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Introduction Homozygous mutations in the survival of motor neuron 1 (SMN1) gene result in reduced levels of the SMN protein and trigger the infantile-onset neuromuscular disease, spinal muscular atrophy (SMA) [...], Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ--skeletal muscle--by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.

B Correction to: Neurol Ther (2023) 12:543-557 b https://doi.org/10.1007/s40120-023-00444-1 In this article the JEWELFISH Study Group members were missing in the Acknowledgements. The members of the JEWELFISH Study are listed online in "Acknowledgements". [Extracted from the article]

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness and atrophy that is caused by survival motor neuron (SMN) protein deficiency resulting from the biallelic loss of the SMN1 gene. The SMN2 gene modulates the SMA phenotype, as a small fraction of its transcripts are alternatively spliced to produce full-length SMN (fSMN) protein. SMN-targeted therapies increase SMN protein; mRNA therapies, nusinersen and risdiplam, increase the amount of fSMN transcripts alternatively spliced from the SMN2 gene, while gene transfer therapy, onasemnogene abeparvovec xioi, increases SMN protein by introducing the hSMN gene into various tissues, including spinal cord via an AAV9 vector. These SMN-targeted therapies have been found effective in improving outcomes and are approved for use in SMA in the US and elsewhere. This article discusses the clinical trial results for SMN-directed therapies with a focus on efficacy, side effects and treatment response predictors. It also discusses preliminary data from muscle-targeted trials, as single agents and in combination with SMN-targeted therapies, as well as other classes of SMA treatments. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to examine the psychometric properties of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) in children and youth with Spinal Muscular Atrophy (SMA). METHODS: In this prospective cross-sectional study, caregivers of children and youth with SMA completed the PEDI-CAT Daily Activities and Mobility domains. A subset of caregivers completed a questionnaire about the measure. RESULTS: Mean ranks of scaled scores for Daily Activities (n = 96) and Mobility (n = 95) domains were significantly different across the three SMA types and across the three motor classifications. Normative scores indicated that 85 participants (89.5%) had limitations in Mobility and 51 in Daily Activities (53.1%). Floor effects were observed in≤10.4% of the sample for Daily Activities and Mobility. On average, caregivers completed the Mobility domain in 5.4 minutes and the Daily Activities domain in 3.3 minutes. Most caregivers reported that they provided meaningful information (92.1%), were willing to use the PEDI-CAT format again (79%), and suggested adding content including power wheelchair mobility items. CONCLUSION: Convergent validity was demonstrated for the Daily Activities and Mobility domains. Normative scores detected limitations in Mobility and Daily Activity performance for most participants with SMA. The PEDI-CATwas feasible to administer and caregivers expressed willingness to complete the PEDI-CAT in the future. [ABSTRACT FROM AUTHOR]

Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding 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, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed.Results: Motor function scores (MFS) and compound muscle action potential (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% confidence interval, 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. Ann Neurol 2017;82:883-891. [ABSTRACT FROM AUTHOR]

Introduction: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA).Methods: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types.Results: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types.Conclusions: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016. [ABSTRACT FROM AUTHOR]

Introduction: The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA.Methods: Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients.Results: Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE.Conclusions: This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016. [ABSTRACT FROM AUTHOR]

Objective This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy ( SMA). Methods This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (Neuro NEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. Results Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items ( TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders ( CHOP- INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude ( CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography ( EIM) high-frequency reactance slope (Ohms/ MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron ( SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. Interpretation By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study aimed at documenting the setting, frequency, duration, and type of physical therapy (PT) services received by patients with spinal muscular atrophy (SMA). Topics mentioned include the variability of services received among patients with SMA, what future studies should consider, and parent report for the type of intervention the PT administered for their child by SMA type.

Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA).Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale-Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6-minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores.Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component.Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Spinal muscular atrophy (SMA) causes muscle weakness and fatigue. Better understanding of the relationship between weakness and fatigue may help identify potential targets for rehabilitation. Methods: Gait and surface electromyography (EMG) from 4 muscle groups were measured during the Six-Minute Walk Test (6MWT) in 10 ambulatory participants, aged 9-49 years. Average root mean square amplitude (RMS) of muscle activity was calculated. Strength was assessed using manual and quantitative methods. Results: RMS, stride length, and velocity decreased during the 6MWT. Knee flexor and hip abductor strength was associated with fatigue-related changes; overall strength correlated with disease duration; and leg strength was associated with 6MWT distance. Conclusions: Clinical measures are valid in assessing fatigue and function in SMA, and these assessments can be enhanced by use of gait analysis and EMG. Disease duration and strength measures may represent further stratification refinements when enrolling patients in clinical trials. Muscle Nerve 50: 34-39, 2014 [ABSTRACT FROM AUTHOR]

Weakness and fatigue are captured by the 6-minute walk test, but the relationship between these symptoms is uncertain. Comparison across neuromuscular diseases has not been examined. A cohort study of 114 patients with spinal muscular atrophy, Duchenne/Becker muscular dystrophy, myasthenia gravis, and energy failure syndromes were included. Percent-predicted distance on the 6-minute walk test was computed from normative values to determine weakness. Fatigue was determined by the decrement in distance from the first to sixth minute. Weakness was seen across all groups (61.9%) but significant fatigue was seen only in spinal muscular atrophy (21.0%). Other groups showed little fatigue. Correlation between weakness and fatigue was significant only in spinal muscular atrophy (R = –0.71; P < .001). Longitudinally, distance walked declined only in Duchenne/Becker muscular dystrophy. In spinal muscular atrophy, weakness did not change, but fatigue increased significantly. These findings suggest independent mechanisms underlying weakness and fatigue in diverse neuromuscular conditions. [ABSTRACT FROM PUBLISHER]

Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.Funding: Novartis Gene Therapies. [ABSTRACT FROM AUTHOR]

• A novel smartphone sensor-based assessment suite was developed for people with spinal muscular atrophy (SMA). • Tests were reliable, engaging, and easy for most people with SMA to complete. • Tests showed convergent validity with established SMA clinical assessments. • Our study demonstrates potential for digital monitoring of disease in SMA. Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness and paralysis. Motor function is monitored in the clinical setting using assessments including the 32-item Motor Function Measure (MFM-32), but changes in disease severity between clinical visits may be missed. Digital health technologies may assist evaluation of disease severity by bridging gaps between clinical visits. We developed a smartphone sensor-based assessment suite, comprising nine tasks, to assess motor and muscle function in people with SMA. We used data from the risdiplam phase 2 JEWELFISH trial to assess the test–retest reliability and convergent validity of each task. In the first 6 weeks, 116 eligible participants completed assessments on a median of 6.3 days per week. Eight of the nine tasks demonstrated good or excellent test–retest reliability (intraclass correlation coefficients >0.75 and >0.9, respectively). Seven tasks showed a significant association (P < 0.05) with related clinical measures of motor function (individual items from the MFM-32 or Revised Upper Limb Module scales) and seven showed significant association (P < 0.05) with disease severity measured using the MFM-32 total score. This cross-sectional study supports the feasibility, reliability, and validity of using smartphone-based digital assessments to measure function in people living with SMA. [ABSTRACT FROM AUTHOR]