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Introduction/aims: Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time., Methods: Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups., Results: HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P < .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68-0.92, P < .001). Individual muscle groups, however, showed high levels of variability between visits., Discussion: Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints., (© 2022 Wiley Periodicals LLC.)

The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10 m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population., Competing Interests: Declaration of Competing Interests Anna G. Mayhew has participated in SAB meetings for Roche, Regenxbio, Summit, PTC and Biogen and performs Consultancy work (training physiotherapists for trial in DMD) for Roche, Pfizer, PTC, Summit, Sarepta, Lysogene, Italfarmaco, Amicus, Biogen and Avexis. Dionne Moat provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd, Reveragen, Sarepta Therapeutics), outside the submitted work. Michael McDermott has been supported by a research grant from PTC Therapeutics, has received compensation for consulting from Fulcrum Therapeutics, Inc., and NeuroDerm, Ltd., and has served on Data and Safety Monitoring Boards (DSMBs) for AstraZeneca, Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Cynapsus Therapeutics, Neurocrine Biosciences, Inc., Voyager Therapeutics, Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS Pharma, Inc. Michelle Eagle is Managing Director at ATOM International Limited and is contracted with the following companies through ATOM: Amicus, Biomarin, Capricor, Catabasis, Denali, Dyne, Edgewise, Faraday, Fibrogen, Genethon, Italfarmaco, Lysogen, Modis, NSPharma, PTC, Sarepta, Solid, Referagen. Robert Griggs receives research support from the NIH, the Muscular Dystrophy Association, the Parent Project for Muscular Dystrophy, and from Sarepta Biopharma, PTC Therapeutics and Santhera Pharmaceuticals. He serves as a Consultant for Strongbridge and Stealth Pharmaceuticals. He is Chair of a DSMB for Solid Pharmaceuticals. He receives monies for editorial work from Elsevier as an Editor of Cecil Essentials and Cecil Textbook of Medicine. He serves as Chair of the Research Advisory Committee and is a Board Member of the American Brain Foundation. He is on the Executive Committee of the Muscle Study Group, which receives support for its activities from Pharmaceutical companies. Meredith K. James provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd, Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd, Reveragen, Sarepta Therapeutics), outside the submitted work. MKJ has received payment for participation on advisory boards for F. Hoffman La Roche AG, PTC Therapeutics and fee support for PhD studies from the Jain Foundation, outside the submitted work. Robert Muni-Lofra has participated in the advisory board for Biogen and Roche and performs consultancy work (training physiotherapists for trial in DMD and SMA) for Roche, Pfizer, PTC, Summit, Sarepta, Italfarmaco, Amicus, Biogen and Avexis. Lindsey Pallant has performed consultancy work (workshops and training physiotherapists in trials for DMD) for PTC and Sarepta. Katy Eichinger has received personal compensation for serving on advisory boards and/or as a consultant for Ionis, Biogen, Acceleron, Fulcrum, Avidity, PTC and the Myotonic Dystrophy Foundation. Dr. Eichinger has received personal compensation for serving as a speaker from Cure SMA, FSH Society, and Ology. She has received research/grant support from the CMTA. Heather McMurchie has received financial support from PTC and Biogen to access and provide training. Marina DiMarco attended a World Muscle Society conference sponsored by PTC Therapeutics and is a Consultant Physiotherapist presenting at PTC workshops. Lindsay N. Alfano provides consultancy services through ATOM International, Ltd for the following companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics); reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; advisory board for Biogen. Linda P. Lowes provides consultancy services through ATOM International, Ltd for the following companies: Amicus Therapeutics Pty Ltd, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics); reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; advisory board for Biogen. Amy Pasternak has participated in advisory boards for Roche, Biogen, Avexis, Scholar Rock and Audentes. Victoria Kern has received an honorarium from the MDA USA for a presentation. Cheryl Scholtes has sat on advisor panels for Biogen Canada and Roche Canada, and has been provided education on behalf of Biogen Canada and Roche Canada. Catherine Lacroix has acted as a consultant and advisory board participant to Biogen. Katherine Kundrat has participated in an advisory board for Biogen. Michela Guglieri is the study chair for a ReveraGen study. MG has research collaborations with ReveraGen and Sarepta. MG is (has been over the past 5 years) PI for clinical trials sponsored by Pfizer, Italfarmaco, Santhera, ReveraGen, Dynacure, Roche, PTC, Summit. MG has been participating in advisory boards for Pfizer, NS Pharma, Dyne (consultancies through Newcastle University). MG has performed consultancy work (speaker) for Sarepta. Declarations of interest: none for remaining authors, (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction/aims: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype., Methods: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo)., Results: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population., Discussion: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Patients with Duchenne muscular dystrophy (DMD) adopt compensatory movement patterns as muscles weaken. The Duchenne Video Assessment (DVA) measures patient ease of movement through identification of compensatory movement patterns. The DVA directs caregivers to video record patients performing specific movement tasks at home using a secure mobile application, and DVA-certified physical therapists (PTs) score the videos using scorecards with prespecified compensatory movement criteria. The goal of this study was to develop and refine the DVA scorecards., Methods: To develop the initial scorecards, 4 PTs collaboratively created compensatory movement lists for each task, and researchers structured the lists into scorecards. A 2-round modified Delphi process was used to gather expert opinion on the understandability, comprehensiveness, and clinical meaningfulness of the compensatory movements on the scorecards. Eight PTs who had evaluated ≥50 patients with DMD and participated in ≥10 DMD clinical trials were recruited for the panel. In Round 1, panelists evaluated compensatory movement criteria understandability via questionnaire and tested the scorecards. In Round 2, panelists participated in an in-person meeting to discuss areas of disagreement from Round 1 and reach consensus (≥75% agreement) on all revisions to the scorecards., Results: During the Round 1 revisions to the scorecards, there were 67 changes (44%) to the wording of 153 original compensatory movement criteria and 3 criteria were removed. During the Round 2 revisions to the scorecards, there were 47 changes (31%) to the wording of 150 compensatory movement criteria, 20 criteria were added, and 30 criteria were removed. The panel reached 100% agreement on all changes made to scorecards during Round 2., Conclusion: PTs with extensive experience evaluating patients with DMD confirmed that the compensatory movement criteria included in the DVA scorecards were understandable, comprehensive, and clinically meaningful., Competing Interests: I have read the journal’s policy and the authors of the manuscript have the following competing interests: Marielle Contesse, Christine McSherry, and Mindy Leffler are all employed by Casimir LLC. Additionally, Christine McSherry and Mindy Leffler are 50/50 owners of Casimir LLC. Casimir LLC developed the Duchenne Video Assessment and uses it commercially. Their employment at Casimir did not interfere with the full and objective presentation of the research.

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy., Competing Interests: MJ receives fee support for PhD studies from the Jain Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori-Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub.)

Background: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death., Objective: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study., Methods: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed., Results: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort., Conclusions: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

This study determined the frequency and impact of symptoms on quality of life in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach., Methods: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850., Results: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%., Interpretation: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life., Funding: PCORI, NIH., Competing Interests: Drs. Gauthier, Borstad, Lowes, and Crawfis co-founded Games That Move You, PBC to commercialize the gaming technology utilized in this research; conflict management plans were put in place through The Ohio State University prior to conducting this trial to ensure research integrity., (© 2021 The Author(s).)

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center's expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naïve to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings., Competing Interests: TD has served on medical advisory boards and/or consultant for Scholar Rock, Genentech, F. Hoffman La Roche, Biogen, Sarepta, Novartis, Solid Biosciences, Dynacure, Dyne, and Audentes Consultancy also through ATOM International and Trinds (Biomarin, Pfizer, Solid Biosciences, Sarepta, and Astellas). She has received research grant support from Ionis. KJK receives consulting fees from Cure SMA, ASPA Therapeutics, and Biogen and Honoraria from Stanford University and Cure SMA; Advisory Board member of Biogen and Cure SMA; Roche; Grant funding: Academy of Pediatric PT, APTA; subcontracts from Lurie Children’s for Biogen, Cytokinetics, Avexis, and Scholar Rock and NIH iAcquire clinical trial. MKJ provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty., Ltd., Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd., Reveragen, and Sarepta Therapeutics). MKJ has received payment for participation on Advisory Boards for F. Hoffman La Roche AG, PTC Therapeutics and fee support for Ph.D. studies from the Jain Foundation. LN has served on Medical Advisory Boards and as a consultant for Sarepta, Pfizer, Biogen, Novartis, Scholar Rock, Genentech, and F. Hoffmann-La Roche. She served as a member of ATOM from 2015 to 2020. LNA provides consultancy services through ATOM International for the following companies: Amicus Therapeutics Pty., Ltd., Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, and PTC Therapeutics; reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; and advisory board for Biogen. KE has received personal compensation for serving on advisory boards and/or as a consultant for Ionis, Biogen, Acceleron, Fulcrum, Avidity, PTC, F. Hoffman-La Roche, and the Myotonic Dystrophy Foundation. KE has received personal compensation for serving as a speaker from Cure SMA, FSH Society, and Ology. She has received research/grant support from the CMTA. EM has served on medical advisory boards and/or consultant for Scholar Rock, F. Hoffman La Roche, Italfarmaco, Biogen, Sarepta, Novartis, Avexis, and PTC Therapeutics. KR provides consultancy services (training in clinical outcome measures and quality assurance implementation for clinical outcome assessments) for the following companies: ATOM International (under ATOM consultancy services provided to Amicus Therapeutics Pty., Ltd., Ascendis Pharma, BioMarin, Catabasis, FibroGen, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics, Ltd., Sarepta Therapeutics, and Summit Pharmaceuticals International). KR also provides independent consultancy services to Biogen and F. Hoffman La Roche AG and receives payment for participation on Advisory Boards and publication steering committees and for assisting to deliver education initiatives for Biogen and F. Hoffman La Roche AG. LPL provides consultancy services through ATOM International for the following companies: Amicus Therapeutics Pty., Ltd., Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, and PTC Therapeutics; reports royalties and other support from Sarepta Therapeutics; royalties for licensed technologies; other support from Novartis Gene Therapies; and advisory board for Biogen. AM provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty., Ltd., Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd., Reveragen, and Sarepta Therapeutics). AM has received payment for participation on Advisory Boards for F. Hoffman La Roche AG, PTC Therapeutics. AM also provides independent consultancy services to Biogen and F. Hoffman La Roche AG. ME is Managing Director of ATOM International Limited and provides consultancy services for the following companies: Amicus Therapeutics Pty., Ltd., Ascendis Pharma, Biomarin, Catabasis, Capricor, Denali Therapeutics, Faraday, FibroGen Inc., Genethon, Italfarmaco, Lysogene, Modis, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics, Ltd., Reveragen, Sarepta Therapeutics, and Solid Biosciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Duong, Krosschell, James, Nelson, Alfano, Eichinger, Mazzone, Rose, Lowes, Mayhew, Florence, King, Senesac and Eagle.)

Clinical outcome assessments of function or strength, assessed by physical therapists, are commonly used as primary endpoints in clinical trials, natural history studies and within clinics for individuals with neuromuscular disorders. These evaluations not only inform the efficacy of investigational agents in clinical trials, but also importantly track disease trajectory to prospectively advise need for equipment, home and work modifications, and other assistive devices. The COVID-19 pandemic had a global impact on the safety and feasibility of in-person visits and assessments, necessitating rapid development of mitigation strategies to ensure ongoing collection of key clinical trial endpoints and access to expert clinical care despite travel restrictions. Physical therapists who are expert in neuromuscular disorders working across clinics, countries, and clinical trials developed initial guidelines and methods for the suitability and feasibility of performing remote evaluations. A number of Sponsors introduced amendments to their study protocols to enable remote evaluations, supported by live video streaming of the assessment to their local clinical evaluators. Similarly, application of these techniques to clinical telemedicine enabled objective evaluations for use in payer discussions, equipment procurement, and general access to expert physical therapy services. Here we report on our methodology for adapting current practices to remote testing and considerations for remote evaluations., Competing Interests: MJ provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd., Ascendis Pharma, Biomarin, Catabasis, Faraday, FibroGen, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics Ltd., Reveragen, Sarepta Therapeutics). MJ has received payment for participation on Advisory Boards for F. Hoffman La Roche AG, PTC Therapeutics and fee support for PhD studies from the Jain Foundation. KR provides consultancy services for the following companies: ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd., Ascendis Pharma, BioMarin, Catabasis, FibroGen, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics, Ltd., Sarepta Therapeutics and Summit Pharmaceuticals International) as well as consultancy services provided independently to Biogen and F. Hoffman La Roche AG. KR also receives payment for participation on Advisory Boards and steering committees and for assisting to deliver education initiatives for Biogen and F. Hoffman La Roche AG. LA reports royalties and other support from Sarepta Therapeutics, royalties for licensed technologies, other support from Novartis Gene Therapies, personal fees from Biogen. Also provides consultancy services for ATOM International (Amicus Therapeutics Pty Ltd., Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics), outside the submitted work. NR reports support from Sarepta Therapeutics and as a trainer for ATOM International, Ltd. (Amicus Therapeutics Pty Ltd., Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics), outside the submitted work. LL reports royalties and other support from Sarepta Therapeutics, royalties for licensed technologies, other support from Novartis Gene Therapies, personal fees from Biogen and as a trainer for ATOM International (Amicus Therapeutics Pty Ltd., Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics), outside the submitted work. ME is the Managing Director of ATOM International (covers consultancy services provided to Amicus Therapeutics Pty Ltd., Ascendis Pharma, Biomarin, Capricor Catabasis, Denali, Faraday, FibroGen, Genethon, Italfarmaco, Lysogene, Modis, NS Pharma, Pfizer, PTC Therapeutics, QED Therapeutics, Ltd., Reveragen, Sarepta Therapeutics, Solid Biosciences)., (Copyright © 2021 James, Rose, Alfano, Reash, Eagle and Lowes.)

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities., Methods: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes., Results: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort., Conclusion: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification., Summary: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development., Competing Interests: Dr. Servais reports grants and personal fees from Roche, grants and personal fees from AveXis, grants and personal fees from Biogen, personal fees from Cytokinetics, grants and personal fees from Dynacure, personal fees from Audentes, personal fees from Santhera, personal fees from Sarepta, personal fees from Affinia, personal fees from Pfizer, personal fees from REGENXBIO, personal fees from Lupin Pharmaceuticals, and personal fees from FibroGen, outside the submitted work; in addition, Dr. Servais is a coinventor of a device for measuring upper limb activity: “method for estimating the physical activity of an upper limb” and a coinventor on a patent for a method to estimate power at the upper limb level (this method can be used by ActiMyo®). Dr. Servais has no financial return from these patents, which are held by his previous institution. Dr. Clement, Dr. Lukawy, and Dr. Strijbos are or were employees of F. Hoffmann-La Roche and have nothing else to disclose. Dr. McDonald reports grants from Capricor, grants from Catabasis, grants from Edgewise Therapeutics, grants from Epirium Bio, grants from Italfarmaco, grants from Pfizer, grants from PTC Therapeutics, grants from Santhera Pharmaceuticals, grants from Sarepta Therapeutics, other from Capricor, other from Catabasis, other from PTC Therapeutics, other from Santhera Pharmaceuticals, and other from Sarepta Therapeutics, outside the submitted work. Dr. Eggenspieler has nothing to disclose other than his affiliation with SYSNAV, a company that collaborated with the Institute of Myology to create ActiMyo®. Dr. ­Eggenspieler is an employee of SYSNAV. Dr. Cerreta reports working for the European Medicines Agency. She disclaims that these opinions are presented in her personal capacity and do not represent the view of the Agency. Dr. Lowes and Dr. Camino have nothing to disclose., (Copyright © 2021 by S. Karger AG, Basel.)

Introduction: The Duchenne Video Assessment (DVA) assesses quality of movement as an indication of Duchenne muscular dystrophy (DMD) disease severity. Caregivers video record patients performing home-based movement tasks using a mobile application, and physical therapists (PTs) rate the videos using scorecards with prespecified compensatory movement criteria. Reliability and construct validity of the DVA were tested using video and Pediatric Outcomes Data Collection Instrument (PODCI) data from patients with DMD and healthy controls from a separate study., Methods: Fifteen PTs were trained and certified as DVA raters. All raters scored videos of five subjects performing each movement task; nine raters rescored the same videos four weeks later. Three raters scored videos from an average of 25 subjects for each movement task. Aggregate scores were used to test construct validity. An expert DMD clinician assigned each video to a severity group for known-groups analyses. Differences between rater scores across severity groups were tested and correlations between DVA and PODCI scores were calculated., Results: Inter-rater reliability (intraclass correlation coefficient [ICC]) between all 15 raters ranged from 0.70 to 0.97 for all movement tasks. Mean intra-rater reliability ICC for nine raters ranged from 0.82 to 0.98 for all movement tasks. There were statistically significant differences between known severity groups for all movement tasks. The DVA correlated strongly with related PODCI constructs of physical function and weakly with unrelated constructs., Discussion: The DVA was found to be a reliable and valid tool for measuring quality of movement as an indication of disease severity., (© 2021 Casimir LLC. Muscle & Nerve published by Wiley Periodicals LLC.)

Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy., Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained., Design, Setting, and Participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020., Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort., Main Outcomes and Measures: The primary outcome measure was the incidence of serious adverse events (SAEs)., Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen., Conclusions and Relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose., Trial Registration: ClinicalTrials.gov Identifier: NCT03421977.

Objective: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD., Methods: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories., Results: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline., Interpretation: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD., Objective: Compare long-term ambulatory function in eteplirsen-treated patients versus controls., Methods: Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries., Results: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available., Conclusion: In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

This analysis aims to describe the outcomes of two nonambulatory patients with Duchenne muscular dystrophy (DMD) who participated in two clinical studies. The two consecutive trials of eteplirsen (studies 201 and 202) were conducted in patients with DMD (N = 12) and confirmed genetic mutations amenable to exon 51 skipping.In study 201, 12 patients were randomized to receive once-weekly, double-blind intravenous infusions of eteplirsen 30 or 50 mg/kg or placebo for 24 weeks; patients then received open-label eteplirsen during weeks 25 through 28. All 12 patients continued onto open-label extension study 202 and received long-term treatment with eteplirsen. We compared cardiac, pulmonary, and upper limb function and dystrophin production in the nonambulatory twin patients versus the 10 ambulatory patients through 240 combined treatment weeks.Ten study patients remained ambulatory through both studies, while the identical twin patients both experienced early, rapid loss of ambulation. The twin patients had greater disease severity at baseline (6-minute walk test [6MWT], 330 and 256 m) versus the other patients (n = 10; 6MWT range, 341-418 m). They maintained cardiac and upper limb function through combined week 240, with outcomes similar to those of the patients who remained ambulatory. Dystrophin production was confirmed following eteplirsen treatment.Despite the loss of ambulation, other markers of disease progression remained relatively stable in the eteplirsen-treated twin patients and were similar to those of the ambulatory patients.

Objective: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year., Methods: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis., Results: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint., Conclusion: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials., Clinicaltrialsgov Identifier: NCT01676077., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years., Objective: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls., Methods: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change., Results: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons)., Conclusions: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Aim: We created a Learning Health System, the "Learn From Every Patient" program, embedded in our cerebral palsy team clinic. This program was designed to simultaneously provide clinical care while systematically collecting data for quality improvement and research projects on all patients., Method: Clinicians created tools within the Electronic Health Record to discretely capture data for clinical use which was also available for quality improvement/research efforts. At baseline, all patients in our clinic received annual hip x-rays to screen for hip displacement. Using our "Learn From Every Patient" database, we reviewed the outcomes for the most mildly affected patients, Level I on the Gross Motor Functional Classification System., Results: One hundred thirty-two patients were classified as Gross Motor Functional Classification System Level I. During the study period, these patients received 212 pelvis x-rays, viewing 424 hips, of which 419 (98.8%) were normal. Five hips (1.2%) had < 30% displacement. None had any hip-related symptoms nor required any procedures during the period. We used these data to create an evidence-based change in our standardized hip screening procedure by eliminating annual screening x-rays for this population., Interpretation: This implementation of a local learning health system approach to systematically collect research data simultaneously with routine clinical care enabled us to implement an evidence-based improvement in clinical practice. This complete integration of research into clinical care improved care by reducing radiation exposure, while simultaneously reducing health care costs.

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 .).

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 10 11 vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58-153 m, whereas two were minimally improved (5-23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Aim: The convergence of three major trends in medicine, namely conversion to electronic health records (EHRs), prioritization of translational research, and the need to control healthcare expenditures, has created unprecedented interest and opportunities to develop systems that improve care while reducing costs. However, operationalizing a 'learning health system' requires systematic changes that have not yet been widely demonstrated in clinical practice., Method: We developed, implemented, and evaluated a model of EHR-supported care in a cohort of 131 children with cerebral palsy that integrated clinical care, quality improvement, and research, entitled 'Learn From Every Patient' (LFEP)., Results: Children treated in the LFEP Program for a 12-month period experienced a 43% reduction in total inpatient days (p=0.030 vs prior 12mo period), a 27% reduction in inpatient admissions, a 30% reduction in emergency department visits (p=0.001), and a 29% reduction in urgent care visits (p=0.046). LFEP Program implementation also resulted in reductions in healthcare costs of 210% (US$7014/child) versus a Time control group, and reductions of 176% ($6596/child) versus a Program Activities control group. Importantly, clinical implementation of the LFEP Program has also driven the continuous accumulation of robust research-quality data for both publication and implementation of evidence-based improvements in clinical care., Interpretation: These results demonstrate that a learning health system can be developed and implemented in a cost-effective manner, and can integrate clinical care and research to systematically drive simultaneous clinical quality improvement and reduced healthcare costs., (© 2016 Mac Keith Press.)

Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC)., Methods: Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype., Results: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping., Interpretation: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Introduction: Traditional upper extremity measures typically focus on distal abilities and do not quantify the unique progression of decline in dystrophinopathy. We designed ACTIVE-seated to meet this need. Our objective was to establish the tool's validity and reliability., Methods: ACTIVE-seated uses the Microsoft Kinect gaming interface to quantify functional reaching ability while playing a custom-designed game. A skeletal tracking algorithm was used to determine the furthest arm excursion in all planes in 61 subjects with dystrophinopathy and 16 controls., Results: Total reachable area was scaled based on arm length to standardize comparisons across subjects and accommodate growth. ACTIVE-seated discriminately ranked subjects from normal controls and by Brooke level (P < 0.001). Scores were highly correlated with parent reports of daily activities and mobility (P < 0.05). Test-retest reliability of ACTIVE-seated was excellent (ICC = 0.97, P < 0.0001)., Conclusions: Initial evaluation of reliability and validity suggests that ACTIVE-seated shows promise as a clinical and research outcome for individuals with dystrophinopathy., (© 2014 Wiley Periodicals, Inc.)

Children with cerebral palsy frequently receive therapeutic intervention to remediate standing balance deficits. Evaluation of the impairments associated with poor balance could facilitate more effective treatment programs. This study evaluated the relationship between lower extremity force production, range of motion and standing balance in thirty-five children between the ages of 6 and 14 years of age with spastic cerebral palsy. Standing balance was evaluated using the Pediatric Clinical Test of Sensory Interaction (P-CTSIB). Hand-held dynamometry was used to assess force production and goniometry was used to assess range of motion. The results indicated that force production and range of motion are highly related to standing balance. Blocked, hierarchical multiple regression analysis revealed that force production explained 41% of the variance in P-CTSIB scores in this sample, while range of motion explained an additional 13%. Therefore, the total variance explained by these variables was 54%. Results of this study suggest that impairment level testing may allow the development of more effective individualized intervention programs to remediate balance deficits. Clinical suggestions are provided.