is essential to ensure optimal timing of the therapeutic interventions, which must be performed under the best possible conditions in these usually frail patients. Timing is particularly crucial for the treatment of spinal deformities due to paraspinal muscle hypotonia during growth: depending on the disease and natural history, the treatment may involve non-operative methods or growing rods, followed by spinal fusion. A multidisciplinary approach is always required. Finally, the survival gains achieved in recent years increasingly require attention to preparing for adult life, to orthopaedic problems requiring treatment before the patient leaves the paediatric environment, and to the transition towards the adult healthcare system.

Muscle strength and motor function throughout life in a cross- sectional cohort of 180 patients with SMA types 1c-4.Publié le 02 12 2017

BACKGROUND: Natural history studies in SMA have primarily focused on infants and children. Natural history studies encompassing all age groups and SMA types are important for the interpretation of treatment effects of recently introduced SMN augmenting therapies.
METHODS: We conducted a cross-sectional study to investigate muscle strength, Hammersmith Functional Motor Scale (Expanded) scores and the patterns of muscle weakness in relation to age and SMA type.
RESULTS: We included 180 patients with SMA types 1-4 in the age range 1-77.5 years and median disease duration of 18 years (range 0-65.8 years). With the exception of the early phases of disease in which children with SMA types 2 and 3 may achieve new motor skills and show a temporary increase in muscle strength, cross sectional data suggest that declining muscle strength and loss of motor skills over time are characteristic for all SMA types. Mean loss of strength is at least 1 point on the MRC and 0.5 point on the HFMS(E) scores per year. Trend lines compatible with deterioration of motor function and muscle strength start in childhood and continue into adulthood. The age at loss of specific motor skills is associated with disease severity. Triceps, deltoid, iliopsoas and quadriceps are the weakest muscles in all patients. Hierarchical cluster analysis did not show a segmental distribution of muscle weakness as was suggested previously.
CONCLUSIONS: Progressive muscle weakness, and loss of motor function are characteristic of all SMA types and all ages. This article is protected by copyright. All rights reserved.

Antisense oligonucleotides: the next frontier for treatment of neurological disorders.Publié le 02 12 2017

Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future.

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities.Publié le 02 12 2017

Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality to only mild muscular weakness, and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein; however, understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients. Research has shown that SMN, both on the mRNA and protein level, is highly affected by cellular stress. In this review we will summarize the research that highlights the roles of SMN in the disease process and the response of SMN to various environmental stresses.

Modulation of aberrant splicing in human RNA diseases by chemical compounds.Publié le 02 12 2017

Pre-mRNA splicing is an essential step for gene expression in higher eukaryotes. Alternative splicing contributes to diversity of the expressed proteins from the limited number of genes. Disruption of splicing regulation often results in hereditary and sporadic diseases called as 'RNA diseases'. Modulation of splicing by small chemical compounds and nucleic acids has been tried to target aberrant splicing in those diseases. Several RNA diseases and splicing-target therapeutic approaches will be briefly introduced in this review. Accumulating knowledge about molecular mechanism of aberrant splicing and their correction by chemical compounds is important not only for RNA biologists, but also for clinicians who desire therapies for those diseases.

Two Cases of Spinal Muscular Atrophy Type II with Eosinophilic Oesophagitis.Publié le 26 11 2017

Although primarily characterised by loss of motor neurons from the anterior horn of spinal cord and muscle atrophy, spinal muscular atrophy (SMA) is now recognised as a multi-systemic disorder. Here, we report two SMA Type II patients with eosinophilic oesophagitis (EoE), a rare, chronic immune/antigen-mediated condition. One patient presented with dysphagia and poor weight gain, and the second patient had symptoms of gastro-oesophageal reflux (GOR) and poor weight gain. In both patients, macroscopic observations during gastroscopy indicated typical signs of EoE, which were verified during histological examination of oesophageal biopsies. Given that there is a specific treatment strategy for EoE, these cases highlight the importance of considering this condition in clinical investigations - especially for patients with SMA - who have GOR, discomfort, and oral aversion.

Newborn genetic screening for spinal muscular atrophy in the UK: The views of the general population.Publié le 24 11 2017

BACKGROUND: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and a leading genetic cause of infant death worldwide. However, there is no routine screening program for SMA in the UK. Lack of treatments and the inability of screening tests to accurately predict disease severity are among the key reasons implementation of screening has faltered in the UK. With the recent release of the first therapy for SMA (Nusinersen), calls are being made for a reconsideration of this stance; however, very little is known about the views of the general public.
METHODS: An online survey was administered to 232 individuals with no prior relationship with SMA to assess their attitudes toward a newborn screening program for it. Results are compared with previously gathered data on the views of SMA-affected families toward screening.
RESULTS: Eighty-four percent of participants were in favor of newborn screening. Key reasons for support were a belief that it would lead to better healthcare and life expectancy for affected infants and facilitate informed decision-making for future pregnancies. Key reasons for nonsupport were a belief in the potential for significant negative impact on the family unit in terms of bonding and stress.
CONCLUSIONS: Public acceptability is a key component in the evaluation of any potential screening program in the UK. This study demonstrates that newborn screening for SMA is viewed largely positively by people unfamiliar with the condition. The importance of early identification overrode all other social and ethical concerns about screening for the majority of participants.

Self-oligomerization regulates stability of Survival Motor Neuron (SMN) protein isoforms by sequestering an SCF(Slmb) degron.Publié le 24 11 2017

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1 Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMN?7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCF(Slmb) ubiquitin E3 ligase complex as a novel SMN binding partner. SCF(Slmb) interacts with a phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCF(Slmb) binding and stabilizes SMN?7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMN?7(S270A), but not wild-type SMN?7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric, and sequestered when SMN forms higher-order multimers.

miRNA in spinal muscular atrophy pathogenesis and therapy.Publié le 22 11 2017

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the selective death of lower motor neurons in the brain stem and spinal cord. SMA is caused by mutations in the survival motor neuron 1 gene (SMN1), leading to the reduced expression of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that regulate post-transcriptional gene expression. Recent findings have suggested an important role for miRNAs in the pathogenesis of motor neuron diseases, including SMA. Motor neuron-specific miRNA dysregulation in SMA might be implicated in their selective vulnerability. In this study, we discuss recent findings regarding the consequences of SMN defects on miRNAs and their target mRNAs in motor neurons. Taken together, these data suggest that cell-specific changes in miRNAs are not only involved in the SMA motor neuron phenotype but can also be used as biomarkers and therapeutic targets.

Natural History of Infantile-Onset Spinal Muscular Atrophy.Publié le 18 11 2017

OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.
METHODS: A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed.
RESULTS: Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17).
INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real world", prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved.

Spinal Muscular Atrophy: The Treatment Approved.Publié le 17 11 2017

Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder resulting in progressive muscle weakness and atrophy. It is universally fatal, especially if the respiratory muscles are involved leading to repetitive aspiration and respiratory failure. Historically, the treatment for this disease was only supportive. Herein we describe an adult patient who presented with worsening weakness and fatigue and was subsequently diagnosed with spinal muscular atrophy. Increased awareness of this condition and a new treatment modality is required.

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers.Publié le 15 11 2017

Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.

Transforaminal intrathecal delivery of nusinersen using cone-beam computed tomography for children with spinal muscular atrophy and extensive surgical instrumentation: early results of technical success and safety.Publié le 14 11 2017

BACKGROUND: Nusinersen, the only treatment approved by the United States Food and Drug Administration for spinal muscular atrophy (SMA), is delivered intrathecally. Many children with SMA have extensive spinal instrumentation and deformities, often precluding the use of standard approaches for gaining intrathecal access. Furthermore the anatomical distortion that often occurs with rotoscoliosis can complicate the use of fluoroscopic guidance. Compared to fluoroscopy, CT affords superior guidance for complex needle placements. This opens up alternatives to the posterior (interlaminar) technique, including transforaminal and caudal approaches.
OBJECTIVE: This study describes the early results of technical success, complications and radiation dose of intrathecal delivery of nusinersen using cone-beam CT guidance with two-axis fluoroscopic navigational overlay.
MATERIALS AND METHODS: We conducted a retrospective review of 15 consecutive nusinersen injections performed in four children with SMA and extensive spinal hardware precluding standard posterior lumbar puncture techniques. These children were treated using transforaminal thecal access employing cone-beam CT with navigational overlay. We analyzed results including technical success, complications and total fluoroscopy time.
RESULTS: All procedures were technically successful. No major complications and one minor complication were reported; the minor complication was a post-procedural neuropathic headache that was attributed to procedural positioning and was treated successfully with gabapentin. The average procedural fluoroscopy time and air kerma were 1.9 min and 55.8 mGy, respectively.
CONCLUSION: Cone-beam CT guidance with two-axis navigational overlay is a safe, effective method for gaining transforaminal intrathecal access in children with spinal abnormalities and hardware precluding the use of standard techniques.

Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing.Publié le 14 11 2017

Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.

[Spinal muscular atrophy : Time for newborn screening?]Publié le 05 11 2017

The most common neurodegenerative disease in childhood is spinal muscular atrophy (SMA). The severe infantile type 1 (Werdnig-Hoffman disease) makes 60% of SMA in total. These children usually die within 18 months without ventilation. New therapeutic approaches have led from the theoretical concept to randomized controlled clinical trials in patients. For the first time, a pharmacological treatment of SMA has been approved. The early detection of the disease is decisive for the success of therapy. All previous data suggest starting treatment early and when possible prior to the onset of symptoms considerably improves the outcome in comparison to a delayed start. The goal must be the presymptomatic diagnosis in order to initiate treatment before motor neuron degeneration. Technical and ethical prerequisites for a molecular genetic newborn screening are given.

The Dilemma of Two Innovative Therapies for Spinal Muscular Atrophy.Publié le 04 11 2017

PMID: 29091554 [PubMed - indexed for MEDLINE]

Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.Publié le 04 11 2017

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.

Segmental Pedicle Screw Instrumentation and Fusion Only to L5 in the Surgical Treatment of Flaccid Neuromuscular Scoliosis.Publié le 03 11 2017

STUDY DESIGN: A retrospective cohort study was performed.
OBJECTIVE: The purpose of this study was to determine the efficacy and safety of stopping segmental pedicle screw instrumentation constructs at L5 in the treatment of neuromuscular scoliosis.
SUMMARY OF BACKGROUND DATA: Duchenne muscular dystrophy and spinal muscular atrophy are flaccid neuromuscular disorders in which gradual deterioration is the hallmark and have a lot of characteristics in common despite differences in etiology. Instrumentation and fusion to the sacrum/pelvis has been a mainstay in the surgical treatment of flaccid neuromuscular scoliosis and recommended to correct pelvic obliquity. However, the caudal extent of instrumentation and fusion in the surgical treatment of flaccid neuromuscular scoliosis has remained a matter of considerable debate and there have been few studies on the use of segmental pedicle screw instrumentation for flaccid neuromuscular scoliosis.
METHOD: From 2005 to 2007, a total of 27 consecutive patients with neuromuscular disorders (20 Duchenne muscular dystrophy and 7 spinal muscular atrophy), aged 11 to 17 years, underwent segmental pedicle screw instrumentation and fusion only to L5. Assessment was performed clinically and with radiologic measurements. Minimum 2-year follow-up was required for inclusion in this study.
RESULTS: Twenty patients were enrolled in this study. No patient was lost to follow-up. All patients had L5 tilt of less than 15° and a coronal curve with apex L2 or higher preoperatively. Preoperative coronal curve averaged 70° (range: 51°-88°), with a postoperative mean of 15° (range: 5°-25°) and 17° (range: 6°-27°) at the last follow-up. The pelvic obliquity improved from 15° (range: 9°-25°) preoperatively to 5° (range: 3°-8°) postoperatively and 6° (range: 3°-8°) at the last follow-up. The L5 tilt improved from 9° (range: 2°-14°) preoperatively to 2° (range: 0°-4°) postoperatively and 2° (range: 0°-5°) at the last follow-up. Physiologic sagittal plane alignment was recreated after surgery and maintained long-term. There was no significant loss of correction of coronal curve and pelvic obliquity. There was no major complication.
CONCLUSION: Segmental pedicle screw instrumentation and fusion to L5 was safe and effective in patients with flaccid neuromuscular scoliosis with apex L2 or higher and minimal L5 tilt of less than 15°. Segmental pedicle screw instrumentation ending at L5 offered the ability to correct spinal deformity and pelvic obliquity initially, intermediate and even long-term, with no major complications. This method in appropriate patients can be a viable alternative to instrumentation and fusion to the sacrum/pelvis in the surgical treatment of flaccid neuromuscular scoliosis.

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.Publié le 02 11 2017

Background Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. Conclusions Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.Publié le 02 11 2017

Background Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. Methods Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10(13) vg per kilogram of body weight), and 12 received a high dose (2.0×10(14) vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). Results As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. Conclusions In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

Free-Aspire: A new device for the management of airways clearance in patient with ineffective cough.Publié le 31 10 2017

A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physical examination pulmonary auscultation revealed an asymmetry of breath sounds between the 2 hemithoraces, owing to decreased breath sounds in the right hemithorax. Blood tests were normal. The initial working diagnosis was a suspected area of mucus accumulation. A treatment with Free Aspire was started. Within a few days, the girl was discharged with a normal physical examination and X-ray study result. Spinal Muscular Atrophy is a rare neuromuscular disorder characterized by loss of motor neurons and progressive muscle wasting. Cough in these patients result ineffective. Free-Aspire is an electromedical machine for removing bronchoalveolar secretions. The case show that Free Aspire in patients with ineffective cough and impaired removal of secretions is a safe and effective device for the removal of bronchial secretions and could be an another help in the management of airway clearance.

Long-term ventilation in spinal muscular atrophy: the price of progress.Publié le 31 10 2017

PMID: 28691265 [PubMed - indexed for MEDLINE]

A Historical and Current Review of Newborn Screening for Neuromuscular Disorders From Around the World: Lessons for the United States.Publié le 29 10 2017

BACKGROUND: We aimed to review the history of newborn screening for three neuromuscular disorders (Duchenne muscular dystrophy, Pompe disease, and spinal muscular atrophy [SMA]) to determine best practices.
METHODS: The history of newborn screening for Duchenne muscular dystrophy began in 1975 with the measurement of creatinine kinase on newborn male blood spots from two Midwestern hospitals in the United States. Over the next 40 years, ten programs were implemented around the globe although none currently remain. The first experimental pilot program for Pompe disease began in 2005 in Taiwan. In 2013, Missouri was the first US state to implement Pompe newborn screening before its inclusion in the Recommended Uniform Screening Panel (RUSP) in 2015 by the Advisory Committee on Heritable Disorders in Newborns and Children (United States). In 2008, SMA was reviewed and rejected for inclusion in the RUSP because no treatment existed. With the approval of nusinersen in late 2016, spinal muscular atrophy is being reconsidered for the RUSP.
RESULTS: A condition should meet public health screening criteria to be included in the RUSP. Duchenne muscular dystrophy, Pompe, and SMA challenge traditional screening criteria: Duchenne muscular dystrophy does not present in infancy and lacks effective treatment; Pompe and SMA may not present until adulthood; and safety and efficacy of long-term intrathecal treatment for SMA is unknown. Potential reproductive benefit and improved research recruitment do not justify a public health screening program.
CONCLUSIONS: This review provides lessons that could benefit US public health departments as they consider expanding screening to include neuromuscular disorders like Duchenne muscular dystrophy, Pompe, and SMA.

Segmental Spinal Muscular Atrophy Localised to the Lower Limbs: First case from Oman.Publié le 25 10 2017

Spinal muscular atrophy (SMA) is a genetic lower motor neuron disease. It usually involves all of the skeletal muscles innervated by the anterior horn cells of the spinal cord. In rare cases, there is also localised involvement of the spinal cord. We report a 10-year-old boy who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2015 with muscle weakness restricted to the lower limbs. The presence of a homozygous deletion within the survival of motor neuron 1 gene confirmed the diagnosis of SMA. To the best of the authors' knowledge, this is the first report of an Omani patient with segmental SMA involving only the lower limbs. Treatment for this rare and relatively benign form of SMA is symptomatic and includes physiotherapy.

Population screening for spinal muscular atrophy: A mixed methods study of the views of affected families.Publié le 25 10 2017

Autosomal recessive conditions are a significant health burden with few treatments. Population carrier screening has been suggested as a means to tackle them. Little is known about the views of affected families despite the potential for direct impacts on them. Data are presented on attitudes among families affected by Spinal Muscular Atrophy (SMA) toward two population screening programs, pre-conception, and prenatal. Data were gathered through qualitative interviews (n?=?36) and a survey (n?=?337). Eighty-two survey participants had SMA and 255 were family members. The majority were in favor of screening (75%). Reasons for supporting pre-conception screening support were a belief that it would reduce SMA-related terminations and raise awareness of SMA in the population. For prenatal screening, reasons for support included a belief in the importance of informed decision-making and the need to reduce suffering. Key reasons for non-support of pre-conception screening included concerns about carrier stigmatization and social engineering. For prenatal screening, concerns focused on the collateral loss of high quality of life lives affected by SMA. This study highlights that those affected by SMA are predominantly in favor of screening, although pre-conception screening is most favored. While family members and adults with SMA had largely consistent views, perceptions varied according to the severity (type) of SMA, with those affected by SMA type II the least likely to support screening. These findings suggest that screening for SMA is a complex issue for affected families, underscoring the need to consider and include their views when planning and implementing screening programs. © 2016 Wiley Periodicals, Inc.

Pathophysiological Concepts and Treatment of Camptocormia.Publié le 22 10 2017

Camptocormia is a disabling pathological, non-fixed, forward bending of the trunk. The clinical definition using only the bending angle is insufficient; it should include the subjectively perceived inability to stand upright, occurrence of back pain, typical individual complaints, and need for walking aids and compensatory signs (e.g. back-swept wing sign). Due to the heterogeneous etiologies of camptocormia a broad diagnostic approach is necessary. Camptocormia is most frequently encountered in movement disorders (PD and dystonia) and muscles diseases (myositis and myopathy, mainly facio-scapulo-humeral muscular dystrophy (FSHD)). The main diagnostic aim is to discover the etiology by looking for signs of the underlying disease in the neurological examination, EMG, muscle MRI and possibly biopsy. PD and probably myositic camptocormia can be divided into an acute and a chronic stage according to the duration of camptocormia and the findings in the short time inversion recovery (STIR) and T1 sequences of paravertebral muscle MRI. There is no established treatment of camptocormia resulting from any etiology. Case series suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) is effective in the acute but not the chronic stage of PD camptocormia. In chronic stages with degenerated muscles, treatment options are limited to orthoses, walking aids, physiotherapy and pain therapy. In acute myositic camptocormia an escalation strategy with different immunosuppressive drugs is recommended. In dystonic camptocormia, as in dystonia in general, case reports have shown botulinum toxin and DBS of the globus pallidus internus (GPi-DBS) to be effective. Camptocormia in connection with primary myopathies should be treated according to the underlying illness.

Challenges and Advances in Gene Therapy Approaches for Neurodegenerative Disorders.Publié le 17 10 2017

INTRODUCTION: The recent approval of Spinraza (nusinersen), an antisense oligonucleotide, by U.S. Food and Drug Administration to treat patients with spinal muscular atrophy, has reignited interests of researchers in designing and testing new gene therapy approaches to treat neurological disorders, in particular, to curb neurodegenerative diseases of the central nervous system which represent an everincreasing public health burden to today's society.
CONCLUSION: This review highlights several key factors to be taken into consideration to design successful preclinical and clinical gene therapy experiments with respect to the vehicle of delivery and the route of administration to CNS-specific targets, with an additional focus on antisense oligonucleotide therapy and recent clinical trial developments.

Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy.Publié le 17 10 2017

Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( UBA1). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). Methods: In this study, our group characterized the three known missense variants in vitro. Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants. Results: Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1's enzymatic activity with Ubiquitin, to other roles such as altering UBA1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners.  These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations' biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.

Predictors of radial nerve palsy recovery in humeral shaft fractures: A retrospective review of 17 patients.Publié le 13 10 2017

BACKGROUND: Radial nerve injury is common in humeral shaft fractures and fails to recover spontaneously in 30% of cases. Few studies have evaluated predictors of recovery. The objectives of this study were to identify predictors of radial nerve palsy recovery and to assess the usefulness of surgical radial nerve exploration in patients with preoperative radial nerve palsy.
HYPOTHESIS: Factors predicting the outcome of radial nerve palsy can be identified.
METHODS: Of 373 patients with humeral shaft fractures between 2005 and 2012, 43 had radial nerve palsy, including 23 who were lost to follow-up and 17 who were evaluated retrospectively at a mean of 26 months (range, 12-84 months) after internal fixation. The following were studied: age, smoking history, energy of the trauma, fracture type and displacement, skin integrity and intra-operative appearance of the radial nerve.
RESULTS: Of the 17 palsies, 13 were present preoperatively, including 10 that recovered (PreR group) and 3 that did not recover (PreNR group). Plate fixation and radial nerve exploration were performed in all patients. Of the 10 PreR patients, 6 had nerve contusion and 2-nerve entrapment. Of the 3 PreNR patients, 2 had gross nerve damage and 1 nerve contusion and a history of spinal muscular atrophy. Only age and presence of gross nerve damage differed significantly between the PreR and PreNR groups; trends towards significant differences were noted for skin breach and fracture displacement. Of the 4 postoperative radial nerve palsies, 2 recovered fully and 2 partially; mean age was higher in the 2 patients with partial recovery.
DISCUSSION: These findings are consistent with the few previous studies of outcome predictors in radial nerve palsy. Factors such as major fracture displacement and high-grade skin wounds probably promote the occurrence of gross nerve lesions. The high incidence of nerve entrapment and stretching supports routine nerve exploration during internal fixation in patients with preoperative radial nerve palsy.
LEVEL OF EVIDENCE: IV, retrospective study with no control group.

Treatment Advances in Spinal Muscular Atrophy.Publié le 07 10 2017

PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development.
RECENT FINDINGS: Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2. The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.

Activation of a cryptic 5' splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene.Publié le 06 10 2017

Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5' splice site (5'ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5'ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7. We show that Cr1-activating engineered U1 snRNAs (eU1s) have the unique ability to reprogram pre-mRNA splicing and restore exon 7 inclusion in SMN1 carrying a broad spectrum of pathogenic mutations at both the 3'ss and 5'ss of the exon 7. Employing a splicing-coupled translation reporter, we demonstrate that mRNAs generated by an eU1-induced activation of Cr1 produce full-length SMN. Our findings underscore a wider role for U1 snRNP in splicing regulation and reveal a novel approach for the restoration of SMN exon 7 inclusion for a potential therapy of SMA.

Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape.Publié le 05 10 2017

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMN?7 protein, but from which functional full length SMN protein is produced at very low levels (?10%). Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.

Application of urine cells in drug intervention for spinal muscular atrophy.Publié le 01 10 2017

Spinal muscular atrophy (SMA) is a lethal childhood neurodegenerative disorder that is caused by the homozygous deletion of survival motor neuron 1 (SMN1). To date, no effective treatments are available. In the current study, urine cells taken from SMA patients were cultured and the application of patient-derived urine cells was determined in drug intervention. A total of 13 SMA patient-derived urine cell lines and 40 control cell lines were established. SMN was highly expressed in the nucleus and cytoplasm. Patient-derived urine cells expressed low levels of SMN protein compared with controls, they exhibited good tolerance to chemical and electrical damage. SMN expression was upregulated following treatment with histone deacetylase inhibitors and the effect was greater in groups treated with morpholino modified antisense oligo, which targets ISS-N1 in SMN2 intron 7. The results of the current study indicated that SMA patient-derived urine cells may be useful in the initial screening of potential compounds and drugs to treat SMA.

Genome engineering: a new approach to gene therapy for neuromuscular disorders.Publié le 30 09 2017

For many neuromuscular disorders, including Duchenne muscular dystrophy, spinal muscular atrophy and myotonic dystrophy, the genetic causes are well known. Gene therapy holds promise for the treatment of these monogenic neuromuscular diseases, and many such therapies have made substantial strides toward clinical translation. Recently, genome engineering tools, including targeted gene editing and gene regulation, have become available to correct the underlying genetic mutations that cause these diseases. In particular, meganucleases, zinc finger nucleases, TALENs, and the CRISPR-Cas9 system have been harnessed to make targeted and specific modifications to the genome. However, for most gene therapy applications, including genome engineering, gene delivery remains the primary hurdle to clinical translation. In preclinical models, genome engineering tools have been delivered via gene-modified cells or by non-viral or viral vectors to correct a diverse array of genetic diseases. In light of the positive results of these studies, genome engineering therapies are being enthusiastically explored for several genetic neuromuscular disorders. This Review summarizes the genome engineering strategies that are currently under preclinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on the molecular tools that show the greatest potential for clinical translation of these therapies.

p.Val19Glyfs*21 and p.Leu228* variants in the survival of motor neuron 1 trigger nonsense-mediated mRNA decay causing the SMN1 PTC+ transcripts degradation.Publié le 28 09 2017

Spinal Muscular Atrophy (SMA) results from loss-of-function mutations in the survival of motor neuron 1 (SMN1) gene. Our previous research showed that 40% of variants were nonsense or frameshift variants and SMN1 mRNA levels in the patients carrying these variants were significantly decreased. Here we selected one rare variant (p.Val19Glyfs*21) and one common variant (p.Leu228*) to explore the degradation mechanism of mutant transcripts. The levels of full-length (FL)-SMN1 transcripts and SMN protein in the cell lines from the patients with these variants were both significantly reduced (p<0.01). Treatment with two translation inhibitors (puromycin and Cycloheximide (CHX)) markedly increased the levels of FL-SMN1 transcripts with premature translation termination codons (PTCs) (p<0.01) and showed time-dependent (10h>5.5h) but not dose-dependent effects. Moreover, the knockdown of UPF1, a key factor in nonsense-mediated mRNA decay (NMD) by lentivirus, led to a 3.1-fold increase (p<0.01) in FL-SMN1 transcript levels in patient fibroblasts. Our research provides evidence that these two PTC-generating variants (p.Val19Glyfs*21 and p.Leu228*) can trigger NMD, causing rapid degradation of SMN1 transcripts thereby resulting in SMN protein deficiency. These two variants are highly pathogenic and are associated with more severe SMA phenotypes. Varying NMD efficiency after treatment with puromycin and CHX in different cell types was also observed.

Treatment of Mild Camptocormia with Selegiline in Patients with Parkinson's Disease.Publié le 28 09 2017

BACKGROUND: Camptocormia in Parkinson's disease (PD) is unresponsive to various therapies and induced difficulties in their day-to-day life.
OBJECTIVE: This study, an open trial, was aimed at assessing the efficacy of selegiline in the treatment of mild camptocormia in PD patients.
METHODS: Participants were administered 5 mg of selegiline for the first 8 weeks and 7.5 mg for the second 8 weeks.
RESULTS: As primary endpoints, the degree of thoracolumbar anteflexion decreased from 23.2° (mean) (11.8° (SD)) at baseline to 18.3° (7.1°) at 16 weeks, and the area of postural sway measured using a Gravicorder increased. However, the differences were not significant. Thoracolumbar anteflexion improved in 60% of the participants.
CONCLUSIONS: In this study, 60% of the participants showed an improvement in anteflexion of the thoracolumbar spine with selegiline, but the change in the degree of anteflexion was 5°, which was not statistically significant. Participants with significant improvement in thoracolumbar anteflexion had an increased postural sway. This change was induced by a decrease in truncal muscle tonus or change in the center of gravity. This study combined the study of anteflexion and stability, and provides information on the treatment of short-term or mild camptocormia.

In vitro and in vivo effects of 2,4 diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS: Context-specific modulation of SMN transcript levels.Publié le 26 09 2017

C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for the treatment of spinal muscular atrophy (SMA), which is caused by genetic deficiency in the Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim are equivocal. In addition it is unclear whether the claimed effects on SMN2 are a direct consequence of DcpS inhibitor or might be a consequence of lysosomotropism, which is known to be neuroprotective. DAQ-DcpSi effects were characterized in cells in vitro utilizing DcpS knockdown and 7-methyl analogues as probes for DcpS vs non-DcpS-mediated effects. We also performed analysis of Smn transcript levels, RNA-Seq analysis of the transcriptome and SMN protein in order to identify affected pathways underlying the therapeutic effect, and studied lysosomotropic and non-lysosomotropic DAQ-DCpSi effects in 2B/- SMA mice. Treatment of cells caused modest and transient SMN2 mRNA increases with either no change or a decrease in SMN?7 and no change in SMN1 transcripts or SMN protein. RNA-Seq analysis of DAQ-DcpSi-treated N2a cells revealed significant changes in expression (both up and down) of approximately 2,000 genes across a broad range of pathways. Treatment of 2B/- SMA mice with both lysomotropic and non-lysosomotropic DAQ-DcpSi compounds had similar effects on disease phenotype indicating that the therapeutic mechanism of action is not a consequence of lysosomotropism. In striking contrast to the findings in vitro, Smn transcripts were robustly changed in tissues but there was no increase in SMN protein levels in spinal cord. We conclude that DAQ-DcpSi have reproducible benefit in SMA mice and a broad spectrum of biological effects in vitro and in vivo, but these are complex, context specific, and not the result of simple SMN2 transcriptional activation.

Short (16-mer) locked nucleic acid splice-switching oligonucleotides restore dystrophin production in Duchenne Muscular Dystrophy myotubes.Publié le 26 09 2017

Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo. Here, we designed a series of LNA-based SSOs complementary to two sequences of the human dystrophin exon 51 that are most evolutionary conserved and evaluated their ability to induce exon skipping upon transfection into myoblasts derived from a DMD patient. We show that 16-mers with 60% of LNA modification efficiently induce exon skipping and restore synthesis of a truncated dystrophin isoform that localizes to the plasma membrane of patient-derived myotubes differentiated in culture. In sum, this study underscores the value of short LNA-modified SSOs for therapeutic applications.

Role of Ethnicity in Alignment Compensation: Propensity Matched Analysis of Differential Compensatory Mechanism Recruitment Patterns for Sagittal Malalignment in 288 ASD Patients From Japan, Korea, and United States.Publié le 22 09 2017

STUDY DESIGN: Retrospective review of adult spinal deformity patients in a multiethnic database.
OBJECTIVE: To investigate the role of ethnicity on recruitment of compensatory mechanisms for sagittal spinal deformity.
SUMMARY OF BACKGROUND DATA: While the impacts of age, sex, and pelvic morphology on the ability to compensate for sagittal malalignment have been investigated, the role of ethnicity in compensatory mechanism recruitment is poorly understood.
METHODS: Patients from USA (85% Caucasian) >25?y/o were propensity matched by age, sex, and pelvic incidence with patients from Korea and Japan. Only primary patients or those with existing fusion below T12 were retained for analysis. Groups were subclassified by deformity severity (aligned: sagittal vertical axis (SVA)?<50?mm; moderate malalignment: SVA 50-100?mm; severe malalignment: SVA >100?mm). Radiographic measurements including pelvic retroversion, thoracic kyphosis, loss of lumbar lordosis (PI minus LL), cervical lordosis, and cervical SVA were compared between the groups.
RESULTS: There were 288 patients (96 each in USA, KOR, JPN), with similar age (64-67 yr) and PI (49-53°). USA had smaller pelvic incidence minus lumbar lordosis in every alignment group (P?<0.05). In moderate malalignment, JPN had more pelvic retroversion than USA (30° vs. 20°), and KOR had more thoracic hypokyphosis than USA (15 vs. 31°). In severe malalignment, JPN had more pelvic retroversion than USA (39° vs. 27°), and KOR had more thoracic hypokyphosis than USA (15° vs. 31°). KOR had smaller cSVA than USA in both aligned (11 vs. 27?mm) and moderate (19 vs. 31?mm) malalignment. In severe malalignment, KOR had less cervical lordosis (13° KOR vs. 15° USA vs. 27° JPN). All differences with P?<0.05.
CONCLUSION: Compensation for sagittal is ethnicity dependent. Korean patients favor thoracic compensation via hypokyphosis, and Japanese patients favor pelvic compensation via retroversion. Patient ethnicity should be considered when evaluating the sagittal plane and surgical correction strategies.

Gestational Age-Dependent Increase of Survival Motor Neuron Protein in Umbilical Cord-Derived Mesenchymal Stem Cells.Publié le 21 09 2017

BACKGROUND: Spinal muscular atrophy (SMA) is the most common genetic neurological disease leading to infant death. It is caused by loss of survival motor neuron (SMN) 1 gene and subsequent reduction of SMN protein in motor neurons. Because SMN is ubiquitously expressed and functionally linked to general RNA metabolism pathway, fibroblasts (FBs) are most widely used for the assessment of SMN expression in SMA patients but usually isolated from skin biopsy samples after the onset of overt symptoms. Although recent translational studies of SMN-targeted therapies have revealed the very limited time window for effective SMA therapies during perinatal period, the exact time point when SMN shortage became evident is unknown in human samples. In this study, we analyzed SMN mRNA and protein expression during perinatal period by using umbilical cord-derived mesenchymal stem cells (UC-MSCs) obtained from preterm and term infants.
METHODS: UC-MSCs were isolated from 16 control infants delivered at 22-40?weeks of gestation and SMA fetus aborted at 19?weeks of gestation (UC-MSC-Control and UC-MSC-SMA). FBs were isolated from control volunteer and SMA patient (FB-Control and FB-SMA). SMN mRNA and protein expression in UC-MSCs and FBs was determined by RT-qPCR and Western blot.
RESULTS: UC-MSC-Control and UC-MSC-SMA expressed the comparable level of MSC markers on their cell surface and were able to differentiate into adipocytes, osteocytes, and chondrocytes. At steady state, SMN mRNA and protein expression was decreased in UC-MSC-SMA compared to UC-MSC-Control, as observed in FB-SMA and FB-Control. In response to histone deacetylase inhibitor valproic acid, SMN mRNA and protein expression in UC-MSC-SMA and FB-SMA was increased. During perinatal development from 22 to 40?weeks of gestation, SMN mRNA and protein expression in UC-MSC-Control was positively correlated with gestational age.
CONCLUSION: UC-MSCs isolated from 17 fetus/infant of 19-40?weeks of gestation are expressed functional SMN mRNA and protein. SMN mRNA and protein expression in UC-MSCs is increased with gestational age during perinatal development.

ERK and ROCK functionally interact in a signaling network that is compensationally upregulated in Spinal Muscular Atrophy.Publié le 17 09 2017

Spinal Muscular Atrophy (SMA) is a motoneuron disease caused by low levels of functional survival of motoneuron protein (SMN). Molecular disease mechanisms downstream of functional SMN loss are still largely unknown. Previous studies suggested an involvement of Rho kinase (ROCK) as well as the extracellular signal-regulated kinases (ERK) pathways in the pathomechanism. Both pathways are bi-directionally linked and inhibit each other. Thus, we hypothesize that both pathways regulate SMA pathophysiology in vivo in a combined manner rather than acting separately. Here, we applied the repurposed drugs, selumetinib, an ERK inhibitor, and the ROCK inhibitor fasudil to severe SMA mice. Thereby, separately applied inhibitors as well as a combination enabled us to explore the impact of the ROCK-ERK signaling network on SMA pathophysiology. ROCK inhibition specifically ameliorated the phenotype of selumetinib-treated SMA mice demonstrating an efficient ROCK to ERK crosstalk relevant for the SMA pathophysiology. However, ERK inhibition alone aggravated the condition of SMA mice and reduced the number of motoneurons indicating a compensatory hyper-activation of ERK in motoneurons. Taken together, we identified a regulatory network acting downstream of SMN depletion and upstream of the SMA pathophysiology thus being a future treatment target in combination with SMN dependent strategies.

Palliative care in neuromuscular diseases.Publié le 16 09 2017

PURPOSE OF REVIEW: Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness. Neuromuscular disorders (NMDs) are characterized by progressive muscle weakness, leading to pronounced and incapacitating physical disabilities. Most NMDs are not amenable to curative treatment and would thus qualify for palliative care. Amyotrophic lateral sclerosis is a relentlessly progressive disease, which leads to death about 2 years after onset due to respiratory muscle weakness. Increasingly, neurologists caring for these patients learn to apply the principles of palliative care. However, this does not yet apply to other well known and frequently occurring NMDs.
RECENT FINDINGS: There is sparse literature on palliative care in NMDs such as Duchenne muscular dystrophy, spinal muscular atrophy, muscular dystrophies, some congenital myopathies, Pompe's disease and myotonic dystrophy type 1. These NMDs are often associated with imminent respiratory insufficiency and/or heart failure leading to a reduced life expectancy. Reasons for underutilization may include misconceptions about palliative care amongst patients, family carers and healthcare professionals or lack of awareness of the usefulness of this approach in these severely affected patients and the possibilities of integration of palliative principles into care for children and adults with NMDs.
SUMMARY: There is an urgent need for increased attention to the development of palliative care in chronic progressive neuromuscular diseases associated with increasing functional incapacities and premature death. This will require education and training of the healthcare professionals, involvement of patient associations and funding to perform research.

The water extract of Liuwei dihuang possesses multi-protective properties on neurons and muscle tissue against deficiency of survival motor neuron protein.Publié le 14 09 2017

BACKGROUND: Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease.
PURPOSE: This study aimed to investigate the potential protection of LWDH-WE on SMN deficiency-induced neurodegeneration and muscle weakness.
STUDY DESIGN: The effects of LWDH-WE on SMN deficiency-induced neurotoxicity and muscle atrophy were examined by using SMN-deficient NSC34 motor neuron-like cells and SMA-like mice, respectively.
METHODS: Inducible SMN-knockdown NSC34 motor neuron-like cells were used to mimic SMN-deficient condition. Doxycycline (1?µg/ml) was used to induce SMN deficiency in stable NSC34 cell line carrying SMN-specific shRNA. SMA?7 mice were used as a severe type of SMA mouse model. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Apoptotic cells and neurite length were observed by inverted microscope. Protein expressions were examined by western blots. Muscle strength of animals was evaluated by hind-limb suspension test.
RESULTS: LWDH-WE significantly increased SMN protein level, mitochondrial membrane potential and cell viability of SMN-deficient NSC34 cells. LWDH-WE attenuated SMN deficiency-induced down-regulation of B-cell lymphoma-2 (Bcl-2) and up-regulation of cytosolic cytochrome c and cleaved caspase-3. Moreover, LWDH-WE prevented SMN deficiency-induced inhibition of neurite outgrowth and activation of Ras homolog gene family, member A (RhoA)/ Rho-associated protein kinase (ROCK2)/ phospho-LIM kinase (p-LIMK)/ phospho-cofilin (p-cofilin) pathway. Furthermore, in SMA-like mice, LWDH-WE improved muscle strength and body weight accompanied with up-regulation of SMN protein in spinal cord, brain, and gastrocnemius muscle tissues.
CONCLUSION: The present study demonstrated that LWDH-WE protects motor neurons against SMN deficiency-induced neurodegeneration, and it also improves the muscle strength of SMA-like mice, suggesting the potential benefits of LWDH-WE as a complementary prescription for SMN deficiency-related diseases.

Treating pediatric neuromuscular disorders: The future is now.Publié le 11 09 2017

Pediatric neuromuscular diseases encompass all disorders with onset in childhood and where the primary area of pathology is in the peripheral nervous system. These conditions are largely genetic in etiology, and only those with a genetic underpinning will be presented in this review. This includes disorders of the anterior horn cell (e.g., spinal muscular atrophy), peripheral nerve (e.g., Charcot-Marie-Tooth disease), the neuromuscular junction (e.g., congenital myasthenic syndrome), and the muscle (myopathies and muscular dystrophies). Historically, pediatric neuromuscular disorders have uniformly been considered to be without treatment possibilities and to have dire prognoses. This perception has gradually changed, starting in part with the discovery and widespread application of corticosteroids for Duchenne muscular dystrophy. At present, several exciting therapeutic avenues are under investigation for a range of conditions, offering the potential for significant improvements in patient morbidities and mortality and, in some cases, curative intervention. In this review, we will present the current state of treatment for the most common pediatric neuromuscular conditions, and detail the treatment strategies with the greatest potential for helping with these devastating diseases.

Nusinersen for the treatment of spinal muscular atrophy.Publié le 09 09 2017

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness. This review article focuses on a novel antisense oligonucleotide treatment, first ever approved for SMA (nusinersen, Spinraza(TM)) and describes the exciting journey from early ASO clinical trials to regulatory approval of the first ever known effective treatment for SMA. Areas covered: This article reviews the results of the published open label nusinersen studies in infants and children, and briefly covers the preliminary findings of the recently completed but as yet unpublished nusinersen-sham controlled trials, as well as the presymptomatic nusinersen trial known as Nurture. Clinical use of nusinersen is also reviewed. Expert commentary: Collectively, the studies show improvement in motor function across SMA of all types, including SMA type 3. Best motor response was observed with early treatment; presymptomatic treatment prevented disease manifestations. Nusinersen was found to be safe and well tolerated across all age groups studied. Nusinersen has irrevocably altered the natural history of SMA and allowed for the first time children to transition between SMA types. Nusinersen should be considered as standard of care for the treatment of SMA of all types.

Seeking a better landscape for therapy development in neuromuscular disorders.Publié le 08 09 2017

While the neuromuscular field has seen accelerated approval of a drug for Duchenne muscular dystrophy (DMD) and full approval of one for spinal muscular atrophy, these experiences have shown that objective data and an adequate level of effect are essential for drug approval and reimbursement. The appropriateness and validity of biomarkers and clinically meaningful endpoints, and an understanding of disease progression rates, all played essential roles in the levels of evidence for these drugs. Such tools are best developed through integration of clinical data. The siloing of clinical data for rare neuromuscular diseases represents a considerable barrier to achieving better care and novel therapies for patients living with neuromuscular diseases. We discuss a data-sharing model implemented for DMD and urge cultural changes in the ways natural history and clinical trial data are collected and shared across all neuromuscular diseases in order to benefit the primary stakeholder, the patient. This article is protected by copyright. All rights reserved.

CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN.Publié le 08 09 2017

The survival of motor neuron (SMN) protein plays an essential role in the biogenesis of spliceosomal snRNPs and the molecular assembly of Cajal bodies (CBs). Deletion of or mutations in the SMN1 gene cause spinal muscular atrophy (SMA) with degeneration and loss of motor neurons. Reduced SMN levels in SMA lead to deficient snRNP biogenesis with consequent splicing pathology. Here, we demonstrate that SMN is a novel and specific target of the acetyltransferase CBP (CREB-binding protein). Furthermore, we identify lysine (K) 119 as the main acetylation site in SMN. Importantly, SMN acetylation enhances its cytoplasmic localization, causes depletion of CBs, and reduces the accumulation of snRNPs in nuclear speckles. In contrast, the acetylation-deficient SMNK119R mutant promotes formation of CBs and a novel category of promyelocytic leukemia (PML) bodies enriched in this protein. Acetylation increases the half-life of SMN protein, reduces its cytoplasmic diffusion rate and modifies its interactome. Hence, SMN acetylation leads to its dysfunction, which explains the ineffectiveness of HDAC (histone deacetylases) inhibitors in SMA therapy despite their potential to increase SMN levels.

Amphiphilic lipopeptide significantly enhances uptake of charge-neutral splice switching morpholino oligonucleotide in spinal muscular atrophy patient-derived fibroblasts.Publié le 03 09 2017

Splice-switching antisense oligonucleotides (SSOs) are emerging therapeutics with two SSOs recently approved by the FDA for Duchenne muscular dystrophy and spinal muscular atrophy. SSOs are administered without any delivery vector and require large doses to achieve the therapeutic benefit, primarily due to their poor cellular uptake. Although cell-penetrating peptides (CPP) have shown great potential in delivering SSOs into cells, their capacity as delivery vector is limited. Here we have studied the effect of lipid conjugation on the cell permeability of a known CPP (ApoE). Myristic acid, was coupled at the N-terminus of ApoE to a C-terminal cysteine residue. The myristoylated ApoE (Myr-ApoE) was conjugated to a maleimide functionalised phosphorodiamidate morpholino oligonucleotide (PMO). The Myr-ApoE-PMO conjugate showed no cytoxicity and had significantly higher efficiency in cell permeability with 30% higher splice-switching activity compared to ApoE-PMO. The self-assembly properties of this amphiphilic lipopeptide-PMO conjugate was assessed. Transmission electron microscopy showed formation of nanoparticles with amphiphile behaviour and spherical structure. The self-assembly of Myr-ApoE-PMO into nanoparticles enabled it to better bind to cell membranes and to be more efficiently taken up by fibroblast cells. These results showed that modification of physico-chemical properties of peptides to produce peptide amphiphiles enhances cellular uptake and can be used as an efficient delivery vector for therapeutic SSOs.

Clinical Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy Type I.Publié le 24 08 2017

INTRODUCTION: To explore safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA).
METHODS: Open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were safety and adverse events (AEs); secondary outcomes were survival, time to death/> 16 hours/day ventilator support, motor outcomes and maximum ulnar compound motor action potential amplitude.
RESULTS: 245 AEs were observed in 35 of 37 treated subjects (95%). Respiratory events accounted for 49% of all AEs, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts.
DISCUSSION: This trial provides evidence that in infants with SMA type I, L-carnitine/VPA is ineffective in altering survival. The substantial proportion of infants reaching endpoints within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. This article is protected by copyright. All rights reserved.

Social/economic costs and health-related quality of life in patients with spinal muscular atrophy (SMA) in Spain.Publié le 20 08 2017

BACKGROUND: The aim of this study was to determine the economic burden and health-related quality of life (HRQOL) of patients with Spinal Muscular Atrophy (SMA) and their caregivers in Spain.
METHODS: This was a cross-sectional and retrospective study of patients diagnosed with SMA in Spain. We adopted a bottom up, prevalence approach design to study patients with SMA. The patient's caregivers completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and non-healthcare services. Costs were estimated from a societal perspective (including healthcare costs and non-healthcare costs), and health-related quality of life (HRQOL) was assessed using the EQ-5D questionnaire. The main caregivers also answered a questionnaire on their characteristics and on their HRQOL.
RESULTS: A total of 81 caregivers of patients with different subtypes of SMA completed the questionnaire. Based on the reference unitary prices for 2014, the average annual costs per patient were € 33,721. Direct healthcare costs were € 10,882 (representing around 32.3% of the total cost) and the direct non-healthcare costs were € 22,839 (67.7% of the total cost). The mean EQ-5D social tariff score for patients was 0.16, and the mean score of the EQ-5D visual analogue scale was 54. The mean EQ-5D social tariff score for caregivers was 0.49 and their mean score on the EQ-5D visual analogue scale was 69.
CONCLUSION: The results highlight the burden that SMA has in terms of costs and decreased HRQOL, not only for patients but also for their caregivers. In particular, the substantial social/economic burden is mostly attributable to the high direct non-healthcare costs.

Bent spine syndrome as the initial symptom of late-onset Pompe disease.Publié le 20 08 2017

INTRODUCTION: Late-onset Pompe disease (LOPD) is a rare disorder characterized by progressive proximal muscle weakness and early respiratory insufficiency, for which enzyme replacement therapy (ERT) is available.
METHODS: Having diagnosed a case of LOPD presenting with bent spine syndrome, we conducted a brief survey in the French centers involved in management of Pompe disease, from which we collected data on 3 other cases.
RESULTS: The patients (3 women and 1 man) had a mean age of 64 years (range 51-77 years) and a delay in diagnosis of approximately 10 years (range 8-42 years). At diagnosis, 3 patients already had respiratory symptoms. All had normal or very mildly raised creatine kinase levels and magnetic resonance imaging abnormalities in the paraspinal muscles. They exhibited the most frequent mutation in Pompe disease (c.-32-13?T>G).
CONCLUSION: Clinicians should be aware of this atypical presentation of LOPD to enable earlier diagnosis and treatment. Muscle Nerve 56: 167-170, 2017.

[Radiation-Induced Radiculopathy with Paresis of the Neck and Autochthonous Back Muscles with Additional Myopathy].Publié le 18 08 2017

Radiation-induced tissue damage is caused by ionizing radiation mainly affecting the skin, vascular, neuronal or muscle tissue. Early damages occur within weeks and months while late damages may occur months or even decades after radiation.Radiation-induced paresis of the spine or the trunk muscles with camptocormia or dropped-head syndrome are rare but have already been described as long-term sequelae after treatment of Hodgkin's lymphoma. The differential diagnosis includes limb-girdle muscular dystrophy, fascioscapulohumeral muscular dystrophy (FSHD) or lysosomal storage diseases (e.?g. Acid Maltase Deficiency). We present the case of a patient with long lasting diagnostics over many months due to different inconclusive results.

Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons.Publié le 17 08 2017

Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-?B pathway in regulating SMN in motoneurons. NF-?B is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-?B pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-?B pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-?B members and RelA phosphorylation. We describe the alteration of NF-?B pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-?B pathway as a candidate in this new therapeutic approach.

Clinical Characteristics of Spinal Muscular Atrophy in Korea Confirmed by Genetic Analysis.Publié le 11 08 2017

The objective of this study was to review the clinical characteristics of patients with spinal muscular atrophy and to emphasize the importance of performing genetic mutational analysis at initial patient assessment. This is a single center oriented, retrospective, and descriptive study conducted in Seoul, South Korea. Genetic mutational analysis to detect the deletion of exon 7 of the SMN1 gene on chromosome 5q13 was performed by multiplex ligation-dependent probe amplification. Clinical features, electrodiagnostic study results, muscle biopsy results, and laboratory test results were reviewed from patient medical records. Of all 28 patients (15 males and 13 females), all showed bilateral symmetric proximal dominant weakness. Among them, 3 patients were classified as type I, 14 patients as type II, and 11 patients as type III. Twenty-five patients had scoliosis and eight of these patients received surgical treatment for scoliosis with improvement in clinical outcomes. Ventilator support was used in 15 patients. In terms of the diagnostic process, 15 patients had completed an electrodiagnostic study and muscle biopsy before genetic testing, and six of these patients were initially misdiagnosed with myopathy. Owing to the similar clinical features of SMA and congenital myopathy, an electrodiagnostic study and muscle biopsy could create confusion in the correct diagnosis in some cases. Therefore, it is recommended that genetic mutation analysis should be conducted along with an electrodiagnostic study or muscle biopsy in the diagnostic process for spinal muscular atrophy.

Outcomes of Primary Posterior Spinal Fusion for Scoliosis in Spinal Muscular Atrophy: Clinical, Radiographic, and Pulmonary Outcomes and Complications.Publié le 08 08 2017

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease commonly including progressive scoliosis resulting in severe deformity and negatively affecting pulmonary function. Surgical correction and stabilization of this progressive deformity is generally recommended; however, the timing and method of surgical fixation remains controversial.
METHODS: Retrospective review of clinical, radiographic, and pulmonary function data from 16 children with SMA and surgically treated scoliosis between 1985 and 2013. Radiographic data included direct measures of major curve, coronal balance, pelvic obliquity, T1-T12 height, T1-S1 height, and T1-rod length. Estimations of rib collapse, thoracic cavity shape, and space-available-for-lung (T6:T12, width ratio; T6:T10, rib-vertebral-angle difference ratios; and lung height) were determined. Eleven patients were able to complete pulmonary function testing. Results were compared with published outcomes for growing rod constructs.
RESULTS: Posterior spinal fusion was performed at an average age of 9.8±3.6 years. The mean age at most recent follow-up was 19.4 years (range, 10 to 37 y), with a mean follow-up of 10.1 years (range, 3.1 to 26 y). Radiographic measurements improved from preoperative to latest follow-up as follows: major curve, 78±20 degrees to 27±24 degrees; coronal balance, 4.1±4.0 cm to 1.9±2.2 cm; pelvic obliquity (median), 23 to 5 degrees; T1-T12 height, 19±3 cm to 22±3 cm; T1-S1 height, 31±7 cm to 36±6 cm; T1-rod length, 0.8±1.1 cm (postop) to 2.8±1.6 cm (final); and space-available-for-lung ratio, 0.88±0.26 to 0.95±0.25. Rib collapse continued throughout the follow-up period in all but 1 patient. Pulmonary function testing demonstrated a decrease in rate of decline in forced vital capacity and forced expiratory volume when comparing preoperative with postoperative rates. Mean length of stay was 7.8±4.4 days. Complications included reintubation for low tidal volumes (n=1), pneumonia (n=1), superficial wound breakdown (n=1), and superficial infection (n=1).
CONCLUSIONS: Definitive posterior spinal fusion for treatment of scoliosis associated with SMA is effective at controlling curve progression and pelvic obliquity without negatively impacting the space-available-for-lung ratio, trunk height, or pulmonary function at 10 years follow-up.
LEVEL OF EVIDENCE: Therapeutic Level IV.

Therapeutic strategies for spinal muscular atrophy: SMN and beyond.Publié le 08 08 2017

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

Spinal muscular atrophy: A changing phenotype beyond the clinical trials.Publié le 08 08 2017

Spinal muscular atrophy is a monogenic, progressive motor neuron disorder caused by deletion or mutation in the SMN1 gene. A broad range of phenotypic severity, from very weak infants (Type 1) to ambulant children (type 3), is modified mainly by the number of copies of the "backup" SMN2 gene. Since the discovery of the role of both genes, basic research into the pathobiology of SMA, with in vitro and animal model studies, has identified therapeutic targets. Development of clinical outcome measures, natural history studies and standard of care guidelines have contributed to the development of protocols for therapeutic drugs now under clinical investigation. Following regulatory approval of the first drug treatment for SMA in the US (December, 2016) and marketing authorization in Europe (June, 2017), the prospects for care of these patients have changed. The evolution of the phenotype of SMA now needs to be considered beyond the clinical trials. This perspective review discusses potential new trajectories in the phenotype of SMA and the need for multidisciplinary teams to prepare for this changing landscape.

[Congenital neuromuscular diseases with neonatal respiratory failure excluding myotonic dystrophy type 1 and infantile spinal muscular atrophy. Diagnosis strategy according to a 19-child series].Publié le 08 08 2017

UNLABELLED: Apart from spinal muscular atrophy (SMA) and myotonic dystrophy type 1 (DM1), congenital neuromuscular diseases with early neonatal symptoms mean diagnostic and prognostic challenges mainly when infants require ventilatory support.
OBJECTIVES: Consider a standardized strategy for infants suspected of congenital neuromuscular disease from analysis of the literature and retrospective experience with floppy and ventilatory support-dependent infants, after exclusion of well-known diseases (DM1, SMA).
PATIENTS AND METHODS: Floppy infants requiring ventilatory support in their 1st month of life, but showing no evidence of DM1, SMA, Prader-Willi syndrome, or encephalopathy. The retrospective multicenter study was based on the response of regional referent neuropediatricians in the Reference Centre for Neuromuscular Diseases of Greater Southwest France to an inquiry about prenatal and perinatal history, investigations, diagnosis, and outcome of the child and family. It was conducted between 2007 and 2012.
RESULTS: Among the 19 newborns studied, all had severe hypotonia. Prenatal and perinatal features were similar. Their outcome was generally severe: the median survival as measured by the Kaplan-Meier method was 6.9 months. Thirteen children died at a median age of 61 days; ten of them were treated with a palliative procedure. Five children had achieved respiratory independence but suffered from a small delay in motor development. Among the three children who continuously required ventilatory support, only one survived (follow-up period: 23 months); he was the only one undergoing tracheostomy in the cohort. Diagnostic processes were different, leading to pathological and genetic diagnosis for only six infants. There was only histological orientation for seven and no specific diagnostic orientation for the last six. These difficulties have led us to propose an exploration process based on the literature.
CONCLUSION: This study highlights difficulties in obtaining a diagnosis and a precise prognosis for floppy ventilated infants. An exploration-standardized process for infants suspected of congenital neuromuscular diseases was made in order to standardize procedures. It could be used as a tool for all professionals involved.

Nusinersen: The First Option Beyond Supportive Care for Spinal Muscular Atrophy.Publié le 30 07 2017

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal motor neurons and poses significant adverse outcome in affected population. Survival motor neuron 1 (SMN1) protein encoded by SMN1 gene located on 5q(13) is critical for survival and functioning of motor neurons. Almost identical gene SMN2, present on the same chromosome, produces a small truncated protein (SMN2) because of skipping of exon 7 from translation due to translation silent C6U substitution in exon 7 of SMN2 pre-mRNA transcript. Only 10% of the SMN2 mRNAs produce full length SMN2 protein by including exon 7 in healthy individuals. A large deletion or sometimes a point mutation in SMN1 gene is responsible for SMA. In this case the number of copies of SMN2 genes in an individual determines the severity of disease (the more the number of copies the less severe the disease). Nusinersen (ISIS 396443) binds to intron splicing silencer-N1 (ISS-N1; a site present ten nucleotides down to the junction of exon 7 and intron 7), modulating the splicing of SMN2 pre-mRNA transcript to increase the inclusion of exon 7, thereby increasing the production of full length SMN2 protein. Major evidence of its efficacy came from a sham controlled phase 3 clinical study ENDEAR. The study was stopped early based on significantly favorable results in interim analysis and all the patients were transitioned to receive nusinersen in an ongoing open-label, phase 3 study, SHINE, which will evaluate the long-term efficacy, safety and tolerability of the drug. Nusinersen is globally the first drug approved (by the US FDA) for treatment of SMA in children and adults.

Management of neuromuscular diseases and spinal muscular atrophy in Latin America.Publié le 29 07 2017

Latin America (LA) has a population of ~645 million people distributed over 33 countries with marked political, cultural, and economic differences. In LA, patients with inherited neuromuscular diseases (NMD) often do not have access to specialized medical centres and many of them go undiagnosed. General management and care of spinal muscular dystrophy (SMA) patients in the region varies due to heterogeneous health care. An active generation of young clinical neurologists is being trained for the specialized care of SMA and other NM patients, both in the private and public sectors. The Euro-Latin-American Summer School of Myology (EVELAM) as well as efforts of professionals at large public centres in the major cities of LA play a leading role in this development. Different regional academic-scientific organizations as well as the expanding number of Telethon Centres and the creation of parent organizations, mostly concerning SMA, all together are contributing to the increased quality of the management of NMD patients. Over the past years, academic and clinical research, as well as the establishment of qualified centres for the molecular testing of NMD are pushing forward the creation of patient registries and the development of specific clinical trials, with Argentina and Brazil having a major role in this field. Nevertheless, increased awareness and further training of specialized health professionals are necessary to reach patients that are currently lacking care throughout the region.Gene Therapy accepted article preview online, 28 July 2017. doi:10.1038/gt.2017.68.

Assessment of striatal & postural deformities in patients with Parkinson's disease.Publié le 22 07 2017

BACKGROUND & OBJECTIVES: Though striatal and postural deformities are known to occur commonly in atypical Parkinsonism patients, these may also be seen in patients with Parkinson's disease (PD). These are frequently misdiagnosed as joint or orthopaedic pathology leading to unnecessary investigations. This study was conducted to observe the various striatal and postural deformities among patients with PD in India.
METHODS: This study was conducted at a tertiary care teaching institute in north# India. Seventy consecutive patients with PD diagnosed as per the modified UK Brain Bank criteria were included. Various striatal (hand & foot) and postural (antecollis, camptocormia, scoliosis & Pisa syndrome) deformities and their relation with the duration of disease, severity [measured by the Unified Parkinson's Disease Rating Scale (UPDRS)] and levodopa intake were analyzed.
RESULTS: Of the 70 patients with PD, 34 (48.57%) had either striatal or postural deformities. Striatal foot was the most common deformity observed (25.71%). Camptocormia was the second most common deformity (20%). Striatal and postural deformities were seen in more advanced PD as suggested by significantly higher UPDRS and Hoehn and Yahr scale (P<0.001). Striatal deformities were more ipsilateral to PD symptom onset side (agreement 94.44%). Pisa and scoliosis concavity were more on contralateral side to PD symptoms onset side (66.67%).
INTERPRETATION & CONCLUSIONS: Our results showed that striatal and postural deformities were common and present in about half of the patients with PD. These deformities we more common in patients with advanced stage of PD.

The role of experiential knowledge within attitudes towards genetic carrier screening: A comparison of people with and without experience of spinal muscular atrophy.Publié le 14 07 2017

PURPOSE: Autosomal recessive conditions, while individually rare, are a significant health burden with limited treatment options. Population carrier screening has been suggested as a means of tackling them. Little is known, however, about the attitudes of the general public towards such carrier screening and still less about the views of people living with candidate genetic diseases. Here, we focus on the role that such experience has on screening attitudes by comparing views towards screening of people with and without prior experience of the monogenetic disorder, Spinal Muscular Atrophy.
METHODS: An exploratory sequential mixed methods design was adopted. In-depth qualitative interviews were used to develop two surveys. The surveys addressed attitudes towards carrier screening (pre-conceptual and prenatal) for SMA.
PARTICIPANTS: 337 participants with SMA experience completed the SMA Screening Survey (UK) and 336 participants with no prior experience of SMA completed the UK GenPop Survey, an amended version of the SMA Screening Survey (UK).
RESULTS: The majority of both cohorts were in favour of pre-conception and prenatal carrier screening, however people with experience of type II SMA were least likely to support either. Key differences emerged around perceptions of SMA, with those without SMA experience taking a dimmer view of the condition than those with.
CONCLUSION: This study underscores the significance of prior experience with the condition to screening attitudes. It highlights the need for accurate and high-quality educational resources to support any future carrier screening programmes, that particularly in relation to rare genetic disorders like SMA that will fall outside the remit of everyday experience for the majority of the population.

AJRCCM: 100-Year Anniversary. Homeward Bound: A Centenary of Home Mechanical Ventilation.Publié le 14 07 2017

The evolution of home mechanical ventilation is an intertwined chronicle of negative and positive pressure modes and their role in managing ventilatory failure in neuromuscular diseases and other chronic disorders. The uptake of noninvasive positive pressure ventilation has resulted in widespread growth in home ventilation internationally and fewer patients being ventilated invasively. As with many applications of domiciliary medical technology, home ventilatory support has either led or run in parallel with acute hospital applications and has been influenced by medical and societal shifts in the approach to chronic care, the creation of community support teams, a preference of recipients to be treated at home, and economic imperatives. This review summarizes the trends and growing evidence base for ventilatory support outside the hospital.

Antisense rescues babies from killer disease.Publié le 14 07 2017

PMID: 27980162 [PubMed - indexed for MEDLINE]

Medical use of cannabis in Switzerland: analysis of approved exceptional licences.Publié le 12 07 2017

AIMS OF THE STUDY: In recent years, the Swiss Federal Office of Public Health (FOPH) granted exceptional licenses for the medical use of cannabinoids, typically for 6 months with possible extensions. A systematic review of cannabinoids for medical use commissioned by the FOPH supports the use of cannabinoids for the treatment of chronic pain and spasticity. However, little is known about the patients treated with cannabinoids. We aimed to study medical uses of cannabinoids as part of the FOPH's programme of exceptional licenses.
METHODS: We examined all requests for medical use of cannabinoids sent to FOPH in 2013 and 2014. A standardised data sheet was developed to extract data from the files of approved requests. We extracted the duration of the licence, the year it was granted, and the payer of the therapy. At the level of the patient we collected the date of birth, sex, region of residence, diagnosis and the indication. Ethical approval was granted by the Ethics Committee of the Canton of Bern.
RESULTS: We analysed 1193 patients licenced for cannabinoid treatment in 2013 or 2014. During 2013, 542 patients were treated under the exceptional licencing programme (332 requesting physicians) compared with 825 in 2014 (446 physicians). Over half of patients (685; 57%) were women. The mean age was 57 years (standard deviation 15.0), chronic pain (49%) and spasticity (40%) were the most common symptoms, and co-medication was reported for 39% of patients. Seventy-eight different diagnoses were recorded, including multiple sclerosis (257 patients, 22%), soft tissue disorders (119, 10%), dorsalgia (97, 8.1%), spinal muscular atrophy (65, 5.5%) and paraplegia/tetraplegia (62, 5.2%). Licence extensions were granted to 143 patients (26.4%) in 2013 and 324 patients (39.3%) in 2014. There were substantial regional variations of the rates of patients treated with cannabinoids. On average, eight patients per 100 000 residents received an exceptional licence. Most patients (1083, 91%) paid out of pocket.
CONCLUSIONS: Exceptional licences for medical use of cannabinoids have increased substantially in Switzerland, with the programme including patients with a wide range of conditions.

Modifier genes: Moving from pathogenesis to therapy.Publié le 08 07 2017

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its disruption, and possibilities for its repair have never been more important as we search for new therapies.

Use of sugammadex in a patient with progressive muscular atrophy and in a patient with amyotrophic lateral sclerosis: Case report.Publié le 07 07 2017

INTRODUCTION: We herein present 2 cases involving the combination of rocuronium and sugammadex in patients with motor neuron disease. The patients were a 54-year-old man with progressive muscular atrophy who underwent removal of internal fixators in the arm and leg, and a 66-year-old woman with amyotrophic lateral sclerosis who underwent skin grafting in the left lower leg. General anesthesia was induced with propofol, rocuronium, and remifentanil and maintained with desflurane and remifentanil. At the end of the surgical procedure, we administered sugammadex. Three or 4 minutes after administration of sugammadex, the patients began to breathe spontaneously and were extubated without complications.
CONCLUSION: Sugammadex can be used successfully to reverse neuromuscular blockade in patients with motor neuron disease.

The Experience of Families With Children With Spinal Muscular Atrophy Type I Across Health Care Systems.Publié le 05 07 2017

Spinal muscular atrophy type I is a genetic disease characterized by degeneration of spinal cord motor neurons resulting in weakness, technology dependence and early demise. While the newly approved treatment nusinersen may alter the morbidity/mortality of this disease there continues to be complex treatment challenges to consider. The aim of this qualitative study was to understand from the parent's perspective, experiences of the family and child in the emergency center, hospital, and clinical care settings to identify gaps in care. Nineteen families interviewed had 22 children with spinal muscular atrophy I (11 deceased, 11 living). Three overarching themes emerged from parent interviews describing a range of experiences surrounding diagnosis, informed medical decision making and acute care practice. Identified quality improvements include development of a diagnostic screening tool, a medical decision tool, and emergency center informational template individualized to the child and providing an overview of spinal muscular atrophy I.

Splicing-Correcting Therapy for SMA.Publié le 01 07 2017

Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C?T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF.

The effects of C5-substituted 2,4-diaminoquinazolines on selected transcript expression in spinal muscular atrophy cells.Publié le 01 07 2017

C5-substituted 2,4-diaminoquinazolines (2,4-DAQs) ameliorate disease severity in SMA mice. It is uncertain, however, that these compounds increase SMN protein levels in vivo even though they were identified as activators of the SMN2 promoter. These compounds also regulate the expression of other transcripts in neuroblastoma cells. In this study, we investigate the mechanism by which the 2,4-DAQs regulate the expression of SMN2 as well as other targets. D156844, D158872, D157161 and D157495 (RG3039) increased SMN2 promoter-driven reporter gene activity by at least 3-fold in NSC-34 cells. These compounds, however, did not significantly increase SMN2 mRNA levels in type II SMA fibroblasts nor in NSC-34 cells, although there was a trend for these compounds increasing SMN protein in SMA fibroblasts. The number of SMN-containing gems was increased in SMA fibroblasts in response to 2,4-DAQ treatment in a dose-dependent manner. ATOH7 mRNA levels were significantly lower in type II SMA fibroblasts. 2,4-DAQs significantly increased ATOH7, DRNT1 and DRTN2 transcript levels in type II SMA fibroblasts and restored ATOH7 levels to those observed in healthy fibroblasts. These compounds also increase Atoh7 mRNA expression in NSC-34 cells. In conclusion, 2,4-DAQs regulate SMN2 by increasing protein levels and gem localization. They also increase ATOH7, DRNT1 and DRNT2 transcript levels. This study reveals that the protective effects of 2,4-DAQs in SMA may be independent of SMN2 gene regulation. These compounds could be used in concert with a proven SMN2 inducer to develop a multi-faceted approach to treating SMA.

Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: Screening with iPSC-derived neuronal cells.Publié le 27 06 2017

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard. However, clinical trials involving HDACi have been unsatisfactory, possibly because previous efforts to identify HDACi to treat SMA have employed non-neuronal cells as the screening platform. To address this issue, we generated an SMA-patient specific, induced pluripotent stem cell (iPSC) derived neuronal cell line that contains homogenous Tuj1+neurons. We screened a small library of cyclic tetrapeptide HDACi using this SMA neuronal platform and discovered compounds that elevate SMN2 expression by an impressive twofold or higher. These candidates are also capable of forming gems intranuclearly in SMA neurons, demonstrating biological activity. Our study identifies new potential HDACi therapeutics for SMA screened using a disease-relevant SMA neuronal cellular model.

Counting the cost of spinal muscular atrophy.Publié le 27 06 2017

PMID: 27310871 [PubMed - indexed for MEDLINE]

The economic burden of spinal muscular atrophy.Publié le 27 06 2017

AIM: To evaluate the economic burden of spinal muscular atrophy (SMA).
MATERIALS AND METHODS: This study used Department of Defense Military Healthcare System (MHS) data from 2003-2012. Healthcare costs were determined for patients with at least one inpatient or three outpatient claims with a diagnosis of SMA before 18 years of age and who had ? 6 months of data after first SMA diagnosis or expired within 6 months of initial diagnosis. A comparator cohort was selected using a 3:1 match based on age and gender.
RESULTS: A total of 239 individuals with SMA diagnosis met the inclusion criteria along with 717 matched comparator patients. More patients with SMA had hospitalizations (69.5%) compared to the comparator cohort (17.2%, p?<?0.001). Median total expenditures across all years of data for patients with SMA were $83 652 (25-75th percentile = $29 620-228 754) vs the comparator group of $4329 (25-75(th) percentile = $1229-10 062 (p?<?0.001)) over an average (SD) of 6.9?±?3.6 years. The annualized mean costs of total healthcare expenditures were significantly higher for the SMA cases than the comparison cohort, $47 862?±?88 607 compared to $1861?±?6374, respectively (p?<?0.001). The sub-group of patients with early diagnosis (n?=?45) had 4.3?±?2.9 years of observation with a median cost of $167 921 ($53 349-678 412). Mean age (SD) at first observed SMA diagnosis was 7.5?±?6.4 years. Mean (SD) duration of follow-up after initial SMA diagnosis was 4.8?±?3.3 years, with a median post-diagnosis cost of $60 213 ($18 229-192 559). The major costs for all patients were outpatient visits [median = $53 152 ($23 902-136 150)], followed by inpatient costs [median = $11 258 ($0-51 987)] and total prescription costs [median = $3167 ($943-13 283)].
LIMITATIONS: The analysis is limited to the data available and may under-estimate the total cost of SMA.
CONCLUSIONS: Individuals with SMA have a high degree of morbidity, particularly those diagnosed during infancy. SMA patients have significant medical expenditures and high utilization of healthcare services.

Gene therapy for spinomuscular atrophy: a biomedical advance, a missed opportunity for more equitable drug pricing.Publié le 25 06 2017

An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease. This technique represents the first apparently effective therapy for spinal muscular atrophy (SMA) and an important documentation for ASO technology for therapy of neurodegenerative disease. These results with one form of SMA are likely to be relevant for similar applications to other SMA types and are likely to inspire application to a number of other intractable neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and possibly even the extremely common Parkinson's and Alzheimer's diseases and others. Nevertheless, the scientific and medical importance of this advance is marred by a pricing policy by the corporate sponsors that may complicate accessibility of the drug for some desperate patients.Gene Therapy advance online publication, 22 June 2017; doi:10.1038/gt.2017.48.

The clinical landscape for SMA in a new therapeutic era.Publié le 25 06 2017

Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene, provides for the first time a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.Spinal muscular atrophy is a genetic neuromuscular disorder, in which the mainstay of management is physiotherapy, respiratory care and nutritional support, measures which do not affect the underlying biological progression of the disease. The treatment of SMA has now fundamentally changed with the demonstration that nusinersen (Spinraza™), a drug which alters the way in which RNA is processed, can increase the amount of SMN, the protein that is missing from children with SMA. This prevents nerve-muscle connections degenerating and is effective in limiting the severity of the disease, allowing young children to reach developmental milestones which are never normally achieved in SMA. This is a major landmark in the treatment of neurological disease, but only the beginning of the path to making SMA definitively treatable. A number of problems must be solved, including how to deliver the drug efficiently into the brain and spinal cord without the need for a lumbar puncture. There is uncertainty as to whether nusinersen will work for older children and adults with SMA. Despite these unresolved issues the advent of the first effective treatment for SMA ushers in a new era of therapy for this devastating disease and offers hope for the treatment of other neurodegenerative and neuromuscular disorders.Gene Therapy accepted article preview online, 23 June 2017. doi:10.1038/gt.2017.52.

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy.Publié le 22 06 2017

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.

Efficient SMN Rescue following Subcutaneous Tricyclo-DNA Antisense Oligonucleotide Treatment.Publié le 19 06 2017

Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA. However, AON administration to the CNS presents additional hurdles. In this study, we show that systemic delivery of tricyclo-DNA (tcDNA) AONs in a type III SMA mouse augments retention of exon 7 in SMN2 mRNA both in peripheral organs and the CNS. Mild type III SMA mice were selected as opposed to the severe type I model in order to test tcDNA efficacy and their ability to enter the CNS after maturation of the blood brain barrier (BBB). Furthermore, subcutaneous treatment significantly improved the necrosis phenotype and respiratory function. In summary, our data support that tcDNA oligomers effectively cross the blood-brain barrier and offer a promising systemic alternative for treating SMA.

LNA/DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts.Publié le 18 06 2017

Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy. AONs are utilized to block intronic splicing silencer number 1 (ISS-N1) on intron 7 of SMN2, which causes exon 7 inclusion of the mRNA and the recovery of the expression of functional SMN protein from the endogenous SMN2 gene. We developed novel locked nucleic acid (LNA)-based antisense oligonucleotides (LNA/DNA mixmers), which efficiently induce exon 7 inclusion in SMN2 and restore the SMN protein production in SMA patient fibroblasts. The mixmers are highly specific to the targeted sequence, and showed significantly higher efficacy than an all-LNA oligonucleotide with the equivalent sequence. These data suggest that use of LNA/DNA mixmer-based AONs may be an attractive therapeutic strategy to treat SMA.

Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent.Publié le 18 06 2017

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of ?-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

MiR-298 Counteracts Mutant Androgen Receptor Toxicity in Spinal and Bulbar Muscular Atrophy.Publié le 18 06 2017

Spinal and bulbar muscular atrophy (SBMA) is a currently untreatable adult-onset neuromuscular disease caused by expansion of a polyglutamine repeat in the androgen receptor (AR). In SBMA, as in other polyglutamine diseases, a toxic gain of function in the mutant protein is an important factor in the disease mechanism; therefore, reducing the mutant protein holds promise as an effective treatment strategy. In this work, we evaluated a microRNA (miRNA) to reduce AR expression. From a list of predicted miRNAs that target human AR, we selected microRNA-298 (miR-298) for its ability to downregulate AR mRNA and protein levels when transfected in cells overexpressing wild-type and mutant AR and in SBMA patient-derived fibroblasts. We showed that miR-298 directly binds to the 3'-untranslated region of the human AR transcript, and counteracts AR toxicity in vitro. Intravenous delivery of miR-298 with adeno-associated virus serotype 9 vector resulted in efficient transduction of muscle and spinal cord and amelioration of the disease phenotype in SBMA mice. Our findings support the development of miRNAs as a therapeutic strategy for SBMA and other neurodegenerative disorders caused by toxic proteins.

Bovine spastic paresis: A review of the genetic background and perspectives for the future.Publié le 16 06 2017

Bovine spastic paresis (BSP) is a sporadic, progressive neuromuscular disease that is thought to affect all breeds of cattle. The disease manifests as a unilateral or bilateral hyperextension of the hind limb due to increased muscle tone or permanent spasm of mainly the gastrocnemius and/or the quadriceps muscle. Clinical signs only appear in rising, standing and moving animals, which is an important diagnostic feature. Although several medical treatments have been described, surgical procedures such as neurectomy or tenectomy are generally indicated. Even though complete recovery can be achieved, BSP-affected animals should not be used for breeding, since BSP is commonly considered a hereditary disease. The condition therefore negatively affects animal welfare, economics and breeding. When first described in 1922, BSP was already assumed to be heritable, and this assumption has been perpetuated by subsequent authors who have only discussed its possible modes of inheritance, which included monogenetic and polygenetic modes and gene-environment interactions. Besides some clinical aspects and the consideration of the tarsal joint angle as a BSP-correlated trait, this review mainly focuses on the assumed genetic aspects of BSP. Evaluation of the published literature demonstrates that to date, irrevocable proof for the assumed heritability of BSP is still missing. The assumption of heredity is further contradicted by known allele frequencies and incidences of proven hereditary diseases in cattle, such as arachnomelia or bovine spinal muscular atrophy. Consequently, future research is needed to determine the cause of spastic paresis. Procedures that will help test the null-hypothesis ('BSP is not hereditary') and possible modes of inheritance are discussed in this review.

Splice-Switching Therapy for Spinal Muscular Atrophy.Publié le 13 06 2017

Spinal muscular atrophy (SMA) is a genetic disorder with severity ranging from premature death in infants to restricted motor function in adult life. Despite the genetic cause of this disease being known for over twenty years, only recently has a therapy been approved to treat the most severe form of this disease. Here we discuss the genetic basis of SMA and the subsequent studies that led to the utilization of splice switching oligonucleotides to enhance production of SMN protein, which is absent in patients, through a mechanism of exon inclusion into the mature mRNA. Whilst approval of oligonucleotide-based therapies for SMA should be celebrated, we also discuss some of the limitations of this approach and alternate genetic strategies that are currently underway in clinical trials.

Relationships between long-term observations of motor milestones and genotype analysis results in childhood-onset Japanese spinal muscular atrophy patients.Publié le 12 06 2017

AIM: To clarify the long-term natural history of SMA in Japanese patients by investigating the peak motor milestones of cases 7months through 57years of age, in efforts to contribute to evaluating outcomes of new therapeutic interventions.
METHODS: We sub-classified 112 SMA type I-III cases into type Ia, type Ib, type IIa, type IIb, type IIIa and type IIIb, according to peak motor milestone achieved, and analyzed the SMN1, SMN2 and NAIP genes in relation to clinical subtypes.
RESULTS: In type I cases, there was a significant difference (p<0.0001), depending on whether or not head control was obtained, in the time of ventilation support being required. In type II cases as well, the time at which the ability to maintain the sitting position independently was lost also differed significantly (p<0.01) between those acquiring the ability to sit unaided within eight months after birth and those acquiring this ability after eight months of age. In type III cases, being able versus unable to climb stairs was associated with a significant difference (p=0.02) in the median time until loss of walking independently. Positive correlations were also seen between copy numbers and the clinical severity of SMA.
CONCLUSION: Our long-term results show peak motor milestone evaluations distinguishing between subtypes to be useful not only as outcome measures for assessing treatment efficacy in clinical trials but also for predicting the clinical courses of Japanese SMA patients.

Parents' Experiences and Wishes at End of Life in Children with Spinal Muscular Atrophy Types I and II.Publié le 10 06 2017

OBJECTIVE: To explore experiences and wishes of bereaved parents concerning end-of-life care for their child with severe spinal muscular atrophy.
STUDY DESIGN: A follow-up survey was conducted in 2013 on parents of deceased Swedish children who were born between 2000 and 2010 and later diagnosed with spinal muscular atrophy type I or II (n = 48). The questions used in this study covered location of death (LoD), support from health care staff, and parents' wishes and concerns about their child's end-of-life care.
RESULTS: One-half of those who had wishes about LoD (16/32) wanted their child to die at home, rather than at the hospital. All of those who wanted the child to die at the hospital had their wishes fulfilled. Among those who wanted the child to die at home, 10 of 16 got their wish. Among parents who talked with a physician about how they wanted their child to pass away (n = 26), all but 2 had their wishes fulfilled. Thirty-six parents (75%) reported that their child had siblings: 12 reported that the sibling was too young for professional psychological support, and only 4 of the remaining 24 siblings received such support after the death of their brother or sister.
CONCLUSIONS: Parents' communication with the physician about their wishes and concerns regarding their child's end-of-life care and preferred LoD contributed to their wishes being fulfilled. The wish of hospital death was fulfilled more often than the wish of home deaths. A vast majority of siblings did not receive psychological support after death of their brother or sister.

Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy.Publié le 10 06 2017

BACKGROUND: Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of ?-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMN?7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMN?7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides.
OBJECTIVE: The objective was to determine the efficacy of the macrolide Azithromycin (AZM), an FDA approved read-through-inducing compound, in the well-established severe mouse model of SMA.
METHODS: Initially, dosing regimen following ICV administrations of AZM at different post-natal days and concentrations was determined by their impact on SMN levels in disease-relevant tissues. Selected dose was then tested for phenotypic parameters changes as compared to the appropriate controls and in conjugation to another therapy.
RESULTS: AZM increases SMN protein in disease relevant tissues, however, this did not translate into similar improvements in the SMA phenotype in a severe mouse model of SMA. Co-administration of AZM and a previously developed antisense oligonucleotide that increases SMN2 splicing, resulted in an improvement in the SMA phenotype beyond either AZM or ASO alone, including a highly significant extension in survival with improvement in body weight and movement.
CONCLUSIONS: It is important to explore various approaches for SMA therapeutics, hence compounds that specifically induce SMN?7 read-through, without having prohibitive toxicity, may provide an alternative platform for a combinatorial treatment. Here we established that AZM activity at a low dose can increase SMN protein in disease-relevant animal model and can impact disease severity.

Cellular uptake and trafficking of antisense oligonucleotides.Publié le 07 06 2017

Antisense oligonucleotides (ASOs) modified with phosphorothioate (PS) linkages and different 2' modifications can be used either as drugs (e.g., to treat homozygous familial hypercholesterolemia and spinal muscular atrophy) or as research tools to alter gene expression. PS-ASOs can enter cells without additional modification or formulation and can be designed to mediate sequence-specific cleavage of different types of RNA (including mRNA and non-coding RNA) targeted by endogenous RNase H1. Although PS-ASOs function in both the cytoplasm and nucleus, localization to different subcellular regions can affect their therapeutic potency. Cellular uptake and intracellular distribution of PS ASOs are mediated by protein interactions. The main proteins involved in these processes have been identified, and intracellular sites in which PS ASOs are active, or inactive, cataloged.

Diagnosis and New Treatment Avenues in Spinal Muscular Atrophy.Publié le 03 06 2017

PMID: 28571100 [PubMed - as supplied by publisher]

Respiratory involvement in neuromuscular disorders.Publié le 02 06 2017

PURPOSE OF REVIEW: In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs.
RECENT FINDINGS: Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs. Although observing how innovative drugs will change the natural history of these diseases, including respiratory function over time, adequate symptomatic treatment remains meaningful and is strongly recommended. Physicians should systematically take respiratory involvement into account to improve patients' quality of life and prognosis.
SUMMARY: First, it is outlined in which subtypes of NMD respiratory muscle dysfunction is particularly relevant. Second, new developments regarding diagnostic procedures, including respiratory muscle strength testing, spirometry, and sleep studies, are covered. Third, this article gives an overview on current concepts of ventilatory support and management of secretions in patients with NMD.

The SMA Trust: the role of a disease-focused research charity in developing treatments for SMA.Publié le 02 06 2017

SMA is a rare hereditary neuromuscular disease that causes weakness and muscle wasting as a result of the loss of spinal motor neurons. In its most severe form, SMA is the commonest genetic cause of death in infants, and children with less severe forms of SMA face the prospect of lifelong disability from progressive muscle wasting, loss of mobility and limb weakness. The initial discovery of the defective gene has been followed by major advances in our understanding of the genetic, cellular and molecular basis of SMA, providing the foundation for a range of approaches to treatment including gene therapy, antisense oligonucleotide treatments and more traditional drug-based approaches to slow or halt disease progression. The approval by the U.S. Food and Drug Administration (FDA) of Spinraza™ (nusinersen), the first targeted treatment for spinal muscular atrophy (SMA), is a historic moment. Disease-focused research charities, such as The SMA Trust (UK), continue to have a crucial role in promoting the development of additional treatments for SMA, both by funding translational research and by promoting links between researchers, people living with SMA and other stakeholders including pharmaceutical companies and healthcare providers.Gene Therapy accepted article preview online, 31 May 2017. doi:10.1038/gt.2017.47.

Therapeutic approaches for spinal muscular atrophy (SMA).Publié le 02 06 2017

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1. Following successful studies on disease models and intensive studies on SMN functions in the past decade, SMN upregulation targeting SMN2, has been suggested as a possible therapeutic approach. Recently we have witnessed an historical turning point with the first disease-modifying treatment receiving Food and Drug Administration (FDA) approval and now being available to patients also outside the clinical trial. This innovative treatment is an antisense oligonucleotide (ASOs) which, administered intrathecally, is able to increase exon 7 inclusion in the majority of the SMN2 mRNA, and increase the production of fully functional SMN protein. Alternative advanced therapies, such as viral vector mediated gene therapy and orally available small molecules are also showing promising results in early clinical trial phases.Gene Therapy accepted article preview online, 31 May 2017. doi:10.1038/gt.2017.45.

Developmental regulation of SMN expression: pathophysiological implications and perspectives for therapy development in spinal muscular atrophy.Publié le 31 05 2017

Spinal muscular atrophy (SMA), the predominant form of motoneuron diease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn deficient motoneurons which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN up-regulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for therapy, which possibly could be supported by additional strategies which strengthen synaptic transmission.Gene Therapy accepted article preview online, 30 May 2017. doi:10.1038/gt.2017.46.

Utility of repetitive nerve stimulation test for ALS diagnosis.Publié le 31 05 2017

OBJECTIVE: Decremental responses in the repetitive nerve stimulation (RNS) test in amyotrophic lateral sclerosis (ALS) patients have been reported, although their possible diagnostic role has received little investigation. We investigated their diagnostic role in differentiation between ALS and cervical spondylotic amyotrophy (CSA), an important ALS mimic especially in Japan.
METHODS: Patients were prospectively enrolled and the diagnosis was confirmed by follow-up. RNS was performed on the abductor pollicis brevis (APB), upper trapezius (trapezius) and deltoid muscles.
RESULTS: Enrolled subjects consisted of 53 ALS and 37 CSA patients. Abnormal decremental responses (>5%) were observed in 32%, 51% and 75% of ALS patients and 3%, 0% and 20% of CSA patients for the APB, trapezius and deltoid muscles, respectively. The sensitivity for 23 ALS patients with upper-limb onset was 78% for the trapezius and 100% for the deltoid muscles.
CONCLUSIONS: An abnormal decremental response in the trapezius muscle was 100% specific to ALS in comparison with CSA: abnormal decrement in this muscle would strongly suggest ALS. No decrement in the deltoid muscle might exclude ALS in patients having symptoms with upper-limb onset.
SIGNIFICANCE: RNS is useful in differentiation between ALS and CSA.

Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review.Publié le 30 05 2017

Importance: Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1.
Objectives: To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing.
Evidence Review: PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9-mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed.
Findings: Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing-meditated correction of monogenic neuromuscular diseases in cultured cells and animal models.
Conclusions and Relevance: Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies.

Subtly modulating Glycogen Synthase Kinase 3 ?: allosteric inhibitors development and their potential for the treatment of chronic diseases.Publié le 28 05 2017

Glycogen synthase kinase 3 ? (GSK-3?) is a central target in several unmet diseases. To increase the specificity of GSK-3? inhibitors in chronic treatments we are developing small molecules allowing subtle modulation of GSK-3? activity. Design synthesis, structure-activity relationships and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3? are here presented. Furthermore, we show how allosteric binders may overcome the ?-catenin side effects associated to strong GSK-3? inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 34 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3? may be used for future development of drugs for DM1, SMA and other chronic diseases where GSK-3? inhibition exhibits therapeutic effects.

Subthalamic nucleus stimulation improves Parkinson's disease-associated camptocormia in parallel to its preoperative levodopa responsiveness.Publié le 28 05 2017

OBJECTIVE: The aim of this work was to identify factors predictive of postoperative improvement of camptocormia in patients with Parkinson's disease (PD) treated by subthalamic nucleus (STN) stimulation.
BACKGROUND: Camptocormia, one of the most disabling features of PD, often responds poorly to medical therapies. The reported effects of deep brain stimulation on PD-associated camptocormia vary, and preoperative characteristics affecting the surgical outcome remain unclear.
METHODS: We evaluated 17 patients with camptocormia whose preoperative off-medication thoracolumbar angle exceeded 45°. We used photographs to measure their thoracolumbar angle preoperatively, 3?months after surgery, and at the last follow-up (mean 36.5?months postoperatively) in status on-medication and off-medication. The patient age, duration of PD and camptocormia, daily medications, Unified Parkinson's Disease Rating Scale (UPDRS) subscores and the Schwab-England activity of daily living scale (S-E) were also recorded. Univariate analysis was performed to identify factors predictive of the postoperative improvement of camptocormia.
RESULTS: STN stimulation significantly improved the UPDRS subscores and S-E, and resulted in a reduction of daily medications 3?months post-treatment. The preoperative thoracolumbar angle (mean±SD) in status off-medication (84.0±29.5°) was significantly ameliorated 3?months postoperatively (49.8±29.3°) and at the last follow-up (54.8±28.3°). There was no correlation between the postoperative camptocormia improvement rate and preoperative parameters other than the duration and severity of camptocormia and the levodopa responsiveness of the thoracolumbar angle. Symptom duration negatively affected levodopa responsiveness.
CONCLUSIONS: STN stimulation improves PD-associated camptocormia in parallel with preoperative levodopa responsiveness. Long symptom duration interferes with levodopa responsiveness.

[Possible treatments for infantile spinal atrophy].Publié le 20 05 2017

The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future. Nusinersen, a methoxi-ethyl phosphotioate antisense oligonucleotide has recently approved for treatment of patients with SMA type 1 after having proved its efficacy in clinical trial phase 3. The results of nusinersen are reviewed. New modifications of antisense oligonucleotides with better access to brain, spinal cord and peripheral tissues are on the way. There are data of the efficacy of the genetic therapy with SMN1 gene through adenoassociated virus, now in phase 1 trial. A constant feature of these new treatments is that the earlier the treatment, the best are the results, and they are even better in presymptomatic stage. The general standards of care, particularly nutrition and respiratory management are needed in order to reach optimal results with the new therapies.

Cure SMA and our patient community celebrate the first approved drug for SMA.Publié le 17 05 2017

Cure SMA is dedicated to the treatment and cure of spinal muscular atrophy (SMA), the number one genetic cause of death for infants. We fund groundbreaking research and provide families the support they need for today. Today, we have more than 115 000 members and supporters, with 35 volunteer chapters throughout the United States. In the last year, Cure SMA provided direct services to several thousand families. Since 1984, we've led and invested in the research that has made today's breakthroughs possible. With deep connections and expertise in both the patient and research communities, we have been uniquely positioned to direct funds to where they can make the greatest difference as quickly as possible. With the size of our community and the strength of our connections, our goal is to direct research on a comprehensive level with efficiency.Gene Therapy accepted article preview online, 15 May 2017. doi:10.1038/gt.2017.39.

Defective Ribonucleoproteins, Mistakes in RNA Processing, and Diseases.Publié le 17 05 2017

Ribonucleoproteins (RNPs) are vital to many cellular events. To this end, many neurodegenerative diseases and cancers have been linked to RNP malfunction, particularly as this relates to defective processing of cellular RNA. The connection of RNPs and diseases has also propagated a shift of focus onto RNA targeting from traditional protein targeting treatments. However, therapeutic development in this area has been limited by incomplete molecular insight into the specific contributions of RNPs to disease. This review outlines the role of several RNPs in diseases, focusing on molecular defects in processes that affect proper RNA handling in the cell. This work also evaluates the contributions of recently developed methods to understanding RNP association and function. We review progress in this area by focusing on molecular malfunctions of RNPs associated with the onset and progression of several neurodegenerative diseases and cancer and conclude with a brief discussion of RNA-based therapeutic efforts.

Longitudinal characterization of biomarkers for spinal muscular atrophy.Publié le 12 05 2017

OBJECTIVE: Recent advances in understanding Spinal Muscular Atrophy (SMA) etiopathogenesis prompted development of potent intervention strategies and raised need for sensitive outcome measures capable of assessing disease progression and response to treatment. Several biomarkers have been proposed; nevertheless, no general consensus has been reached on the most feasible ones. We observed a wide range of measures over 1 year to assess their ability to monitor the disease status and progression.
METHODS: 18 SMA patients and 19 healthy volunteers (HV) were followed in this 52-weeks observational study. Quantitative-MRI (qMRI) of both thighs and clinical evaluation of motor function was performed at baseline, 6, 9 and 12 months follow-up. Blood samples were taken in patients for molecular characterization at screening, 9 and 12 month follow-up. Progression, responsiveness and reliability of collected indices were quantified. Correlation analysis was performed to test for potential associations.
RESULTS: QMRI indices, clinical scales and molecular measures showed high to excellent reliability. Significant differences were found between qMRI of SMA patients and HV. Significant associations were revealed between multiple qMRI measures and functional clinical scales. None of the qMRI, clinical, or molecular measures was able to detect significant disease progression over 1 year.
INTERPRETATION: We probed a variety of quantitative measures for SMA in a slowly-progressing disease population over 1 year. The presented measures demonstrated potential to provide a closer link to underlying disease biology as compared to conventional functional scales. The proposed biomarker framework can guide implementation of more sensitive endpoints in future clinical trials and prove their utility in search for novel disease-modifying therapies.

How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.Publié le 10 05 2017

Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.Gene Therapy accepted article preview online, 09 May 2017. doi:10.1038/gt.2017.34.

Discovery of a Small Molecule Probe that Post-translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy.Publié le 10 05 2017

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties, but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.

Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis.Publié le 05 05 2017

Homozygous SMN1 loss causes spinal muscular atrophy (SMA), the most common lethal genetic childhood motor neuron disease. SMN1 encodes SMN, a ubiquitous housekeeping protein, which makes the primarily motor neuron-specific phenotype rather unexpected. SMA-affected individuals harbor low SMN expression from one to six SMN2 copies, which is insufficient to functionally compensate for SMN1 loss. However, rarely individuals with homozygous absence of SMN1 and only three to four SMN2 copies are fully asymptomatic, suggesting protection through genetic modifier(s). Previously, we identified plastin 3 (PLS3) overexpression as an SMA protective modifier in humans and showed that SMN deficit impairs endocytosis, which is rescued by elevated PLS3 levels. Here, we identify reduction of the neuronal calcium sensor Neurocalcin delta (NCALD) as a protective SMA modifier in five asymptomatic SMN1-deleted individuals carrying only four SMN2 copies. We demonstrate that NCALD is a Ca(2+)-dependent negative regulator of endocytosis, as NCALD knockdown improves endocytosis in SMA models and ameliorates pharmacologically induced endocytosis defects in zebrafish. Importantly, NCALD knockdown effectively ameliorates SMA-associated pathological defects across species, including worm, zebrafish, and mouse. In conclusion, our study identifies a previously unknown protective SMA modifier in humans, demonstrates modifier impact in three different SMA animal models, and suggests a potential combinatorial therapeutic strategy to efficiently treat SMA. Since both protective modifiers restore endocytosis, our results confirm that endocytosis is a major cellular mechanism perturbed in SMA and emphasize the power of protective modifiers for understanding disease mechanism and developing therapies.

New treatments for serious conditions: Ethical implications.Publié le 04 05 2017

Approval of Spinraza (nusinersen) for treatment of spinal muscular atrophy prompts consideration of a number of ethical issues that arise whenever a new treatment is proposed for a serious condition, especially one that is rare and can devastatingly affect children. Patients, families, clinicians, researchers, institutions, and policymakers all must take account of the ways that newly available treatments affect informed and shared decision-making about therapeutic and research options. The issues to consider include: addressing what is still uncertain and unknown; the possibility that potential benefits will be exaggerated and potential harms underemphasized in the media, by advocacy organizations, and in consent forms and processes; the high cost of many novel drugs and biologics; the effects of including conditions of variable phenotype in state-mandated newborn screening panels; and how new treatments can change the standard of care, altering what is and is not known about a disorder and posing challenges for decision-making at both individual and policy levels. The good news that Spinraza brings thus requires additional attention to its ethical and policy implications, in order to improve counseling and shared decision-making about treatment and research options for patients and all involved in their care.Gene Therapy accepted article preview online, 03 May 2017. doi:10.1038/gt.2017.32.

Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial.Publié le 04 05 2017

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA.
METHODS: This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1?+?D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600.
FINDINGS: The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment.
INTERPRETATION: Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed.
FUNDING: AFM Téléthon and Trophos SA.

A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy.Publié le 02 05 2017

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G>C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ?20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion.

Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy.Publié le 27 04 2017

Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives, such as in-vitro phototoxicity and in-vitro mutagenicity associated with compounds 1 and 2 or the in-vivo retinal findings observed in a long term chronic tox study with 3 at high exposures only. Optimized representative compounds modify the alternative splicing of SMN2, increase the production of full length SMN2 mRNA and therefore levels of full length SMN protein upon oral administration in two mouse models of SMA.

Motor neuropathies and lower motor neuron syndromes.Publié le 25 04 2017

Motor or motor-predominant neuropathies may arise from disease processes affecting the motor axon and/or its surrounding myelin. Lower motor neuron syndrome (LMNS) arises from a disease process affecting the spinal motor neuron itself. The term LMNS is more generally used, rather than motor neuronopathy, although both entities are clinically similar. Common features are muscle weakness (distal or proximal) with atrophy and hyporeflexia, but no sensory involvement. They can be acquired or hereditary. Immune-mediated neuropathies (multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy) are important to identify, as effective treatments are available. Other acquired neuropathies, such as infectious, paraneoplastic and radiation-induced neuropathies are also well known. Focal LMNS is an amyotrophic lateral sclerosis (ALS)-mimicking syndrome especially affecting young adults. The main hereditary LMNSs in adulthood are Kennedy's disease, late-onset spinal muscular atrophy and distal hereditary motor neuropathies. Motor neuropathies and LMNS are all clinical entities that should be better known, despite being rare diseases. They can sometimes be difficult to differentially diagnose from other diseases, particularly from the more frequent ALS in its pure LMN form. Nevertheless, correct identification of these syndromes is important because their treatment and prognoses are definitely different.

Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA).Publié le 25 04 2017

The C-5 substituted 2,4-diaminoquinazoline RG3039 (compound 1), a member of a chemical series that was identified and optimized using an SMN2 promoter screen, prolongs survival and improves motor function in a mouse model of spinal muscular atrophy (SMA). It is a potent inhibitor of the mRNA decapping scavenger enzyme (DcpS), but the mechanism whereby DcpS inhibition leads to therapeutic benefit is unclear. Compound 1 is a dibasic lipophilic molecule that is predicted to accumulate in lysosomes. To understand if the in vivo efficacy is due to DcpS inhibition or other effects resulting from the physicochemical properties of the chemotype, we undertook structure based molecular design to identify DcpS inhibitors with improved physicochemical properties. Herein we describe the design, synthesis, and in vitro pharmacological characterization of these DcpS inhibitors along with the in vivo mouse CNS PK profile of PF-DcpSi (compound 24), one of the analogs found to be efficacious in SMA mouse model.

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.Publié le 21 04 2017

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

ISS-N1 makes the First FDA-approved Drug for Spinal Muscular Atrophy.Publié le 14 04 2017

Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA. Upon procuring exclusive license from the University of Massachussets Medical School in 2010, Ionis Pharmaceuticals (formerly ISIS Pharamaceuticals) began clinical development of Spinraza(™) (synonyms: Nusinersen, IONIS-SMNRX, ISIS-SMNRX), an antisense drug based on ISS-N1 target. Spinraza(™) showed very promising results at all steps of the clinical development and was approved by US Food and Drug Administration (FDA) on December 23, 2016. Spinraza(™) is the first FDA-approved treatment for SMA and the first antisense drug to restore expression of a fully functional protein via splicing correction. The success of Spinraza(™) underscores the potential of intronic sequences as promising therapeutic targets and sets the stage for further improvement of antisense drugs based on advanced oligonucleotide chemistries and delivery protocols.

VEPTR: Are We Reducing Respiratory Assistance Requirements?Publié le 12 04 2017

BACKGROUND: The assisted ventilation rating (AVR) indicates the degree of external respiratory support required in children with thoracic insufficiency syndrome (TIS) and early onset scoliosis. For skeletally immature patients with TIS, the vertical expandable prosthetic titanium rib (VEPTR) device can be used to improve lung volume and growth. We hypothesized that patients who underwent early thoracic reconstruction by VEPTR treatment had an improved respiratory status.
METHODS: Preoperative and postoperative AVR ratings were prospectively collected in a multicenter study group and compared with determine change after VEPTR treatment. Patients under 10 years of age at initial implant with minimum of 2-year follow-up data were included. Patients were excluded if there was incomplete data or if initial AVR was normal (breathing on room air). Statistical analysis was performed on groups which had stable, declined, and improved AVR at final follow-up.
RESULTS: Database search yielded 77 patients with initial abnormal AVR. Average follow-up was 5.6 years. The most frequent primary diagnoses were congenital scoliosis (n=14) and spinal muscular atrophy (n=14). In total, 19 (24%) demonstrated improvement, 9 (12%) patients deteriorated, and 49 (64%) remained at the same level. The average preoperative major curve in those with improvement (58.4 degrees) and those with no change (63.5 degrees) was less than in those with deterioration (85.5 degrees) (P=0.014). The average age in years at implant of those with improvement (4) was less than those declined (6.7) and those with no change (5.5). In total, 16 (84.2%) of those that improved had a normal AVR and did not require respiratory support at last follow-up.
CONCLUSIONS: There is evidence that there is a subset of patients with early onset scoliosis and TIS, who received early thoracic reconstruction with VEPTR treatment show complete resolution of pulmonary support at final follow-up. In total, 89% of 79 patients did not experience respiratory deterioration. A total of 24% (n=19) had a positive change with over 84% (n=16) of this group no longer requiring support.
LEVEL OF EVIDENCE: Level III-prognostic.

Combination of valproic acid and morpholino splice-switching oligonucleotide produces improved outcomes in spinal muscular atrophy patient-derived fibroblasts.Publié le 10 04 2017

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans possess a second nearly identical copy of SMN1, known as SMN2. However, SMN2 produces only 10-20% functional SMN protein due to aberrant splicing of its pre-mRNA that leads to the exclusion of exon 7. This level of SMN is insufficient to rescue the phenotype. Recently developed splice-switching antisense oligonuclotides (SSO) have shown great promise in correcting the aberrant splicing of SMN2 towards producing functional SMN protein. Several FDA approved drugs are being repurposed for SMA treatment including valproic acid (VPA), a histone deacetylase inhibitor, which has been shown to increase overall SMN2 expression. In this study, we have characterised the effects of single and combined treatment of VPA and a SSO based on phosphorodiamidate morpholino oligomer (PMO) chemistry. We conjugated both VPA and PMO to a single cell-penetrating peptide (Apolipoprotein E (ApoE)) for their simultaneous intracellular delivery. Treatment of SMA Type I patient-derived fibroblasts with the conjugates showed no additive increase in the level of full-length SMN2 mRNA expression over both 4 and 16 h treatments indicating that conjugation of VPA to ApoE-PMO has limited benefit. However, treatment with a combination of VPA and ApoE-PMO induced more favourable splice switching activity than either agent alone, promoting exon 7 inclusion in SMN2 transcripts. Our results suggest that combination therapy of VPA and ApoE-PMO is superior in upregulating SMN2 production in vitro, as compared to singular treatment of each compound at both transcriptional and protein levels. This study provides the first indication of a novel dual therapy approach for the potential treatment of SMA.

Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease.Publié le 07 04 2017

Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness and wasting. Until recently there were no effective therapies for these conditions, but antisense oligonucleotides, a new class of synthetic single stranded molecules of nucleic acids, have demonstrated promising experimental results and are at different stages of regulatory approval. The antisense oligonucleotides can modulate the protein expression via targeting hnRNAs or mRNAs and inducing interference with splicing, mRNA degradation, or arrest of translation, finally, resulting in rescue or reduction of the target protein expression. Different classes of antisense oligonucleotides are being tested in several clinical trials, and limitations of their clinical efficacy and toxicity have been reported for some of these compounds, while more encouraging results have supported the development of others. New generation antisense oligonucleotides are also being tested in preclinical models together with specific delivery systems that could allow some of the limitations of current antisense oligonucleotides to be overcome, to improve the cell penetration, to achieve more robust target engagement, and hopefully also be associated with acceptable toxicity. This review article describes the chemical properties and molecular mechanisms of action of the antisense oligonucleotides and the therapeutic implications these compounds have in neuromuscular diseases. Current strategies and carrier systems available for the oligonucleotides delivery will be also described to provide an overview on the past, present and future of these appealing molecules.

A qualitative study of perceptions of meaningful change in spinal muscular atrophy.Publié le 07 04 2017

BACKGROUND: This qualitative study examined how individuals with Spinal Muscular Atrophy (SMA), their caregivers, and clinicians defined meaningful change, primarily in the Type II and non-ambulant type III patient populations, associated with treatment of this condition. In addition, we explored participants' views about two measures of motor function routinely used in clinical trials for these SMA subtypes, namely the expanded version of the Hammersmith Functional Motor Scale (HFMSE) and the Upper Limb Module (ULM).
METHODS: The 123 participants (21 with SMA, 64 parents, and 11 clinicians), recruited through SMA advocacy organizations, participated in one of 16 focus groups or 37 interviews. The sessions were audio-recorded, and verbatim transcripts were analyzed using a grounded theory approach.
RESULTS: For the participants, meaningful change was relative to functional ability, and small changes in motor function could have an important impact on quality of life. Because patients and families feared progressive loss of functional ability, the participants saw maintenance of abilities as a meaningful outcome. They believed that measures of motor function covered important items, but worried that the HFMSE and ULM might not be sensitive enough to capture small changes. In addition, they felt that outcome measures should assess other important features of life with SMA, including the ability to perform daily activities, respiratory function, swallowing, fatigue, and endurance.
CONCLUSIONS: Given the heterogeneity of SMA, it is important to expand the assessment of treatment effects to a broader range of outcomes using measures sensitive enough to detect small changes.

Newborn screening for spinal muscular atrophy: The views of affected families and adults.Publié le 05 04 2017

Spinal muscular atrophy (SMA) is one of the leading genetic causes of infant death worldwide. However, due to a lack of treatments, SMA has historically fallen short of Wilson-Jungner criteria. While studies have explored the acceptability of expanded newborn screening to the general public, the views of affected families have been largely overlooked. This is in spite of the potential for direct impacts on them and their unique positioning to consider the value of early diagnosis. We have previously reported data on attitudes toward pre-conception and prenatal genetic screening for SMA among affected familie