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Background: Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients’ and caregivers’ views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE). Methods: First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE. Results: Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2. Conclusions: Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers. Electronic supplementary material The online version of this article (doi:10.1186/s12883-017-0790-9) contains supplementary material, which is available to authorized users., Version of Record

Background: Cardiopulmonary exercise testing (CPET) is the gold-standard for quantification of peak oxygen uptake (VO 2 ) and cardiorespiratory and muscle responses to exercise. Its application to Duchenne muscular dystrophy (DMD) has been scarce due to the notion that muscle weakness inherent to disease restricts the cardiorespiratory system from reaching maximal capacity., Objective: To investigate the utility of CPET in DMD by 1) establishing whether patients can perform maximal-effort exercise for valid VO 2 peak assessment; 2) quantifying VO 2 peak repeatability; 3) characterizing muscle and cardiorespiratory responses; 4) comparing VO 2 peak to 6-min walk distance (6MWD)., Methods: Twenty-seven DMD and eight healthy boys (6 years and older) underwent CPET using an incremental work-rate protocol for leg (ambulatory) or arm (non-ambulatory) cycling with measurement of heart rate (HR) and gas-exchange variables from rest to maximal-effort. The oxygen cost of work (ΔVO 2 /Δwork-rate) was calculated, and peak exercise parameters (VO 2 , HR, O 2 pulse, ventilation (VE) and ventilatory threshold (VT)) were considered valid if the respiratory exchange ratio ≥1.01., Results: VO 2 peak was valid (81.5% of patients), repeatable (intraclass correlation coefficient = 0.998) and low in ambulatory and non-ambulatory DMD compared to controls (19.0 ± 6.0; 10.7 ± 2; 35.2 ± 4.5 mL/kg/min respectively). VT was low (30.8 ± 10.7; 19.4 ± 3.0; 61.2 ± 6.9% VO 2 peak) reflecting significant muscle metabolic impairment. Peak HR in ambulatory-DMD (172 ± 14 bpm) was similar to controls (183 ± 8.3 bpm), but O 2 pulse was low (3.4 ± 1.0; 6.5 ± 1.1 mL/beat). Peak VE/VO 2 (ambulatory = 42.1 ± 6.8; non-ambulatory = 42.2 ± 7.8; controls = 34.3 ± 4.6) and ΔVO 2 /Δwork-rate were elevated (ambulatory = 12.4 ± 4.9; non-ambulatory = 19.0 ± 9.7; controls = 10.1 ± 0.8) revealing ventilatory and mechanical inefficiency. Despite strong correlation between VO 2 peak and 6MWD, severity of impairment was discordant., Conclusion: Valid CPET is feasible in DMD, revealing low VO 2 peak due to abnormal muscle metabolic and cardiorespiratory responses during dynamic exercise. CPET reveals cardiorespiratory limitations in DMD boys with unremarkable 6MWD, and should be considered an integrative approach in clinical care and assessment of emerging therapeutics., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Dysferlin-deficient limb girdle muscular dystrophy (LGMD R2), also referred to as dysferlinopathy, can be associated with respiratory muscle weakness as the disease progresses. Clinical practice guidelines recommend biennial lung function assessments in patients with dysferlinopathy to screen for respiratory impairment. However, lack of universal access to spirometry equipment and trained specialists makes regular monitoring challenging. This study investigated the use of the Performance of Upper Limb (PUL) clinical scale entry item as a low-cost screening tool to identify patients with dysferlinopathy at risk of respiratory impairment. Using data from 193 patients from the Jain Foundation's International Clinical Outcomes Study, modelling identified a significant positive relationship between the PUL entry item and forced vital capacity (FVC). Eighty-eight percent of patients with the lowest PUL entry item score of 1 presented with FVC % predicted values of <60 %, suggestive of respiratory impairment. By contrast, only 10 % of the remainder of the cohort (PUL entry item of 2 or more) had an FVC of <60 %. This relationship also held true when accounting for ambulatory status, age, and sex as possible confounding factors. In summary, our results suggest that the PUL entry item could be implemented in clinical practice to screen for respiratory impairment where spirometry is not readily available., Competing Interests: Declaration of competing interest Apart from the grant from the Jain Foundation that financed the study, there are no relevant conflicts of interest that impact on the paper referenced above., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort., Methods: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire., Results: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type., Conclusions: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017., (© 2024. The Author(s).)

Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups., Competing Interests: Declaration of competing interest Authors’ declaration of financial interests/personal relationships statements are provided as supplementary material., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: At 12 months in the phase 2 TOPAZ study, treatment with apitegromab was associated with both an improved motor function in patients with Type 2 or 3 spinal muscular atrophy (SMA) and with a favorable safety profile. This manuscript reports the extended efficacy and safety in the nonambulatory group of the TOPAZ study at 36 months., Methods: Patients who completed the primary study (NCT03921528) could enroll in an open-label extension, during which patients received apitegromab 20 mg/kg by intravenous infusion every 4 weeks. Patients were assessed periodically via the Hammersmith Functional Motor Scale-Expanded (HFMSE), Revised Upper Limb Module (RULM), World Health Organization (WHO) motor development milestones, Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) Daily Activities and Mobility domains, and Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire., Results: Of the 58 patients enrolled in TOPAZ, 35 were nonambulatory (mean age 7.3 years). The mean change at 36 months in HFMSE score from baseline was +4.0 (standard deviation [SD]: 7.54), and + 2.4 (3.24) for RULM score (excluding n  = 7 after scoliosis surgery). Caregiver-reported outcomes (PEDI-CAT and PROMIS Fatigue) showed improvements from baseline over 36 months. In addition, most patients (28/32) improved or maintained WHO motor milestones achieved at baseline. The most frequently reported treatment-emergent adverse events were pyrexia (48.6%), nasopharyngitis (45.7%), COVID-19 infection (40.0%), vomiting (40.0%), and upper respiratory tract infection (31.4%)., Conclusion: The benefit of apitegromab treatment observed at 12 months was sustained at 36 months with no new safety findings., Competing Interests: TC is the lead principal investigator of the TOPAZ study; and a consultant and/or advisory board member for AveXis/Novartis, Biogen, Pfizer, and Roche/Genentech. JD has received consulting fees from Biogen, Cytokinetics, Ionis Pharmaceuticals, NGT, Pfizer, Roche, and Sarepta Therapeutics; license fees or royalty payments from Athena Diagnostics; and research funding from Biogen, Cytokinetics, NGT, Roche, Sanofi-Genzyme, and Sarepta Therapeutics. DV reports grants from Biogen during the conduct of the study, Department of Defense, Hope for Children Research Foundation, National Institutes of Health, and Spinal Muscular Atrophy Foundation; and personal fees from AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Inc., Roche, and Sarepta. JK was site principal investigator for clinical trials sponsored by Biohaven, Fibrogen, Novartis Gene Therapies, Inc., and Scholar Rock. EM is a primary investigator and advisory board/consultant for Biogen, Epirium, Novartis, Roche, and Scholar Rock; and has grants to the institution from Biogen, Novartis, and Roche. AN receives honoraria for counseling and invited talks from F. Hoffmann-La Roche, Ltd., Biogen, Novartis, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Inc., Scholar Rock, and UCB Pharma. AP is an advisory board member and consultant for Scholar Rock and has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies and Roche/Genentech. ESM has received consulting fees from Biogen, Novartis, Roche, and Scholar Rock. TD is an advisory board member for Biogen, CureSMA, Novartis, Roche, and Scholar Rock; and a consultant for Astellas, Avidity, Biohaven, Dyne, Genentech, Novartis, Roche, and Sarepta Therapeutics. GS, JM, DY, and LL are all full-time employees of Scholar Rock. SB was a full-time employee of Scholar Rock at the time of the study. BD has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies, Biogen, Pfizer, Roche/Genentech, Sarepta Therapeutics, and Vertex; steering committee chair for Roche FIREFISH and MANATEE studies and DSMB member for Amicus Inc. and Lexeo Therapeutics; he has no financial interests in these companies. He has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund; received grants from Ionis Pharmaceuticals, Inc. for the ENDEAR, CHERISH, and CS2/CS12 studies; from Biogen for CS11; and from AveXis, Fibrogen, Novartis (AveXis), PTC Therapeutics, Roche, Sarepta Pharmaceuticals, and Scholar Rock; and has received royalties for books and online publications from Elsevier and UpToDate, Inc. The authors declare that this study received funding from Scholar Rock, Inc. In collaboration with the academic authors, the funder was involved in the study design, data collection and analysis, interpretation of data, decision to publish, and the preparation of the manuscript. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Crawford, Day, De Vivo, Krueger, Mercuri, Nascimento, Pasternak, Mazzone, Duong, Song, Marantz, Baver, Yu, Liu and Darras.)

Background and Objective: Patients with spinal muscular atrophy (SMA) treated with a disease-modifying therapy (DMT) are often classified as responders or non-responders based on the attainment of a specific improvement threshold on validated functional scales. This categorization may significantly impact treatment reimbursement in some countries. The aim of this research is to evaluate the perception of treatments and their benefit by patients considered as responders or non-responders. Methods: In this non-commercial multicenter study, 99 post-symptomatically treated SMA type I-III patients with a median age of 11.2 (0.39-57.4) years at treatment initiation were stratified into three groups based on their treatment outcomes, i.e., those exhibiting clinically significant improvement (N = 41), those with non-clinically significant improvement (N = 18), or those showing no improvement (N = 40). Fifteen months after treatment, the initiation patients or patients' caregivers were assessed using a patient-rated scoring system based on the Patient Global Impression of Change (PGIC) scale, comprising 22 questions targeting important aspects and tasks in the daily life of patients with SMA. Results: We found no statistical difference in the patient perception of treatment benefits in 17 out of 22 domains across patient groups. Conclusions: Our results suggest that functional motor scales do not recapitulate patients' and patients' caregivers' experience of the effect of nusinersen treatment in SMA.

Background and Objectives: Currently approved therapies for spinal muscular atrophy (SMA) reverse the degenerative course, leading to better functional outcome, but they do not address the impairment arising from preexisting neurodegeneration. Apitegromab, an investigational, fully human monoclonal antibody, inhibits activation of myostatin (a negative regulator of skeletal muscle growth), thereby preserving muscle mass. The phase 2 TOPAZ trial assessed the safety and efficacy of apitegromab in individuals with later-onset type 2 and type 3 SMA., Methods: In this study, designed to investigate potential meaningful combinations of eligibility and treatment regimen for future studies, participants aged 2-21 years received IV apitegromab infusions every 4 weeks for 12 months in 1 of 3 cohorts. Cohort 1 stratified ambulatory participants aged 5-21 years into 2 arms (apitegromab 20 mg/kg alone or in combination with nusinersen); cohort 2 evaluated apitegromab 20 mg/kg combined with nusinersen in nonambulatory participants aged 5-21 years; and cohort 3 blindly evaluated 2 randomized apitegromab doses (2 and 20 mg/kg) combined with nusinersen in younger participants ≥2 years of age. The primary efficacy measure was mean change from baseline using the Hammersmith Functional Motor Scale version appropriate for each cohort. Data were analyzed using a paired t test with 2-sided 5% type 1 error for the mean change from baseline for predefined cohort-specific primary efficacy end points., Results: Fifty-eight participants (mean age 9.4 years) were enrolled at 16 trial sites in the United States and Europe. Participants had been treated with nusinersen for a mean of 25.9 months before enrollment in any of the 3 trial cohorts. At month 12, the mean change from baseline in Hammersmith scale score was -0.3 points (95% CI -2.1 to 1.4) in cohort 1 (n = 23), 0.6 points (-1.4 to 2.7) in cohort 2 (n = 15), and in cohort 3 (n = 20), the mean scores were 5.3 (-1.5 to 12.2) and 7.1 (1.8 to 12.5) for the 2-mg/kg (n = 8) and 20-mg/kg (n = 9) arms, respectively. The 5 most frequently reported treatment-emergent adverse events were headache (24.1%), pyrexia (22.4%), upper respiratory tract infection (22.4%), cough (22.4%), and nasopharyngitis (20.7%). No deaths or serious adverse reactions were reported., Discussion: Apitegromab led to improved motor function in participants with later-onset types 2 and 3 SMA. These results support a randomized, placebo-controlled phase 3 trial of apitegromab in participants with SMA., Trial Registration Information: This trial is registered with ClinicalTrials.gov (NCT03921528)., Classification of Evidence: This study provides Class III evidence that apitegromab improves motor function in later-onset types 2 and 3 spinal muscular atrophy.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS)., Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019)., Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient., Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex., Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Assessing endurance in non-ambulatory individuals with Spinal Muscular Atrophy (SMA) has been challenging due to limited evaluation tools. The Assisted 6-Minute Cycling Test (A6MCT) is an upper limb ergometer assessment used in other neurologic disorders to measure endurance. To study the performance of the A6MCT in the non-ambulatory SMA population, prospective data was collected on 38 individuals with SMA (13 sitters; 25 non-sitters), aged 5 to 74 years (mean = 30.3; SD = 14.1). The clinical measures used were A6MCT, Revised Upper Limb Module (RULM), Adapted Test of Neuromuscular Disorders (ATEND), and Egen Klassifikation Scale 2 (EK2). Perceived fatigue was assessed using the Fatigue Severity Scale (FSS), and effort was assessed using the Rate of Perceived Exertion (RPE). Data were analyzed for: (1) Feasibility, (2) Clinical discrimination, and (3) Associations between A6MCT with clinical characteristics and outcomes. Results showed the A6MCT was feasible for 95% of the tested subjects, discriminated between functional groups ( p = 0.0086), and was significantly associated with results obtained from RULM, ATEND, EK2, and Brooke ( p < 0.0001; p = 0.029; p < 0.001; p = 0.005). These findings indicate the A6MCT's potential to evaluate muscular endurance in non-ambulatory SMA individuals, complementing clinician-rated assessments. Nevertheless, further validation with a larger dataset is needed for broader application.

Background: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1., Methods: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 10 14 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 10 14 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated., Findings: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure)., Interpretation: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing., Funding: Astellas Gene Therapies., Competing Interests: Declaration of interests PBS has received funding and provision of study materials from Astellas Gene Therapies (formerly Audentes Therapeutics) to support clinical trial investigations relating to the present manuscript; has received research grants or contracts from Biogen, Novartis Gene Therapies, Pfizer, PTC Therapeutics, Reveragen, Sanofi, Sarepta, and Solid Biosciences; has received consulting fees for advisory board participation from Alexion, Argenx, Biogen, Genentech, Novartis Gene Therapies, UCB, Sanofi, and Sarepta; and has received honoraria for lectures or presentations from Alexion, Argenx, Biogen, Catalyst, CSL Behring, Genentech, and Grifols. NLK has received research funding from Astellas Gene Therapies to her institute as a study site for the ASPIRO clinical trial; has received support from Astellas Gene Therapies for registration fees to attend and present at the International Congress on Neuromuscular Diseases 2022 (travel costs paid personally); has received research grants from Argenx, Biohaven, Biogen, Novartis, Sarepta, and Scholar Rock, consulting fees for participation on medical advisory boards for Argenx, BioMarin, Capacity Bio, and Sarepta, and honoraria for gene therapy lectures for Sarepta; and is on a data safety monitoring board for Sarepta. JJD has received research grants or contracts from Astellas Gene Therapies to his institute as a study site for the ASPIRO clinical trial and for preclinical studies; and has received an honorarium for a sponsored symposium and support for travel to an international meeting to present data from Astellas Gene Therapies. WM-F has received support for study materials and study personnel relating to the present manuscript from Astellas Gene Therapies; consulting fees from Sarepta, PTC Therapeutics, Novartis, and Roche; personal compensation from Novartis and Biogen and institutional funding from Roche, for lectures; and has served on scientific advisory boards for Deutsche Gesellschaft für Muskelkranke and Glykogenosis. CGB has received research grants, contracts, or travel support for various invited lectures at academic meetings from Noelia Foundation, Muscular Dystrophy UK, and Cure CMD; holds a patent for COL6A1 intron 11 pseudoexon skipping technologies unrelated to the present manuscript; has participated (without fees) in advisory boards for Solid Biosciences (IGNITE trial), Rocket Pharma, and Nationwide Children's Hospital; and is Chair of the Scientific Advisory Board of the MDUK Oxford Neuromuscular Centre. LS has received consulting fees and honoraria for lectures from Astellas Gene Therapies; and is coordinating investigator of the European NatHis-CNM study, funded by Dynacure. BKS has received institutional research grants or contracts for her institution to serve as an INCEPTUS and ASPIRO study site from Astellas Gene Therapies. AB reports institutional grants or contracts from PTC Therapeutics; has received payments or honoraria from Roche, Biogen, and Pfizer; and has participated in advisory boards at Roche and Pfizer. ARF has been a member of an independent data monitoring committee for a different clinical trial for MTM1-related myopathy and DNM2-related myopathy (the trial was terminated early). LNA has received grants or contracts from Astellas Gene Therapies via her institution to provide training and quality control services supporting the ASPIRO clinical trial programme. AHB reports research grants or contracts from the NIH, MDA (USA), AFM Telethon, Alexion Pharmaceuticals, Astellas Gene Therapies, Dynacure SAS, Pfizer, Kate Therapeutics, Chan Zuckerberg Initiative, and Avidity; has received consulting fees from Astellas Gene Therapies, Kate Therapeutics, and Roche Pharmaceuticals; has received honoraria for lectures or presentations from GLG and Guidepoint Global; has received support for travel and meeting attendance at the Muscular Dystrophy Association and World Muscle Society; is an executive board member at the World Muscle Society; is an inventor on and has received royalties for a patent for adeno-associated virus gene therapy for X-linked myotubular myopathy; and holds stocks in Kate Therapeutics and Kinea Bio. AB-B has received consulting fees from Astellas Gene Therapies and research funding from the Myotubular Trust for preclinical work related to the present manuscript; and holds a patent on systemic gene replacement therapy for treatment of X-linked myotubular myopathy. MKC has received consulting fees and institutional research funding supporting preclinical experiments for a US investigational new drug application relating to the gene therapy in the present manuscript; holds a patent for a systemic gene replacement therapy for treatment of X-linked myotubular myopathy; and has received option payments from Wake Forest University for the patent. TD has received consulting fees from Astellas Gene Therapies for study training on CHOP INTEND measurement in ASPIRO. RJG reports limited consulting fees from Astellas Gene Therapies for work on the ASPIRO study design and clinical outcome measures. JC is an employee of Astellas Gene Therapies. VMacB has received study funding relating to the present manuscript, in the form of a research grant and consulting fees from Astellas Gene Therapies paid both directly to her and her institution. ESJ was a former employee of Astellas Gene Therapies and formerly held stock in Astellas Gene Therapies. JL, FMa, WM, and FV were formerly employees of Astellas Gene Therapies. MM has received study funding relating to the present publication from Astellas Gene Therapies, formerly held stock in Astellas Gene Therapies, and was formerly employed by Astellas Gene Therepies. CH is an employee of Astellas Pharma Global Development. MN was formerly employed by Astellas Gene Therepies. MWL has received research funding from Astellas Gene Therapies to his academic institution (Medical College of Wisconsin) and to his company (Diverge Translational Science Laboratory) for work related to the present manuscript; has received research grants or contracts to his academic institution from Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, Ultragenyx, and Prothelia; has received consulting fees from Astellas Gene Therapies, Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, Voyager, BioMarin, Locanabio, and Vertex Pharmaceuticals; has received speaker fees and reimbursement for travel related to sponsored research from Astellas Gene Therapies; has received personal fees for scientific advisory board participation for Astellas Gene Therapies and Solid Biosciences; and his institution has received payment from Taysha Therapeutics for his advisory board participation. MWL is currently Chief Executive Officer, founder, and owner of Diverge Translational Science Laboratory, which continues to work under contracts from many gene therapy companies including Astellas Gene Therapies, Solid Biosciences, Rocket Pharma, Kate Therapeutics, Carbon Biosciences, Dynacure, Nationwide Children's Hospital, Taysha Gene Therapies, and Ultragenyx. SP was an employee at Astellas Gene Therapies from February, 2014, to June, 2019, and was the senior physician overseeing the study relating to the present manuscript. SR reports holding stock in Astellas Gene Therapies and was formerly employed by Astellas Gene Therapies. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Disease-modifying treatments have transformed the natural history of spinal muscular atrophy (SMA), but the cellular pathways altered by SMN restoration remain undefined and biomarkers cannot yet precisely predict treatment response. We performed an exploratory cerebrospinal fluid (CSF) proteomic study in a diverse sample of SMA patients treated with nusinersen to elucidate therapeutic pathways and identify predictors of motor improvement. Proteomic analyses were performed on CSF samples collected before treatment (T0) and at 6 months (T6) using an Olink panel to quantify 1113 peptides. A supervised machine learning approach was used to identify proteins that discriminated patients who improved functionally from those who did not after 2 years of treatment. A total of 49 SMA patients were included (10 type 1, 18 type 2, and 21 type 3), ranging in age from 3 months to 65 years. Most proteins showed a decrease in CSF concentration at T6. The machine learning algorithm identified ARSB, ENTPD2, NEFL, and IFI30 as the proteins most predictive of improvement. The machine learning model was able to predict motor improvement at 2 years with 79.6% accuracy. The results highlight the potential application of CSF biomarkers to predict motor improvement following SMA treatment. Validation in larger datasets is needed.

The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement., Competing Interests: Declaration of Competing Interest Gianpaolo Cicala reports personal fees from BIOGEN S.R.L and ROCHE outside the submitted work; Giorgia Coratti reports personal fees from BIOGEN S.R.L., ROCHE, AVEXIS, NOVARTIS, GENESIS PHARMA and Biologix outside the submitted work; Marika Pane reports personal fees from BIOGEN S.R.L., ROCHE, AVEXIS and NOVARTIS outside the submitted work; Anna Capasso, Martina Ricci report personal fees from BIOGEN S.R.L., ROCHE and NOVARTIS outside the submitted work; Elena Mazzone, reports personal fees from BIOGEN S.R.L., ROCHE, NOVARTIS, DYNE outside the submitted work Nathalie Goemans has received personal fees outside the submitted work as member of data monitoring committee or advisory boards, from Biogen, Pfizer, Genethon,Roche, WAVE ther Eugenio Mercuri is part of advisory boards for BIOGEN S.R.L., ROCHE, AVEXIS and NOVARTIS, Scholar ROCK, EPIRIUM, CYTOKINETICS and NMD PHARMA. Eugenio Mercuri is funded by grant from the Italian Ministry of Health (RF-2019–12,370,334). All remaining authors have nothing to disclose. Funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication., (Copyright © 2023. Published by Elsevier B.V.)

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the M ajor A dverse D ystrophinopathy E vent (MADE ) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation., Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined., Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001., Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam., Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment., Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles., Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients., (© 2023. The Author(s).)

Background: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA., Methods: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete., Findings: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose., Interpretation: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed., Funding: Ionis Pharmaceuticals, Biogen., Competing Interests: Declaration of interests CFB, LM, DAN, and SX are employees of Ionis Pharmaceuticals, which funded the trial, and own stock options in Ionis Pharmaceuticals. CAT received support from Ionis Pharmaceuticals for consultation and sponsored research and carried out collaborative research with CFB under National Institutes of Health (NIH) grant U01NS072323; provides consulting to Biogen, Vertex, Entrada, and Avidity Biosciences; received honoraria from Sanofi; served on scientific advisory boards for Dyne and Pepgen; and serves on the Myotonic Dystrophy Foundation Board. KE received consulting fees from Ionis Pharmaceuticals, Avidity, and Dyne Therapeutics; and received honoraria from the Myotonic Dystrophy Foundation and the Muscular Dystrophy Association. CH receives royalties for the use of multiple disease specific instruments; provided consultation to Biogen, Ionis Pharmaceuticals, aTyr Pharma, AMO Pharma, Acceleron Pharma, Cytokinetics, Expansion Therapeutics, Harmony Biosciences, Regeneron Pharmaceuticals, Astellas Pharmaceuticals, AveXis, Recursion Pharmaceuticals, IRIS Medicine, Takeda Pharmaceutical Company, Scholar Rock, Avidity Biosciences, Novartis Pharmaceuticals Corporation, SwanBio Therapeutics, and the Marigold Foundation; and receives grant support from the Department of Defense, Duchenne UK, Parent Project Muscular Dystrophy, Recursion Pharmaceuticals, Swan Bio Therapeutics, Neurocrine Biosciences, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, Cure Spinal Muscular Atrophy, and the Amyotrophic Lateral Sclerosis Association. WDA received a consulting fee and grant funding from Avidity Biosciences and a consulting fee from Dyne Therapeutics. TA received a grant or contract from the Myotonic Dystrophy Foundation and was on the Myotonic Dystrophy Foundation scientific advisory board. JWD received consulting fees from Affinia Therapeutics and Shift Therapeutics; honoraria from Biogen and Roche Pharmaceuticals; participated in advisory boards for AMO Pharmaceuticals, Avidity Biosciences, Biogen, Cytokinetics, Epirium Bio, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Roche/Genentech Pharmaceuticals, Sarepta Therapeutics, Scholar Rock, Shift Therapeutics, and Vertex Pharmaceuticals; has leadership roles for Muscular Dystrophy Association, Myotonic Dystrophy Foundation, and Cure Congenital Muscular Dystrophy. GD is an employee of Biogen and owns stock options in Biogen. TD received consulting fees from Dyne, Roche/Genentech Pharmaceuticals, Biogen, Trinds, and ATOM; speaking honoraria for Genentech, Biogen, Roche, and Sarepta; has served on Advisory boards for Novartis, Pfizer, Actigraph, Scholar Rock, Sarepta, Sanofi Genzyme, and Cytokinetics; has unpaid leadership roles for myotonic dystrophy exercise recommendations and physical therapy guidance and the CureSMA Medical Advisory Council. NEJ received royalties or licenses from University of Rochester; received consulting fees from AMO Pharma Fulcrum Therapeutics, Avidity Biosciences, Dyne, Vertex, Arthex, and Entrada; participated in a Data Safety Monitoring Board for Biogen; and owns stock or stock options in ML Bio Solutions. DJL received funding from the DuchenneXchange Advisory Council, Cure Duchenne. JMS received consulting fees from Dyne Therapeutics, Roche, Avidity, ML Bio, Fulcrum Therapeutics, MT Pharma, Sarepta, and Amylyx; payment or honorarium from MDA; and stock or stock options from Dyne Therapeutics. SHS received consulting fees from Reata Pharmaceuticals, Avidity Biosciences, and Dyne therapeutics. KMB was an employee of Ionis Pharmaceuticals at the time the trial was conducted; is a current employee of and owns stock options in Acadia Pharmaceuticals; is an advisor to non-profit organisations Myotonic Dystrophy Foundation and SMA Foundation; and is a Board Member of DTx Pharma. CFB is a Board member of Flamingo Therapeutics and Hereditary Disease Foundation. RM is the chair of three clinical trials in Duchenne muscular dystrophy funded by TRiNDS. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

Background: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response., Objective: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects., Methods: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus., Results: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability., Conclusions: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

Background: Novel Spinal Muscular Atrophy (SMA) treatments have demonstrated improvements on motor measures that are clearly distinct from the natural history of progressive decline. Comparable measures are needed to monitor bulbar function, which is affected in severe SMA., Objective: To assess bulbar function with patient-reported outcome measures (PROs) and determine their relationships with clinical characteristics., Methods: We recruited 47 non-ambulatory participants (mean (SD) age = 29.8 (13.7) years, range = 10.3-73.2) with SMA. PROs including Voice Handicap Index (VHI) and Eating Assessment Tool-10 (EAT-10) were collected alongside clinical characteristics and standardized motor assessments. Associations were assessed using Spearman correlation coefficients and group comparisons were performed using Wilcoxon rank sum tests., Results: A majority of the 47 participants were SMA type 2 (70.2%), non-sitters (78.7%), 3 copies of SMN2 (77.5%), and using respiratory support (66.0%). A majority (94%) reported voice issues primarily in 8/30 VHI questions. Problems included: difficulty understanding me in a noisy room (87.2%); difficult for people to hear me (74.5%); and people ask me to repeat when speaking face-to-face (72.3%). A majority (85.1%) reported swallowing issues primarily in 3/10 EAT-10 questions: swallowing pills (68.1%); food sticks to my throat (66.0%); and swallowing solids (61.7%). The two PROs were moderately associated (rs = 0.66)., Conclusions: Weaker individuals with SMA experience bulbar problems including difficulties with voice and swallowing. Further refinement and assessment of functional bulbar scales will help determine their relevance and responsiveness to changes in SMA. Additional study is needed to quantify bulbar changes caused by SMA and their response to disease-modifying treatments.

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations., (© 2022. The Author(s).)

Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs., Competing Interests: Declaration of interests TM is an Onassis Foundation Scholar (Scholarship ID: F ZQ 040-1/2020-2021). MO serves as a methodologist for the American Academy of Neurology and a volunteer member of the Medical and Scientific Advisory Board for Muscular Dystrophy Canada; and is a clinical research scholar supported by the Fonds de recherche du Québec Santé. MAF received grant support from the National Health and Medical Research Council of Australia (APP1194940). NG has participated on data safety monitoring or advisory boards of Pfizer, Wave Life Sciences, Sarepta Therapeutics, Pliant Therapeutics, and Santhera Pharmaceuticals. LS has participated on data safety monitoring or advisory boards of FibroGen, Santhera Pharmaceuticals, RegenexBio, and Catabasis Pharmaceuticals, and is supported by a grant from Muscular Dystrophy UK. TD has received payment for lectures from Sarepta Therapeutics. NG has received payment for lectures from Sarepta Therapeutics and Santhera Pharmaceuticals. TD has received consulting fees from Pfizer, Edgewise Therapeutics, Dyne Therapeutics, Solid Biosciences, and ATOM International. MAF has received consulting fees from Pfizer. LS has received consulting fees from Sarepta, Pfizer, and F Hoffmann La Roche. TD is a member of TreatNMD Advisory Committee for Therapeutics (TACT), Treat-NMD Duchenne muscular dystrophy database committee, CureDuchenne, and Parent Project Muscular Dystrophy. LS is executive secretary of the World Muscle Society., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches., Competing Interests: Declarations of Competing Interest Giorgia Coratti reports personal fees from BIOGEN S.R.L. ITALIA, ROCHE, GENESIS PHARMA, AVEXIS, Biologix, outside the submitted work; Roberto de Sanctis reports personal fees from BIOGEN S.R.L. ITALIA and AVEXIS outside the submitted work; Maria C Pera reports personal fees from ROCHE outside the submitted work; Jacqueline Montes reports personal fees from BIOGEN S.R.L. and ROCHE, outside the submitted work Amy Pasternak reports grants from SMA FOUNDATION, during the conduct of the study; Elena Stacy Mazzone reports personal fees from BIOGEN S.R.L., ROCHE, AVEXIS, SCHOLAR ROCK, outside the submitted work; Allan M Glanzman received travel/lodging and compensation from Biogen to serve on an advisory board, received licensing fees from Children's Hospital of Philadelphia for the CHOP-INTEND motor scale, institutional support from AveXis, Biogen and Roche for trial training and/or outcome measure review, and personal compensation from ATOM International (Mallinckrodt Pharmaceuticals, Catabasis Pharmaceuticals, ReveraGen Biopharma) for trial training; Aspa Theraputics for outcomes consulting; and Audentes Therapeutics for outcome review. Sally Dunaway Young reports grants from Stanford Univesity and Columbia University, during the conduct of the study; personal fees from Biogen, Roche/Genentech, Scholar Rock, Cure SMA, grants from SMA Foundation, outside the submitted work; Marika Pane reports personal fees from BIOGEN S.R.L., PTC, AVEXIS, SAREPTA, outside the submitted work; Mariacristina Scoto was CO-PI for SMA REACH UK, during the conduct of the study; received personal fees from ROCHE as PI (jewelfish) and member of advisory board, outside the submitted work; Sonia Messina reports personal fees from BIOGEN S.R.L., AVEXIS, PTC THERAPEUTICS, SANTHERA, outside the submitted work; Adele D'Amico reports personal fees from BIOGEN S.R.L., SAREPTA, NOVARTIS, outside the submitted work; Emilio Albamonte reports personal fees from BIOGEN S.R.L. outside the submitted work; Basil T Darras reports personal fees from Biogen, Avexis, Roche, Pfizer, Sarepta, PTC, outside the submitted work; Enrico Bertini reports personal fees from BIOGEN S.R.L., AVEXIS, ROCHE, outside the submitted work; Valeria A Sansone reports personal fees from BIOGEN S.R.L, AVEXIS, SANTHERA, SAREPTA, PTC, outside the submitted work; John Day reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work Claudio Bruno reports personal fees from Biogen, from Avexis, from Roche, outside the submitted work; Francesco Muntoni reports grants from Biogen, personal fees from Biogen, grants from Avexis, personal fees from Avexis, personal fees from Roche, during the conduct of the study; personal fees from Pfizer, grants from Sarepta, personal fees from Sarepta, personal fees from PTC, outside the submitted work; Darryl C. De Vivo reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Cytokinetics Pharmaceuticals, outside the submitted work; Richard Finkel reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., Novartis, outside the submitted work; Eugenio Mercuri reports personal fees from AVEXIS, ROCHE, BIOGEN S.R.L., PTC THERAPEUTICS, SAREPTA, SANTHERA, outside the submitted work; Evelin Milev, Laura Antonaci, Annalia Frongia, Matthew Civitello, Maria Sframeli, Massimo Russo, Tina Duong, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study., Competing Interests: Declaration of Competing Interest GC, RDS, JM, AMG, SDY, MP, SM, ADA, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees BIOGEN S.R.L. outside the submitted work; GC, MCP, RDS, JM, AMG, SDY, MS, BTD, EB, JD, FM, DCDV, RF, CB, EM reports personal fees ROCHE outside the submitted work; GC reports personal fees GENESIS PHARMA and Biologix outside the submitted work; GC, RDS, AMG, MP, SM, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees AVEXIS outside the submitted work; AP, SDY, reports personal fees SMA FOUNDATION outside the submitted work; SDY reports personal fees SCHOLAR ROCK outside the submitted work; ADA, JD, RF reports personal fees NOVARTIS outside the submitted work; SL, SC, LA, AF, FS, PT, MC, TD, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA., Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models., Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events., Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA., Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H 2 O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (C max  > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H 2 O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations., (© 2021. The Author(s).)

Background: The 32-item Motor Function Measure (MFM32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases, including those with spinal muscular atrophy (SMA). This two-part study explored the relationship between the functional abilities assessed in the MFM32 and activities of daily living (ADLs) from the perspective of individuals with Type 2 and Type 3 (non-ambulant and ambulant) SMA and their caregivers through qualitative interviews and a quantitative online survey., Methods: In-depth, semi-structured, qualitative interviews were conducted with individuals with SMA and caregivers from the US. Subsequently, a quantitative online survey was completed by individuals with SMA or their caregivers from France, Germany, Italy, Poland, Spain, Canada, the United States (US) and the UK. In both parts of the study, participants were asked to describe the ADLs considered to be related to the functional abilities assessed in the MFM32. Results from the qualitative interviews informed the content of the quantitative online survey., Results: Qualitative interviews were conducted with 15 adult participants, and 217 participants completed the quantitative online survey. From the qualitative interviews, all of the functional abilities assessed in the patient-friendly MFM32 were deemed as related to one or more ADL. The specific ADLs that participants considered related to the patient-friendly MFM32 items could be grouped into 10 key ADL domains: dressing, mobility/transferring, self-care, self-feeding, reaching, picking up and holding objects, physical activity, writing and technology use, social contact/engagement, toileting and performing work/school activities. These results were confirmed by the quantitative online survey whereby the ADLs reported to be related to each patient-friendly MFM32 item were consistent and could be grouped into the same 10 ADL domains., Conclusion: This study provides in-depth evidence from the patient/caregiver perspective supporting the relevance of the patient-friendly MFM32 items to the ADLs of individuals with Type 2 and Type 3 SMA.

Background: Duchenne muscular dystrophy (DMD) is a rare x-linked recessive genetic disorder affecting 1 in every 5000-10000 [1, 2]. This disease leads to a variable but progressive sequential pattern of muscle weakness that eventually causes loss of important functional milestones such as the ability to walk. With promising drugs in development to ameliorate the effects of muscle weakness, these treatments must be associated with a clinically meaningful functional change., Objective: The objective of this analysis is to determine both distribution, minimal detectable change (MDC), and anchor-based, minimal clinically important difference, (MCID) of 12 month change values in standardized time function tests (TFT) used to monitor disease progression in DMD., Method: This is a retrospective analysis of prospectively collected data from a multi-center prospective natural history study with the Cooperative International Neuromuscular Research Group (CINRG). This study calculated MDC and MCID values for 3 commonly used timed function tests typically used to monitor disease progression; supine to stand (STS), 10 meter walk/run (10MWT), and 4 stair climb (4SC). MDC used standard error of measurement (SEM) while MCID measurements used the Vignos scale as an anchor to determine clinical change in functional status., Results: All 3 TFT were significantly important clinical endpoints to detect MDC and MCID changes. MDC and MCID 12 month changes were significant in 10MWT (-0.138, -0.212), Supine to Stand (-0.026, -0.023) and 4 stair climb (-0.034, -0.035) with an effect size greater or close to 0.2., Conclusion: The 3 TFT are clinically meaningful endpoints used to establish change in DMD. MCID values were higher than MDC values indicating that an anchor-based approach using Vignos as a clinically meaningful loss of lower extremity abilities is appropriate to assess change in boys with DMD.

The advent of clinical trials in spinal muscular atrophy (SMA) has highlighted the need to define patterns of progression using functional scales. It has recently been suggested that the analysis of abilities gained or lost applied to functional scales better reflects meaningful changes. We defined as "gain" a positive change between scores from 0 to either 1 or 2 and as "loss" a negative change from either 2 or 1 to 0. The aim of this study was to describe, over 12 months, which abilities on the Hammersmith Functional Motor Scale Expanded (HFMSE) were more frequently lost or gained in patients with SMA II. The cohort included 614 12-month assessments from 243 patients (age range: 30 months - 63 years; mean 9.94, SD ±7.91). The peak of abilities gained occurred before the age of 5 years while the highest number of lost abilities was found in the group 5-13 years. A correlation between the HFMSE baseline score and the ordinal number of the items was found for both lost (p<0.001) or gained (p<0.001) activities. No correlation was found with SMN2 copy number. These findings will have implications for clinical trial design and for the interpretation of real-world data using new therapeutic approaches., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Limb contractures are debilitating complications associated with various muscle and nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19-20, 2018, involving researchers and physicians from diverse disciplines who convened to discuss current clinical and preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, cerebral palsy, and other conditions. Presenters described changes in muscle architecture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development., (© 2020 Wiley Periodicals, Inc.)

Objective: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs)., Methods: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts., Results: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year ( p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% ( p < 0.05) and 2.55% ( p < 0.01). Range-of-motion measurements decreased by 3.21° ( p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° ( p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% ( p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed., Conclusion: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs., (© 2019 American Academy of Neurology.)

Purpose of Review: Myotonic dystrophy type 1 is a multisystemic disorder caused by a noncoding triplet repeat. The age of onset is variable across the lifespan, but in its most severe form, the symptoms appear at birth (congenital myotonic dystrophy) or in the pediatric age range (childhood-onset myotonic dystrophy). These children have a range of disabilities that reduce the lifespan and cause significant morbidity. Currently, there are no agreed upon recommendations for caring for these children., Recent Findings: The Myotonic Dystrophy Foundation recruited 11 international clinicians who are experienced with congenital and childhood-onset myotonic dystrophy to create consensus-based care recommendations. The experts used a 2-step methodology using elements of the single text procedure and nominal group technique. Completion of this process has led to the development of clinical care recommendations for this population., Summary: Children with myotonic dystrophy often require monitoring and interventions to improve the lifespan and quality of life. The resulting recommendations are intended to standardize and improve the care of children with myotonic dystrophy., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Goniometers are commonly used by physical therapists to measure range-of-motion (ROM) in the musculoskeletal system. These measurements are used to assist in diagnosis and to help monitor treatment efficacy. With newly emerging technologies, smartphone-based applications are being explored for measuring joint angles and movement., Objective: This pilot study investigates the intra- and inter-rater reliability as well as concurrent validity of a newly-developed smartphone magnetometer-based goniometer (MG) application for measuring passive shoulder abduction in both sitting and supine positions, and compare against the traditional universal goniometer (UG)., Design: This is a comparative study with repeated measurement design., Methods: Three physical therapists utilized both the smartphone MG and a traditional UG to measure various angles of passive shoulder abduction in a healthy subject, whose shoulder was positioned in eight different positions with pre-determined degree of abduction while seated or supine. Each therapist was blinded to the measured angles. Concordance correlation coefficients (CCCs), Bland-Altman plotting methods, and Analysis of Variance (ANOVA) were used for statistical analyses., Results: Both traditional UG and smartphone MG were reliable in repeated measures of standardized joint angle positions (average CCC > 0.997) with similar variability in both measurement tools (standard deviation (SD) ± 4°). Agreement between the UG and MG measurements was greater than 0.99 in all positions., Conclusion: Our results show that the smartphone MG has equivalent reliability compared to the traditional UG when measuring passive shoulder abduction ROM. With concordant measures and comparable reliability to the UG, the newly developed MG application shows potential as a useful tool to assess joint angles., (Published by Elsevier Ltd.)

Objective: We aimed to perform an observational study of age at loss of independent ambulation (LoA) and side-effect profiles associated with different glucocorticoid corticosteroid (GC) regimens in Duchenne muscular dystrophy (DMD)., Methods: We studied 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). LoA was defined as continuous wheelchair use. Effects of prednisone or prednisolone (PRED)/deflazacort (DFZ), administration frequency, and dose were analyzed by time-varying Cox regression. Side-effect frequencies were compared using χ(2) test., Results: Participants treated ≥1 year while ambulatory (n = 252/340) showed a 3-year median delay in LoA (p < 0.001). Fourteen different regimens were observed. Nondaily treatment was common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED (hazard ratio 0.294 ± 0.053 vs 0.490 ± 0.08, p = 0.003; 2-year difference in median LoA with daily administration, p < 0.001). Average dose was lower for daily PRED (0.56 mg/kg/d, 75% of recommended) than daily DFZ (0.75 mg/kg/d, 83% of recommended, p < 0.001). DFZ showed higher frequencies of growth delay (p < 0.001), cushingoid appearance (p = 0.002), and cataracts (p < 0.001), but not weight gain., Conclusions: Use of DFZ was associated with later LoA and increased frequency of side effects. Differences in standards of care and dosing complicate interpretation of this finding, but stratification by PRED/DFZ might be considered in clinical trials. This study emphasizes the necessity of a randomized, blinded trial of GC regimens in DMD., Classification of Evidence: This study provides Class IV evidence that GCs are effective in delaying LoA in patients with DMD., (© 2015 American Academy of Neurology.)

Objective: We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort., Methods: We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression) and for population stratification (multidimensional scaling of genome-wide markers)., Results: Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year-earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC-treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC., Interpretation: SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD., (© 2015 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes., (Published by Elsevier B.V.)