Background and Objectives:Limb-girdle muscular dystrophy type 2I (LGMD2I/R9) is caused by biallelic variants in the gene for Fukutin-related protein (FKRP), an enzyme required for proper glycosylation of α-dystroglycan (⍺DG), a critical structural protein of the dystrophin glycoprotein complex. Hypoglycosylation of αDG results in impaired function of αDG, which in turn leads to chronic myocyte injury and muscular dystrophy. The "Biomarker Development in LGMD2I/R9" (MLB-01-001) natural history study explored glycosylated ⍺DG as a muscle biomarker for LGMD2I/R9 to support clinical trial design for the development of potential therapeutics. Methods:MLB-01-001 was a prospective, 12-month observational study of clinically affected participants 10-65 years of age with genetically confirmed LGMD2I/R9 at 11 academic centers in the United States and Denmark. Tibialis anterior (TA) muscle biopsies were obtained at baseline, month 6, month 9, and/or month 12 and measured for glycosylated ⍺DG levels relative to that of an unaffected human control using a validated, quantitative western blot assay. Results:Of 96 participants enrolled, 71 participants underwent at least 1 TA biopsy (54 homozygous for the c.826C>A variant and 17 with other FKRP genotypes). Participants who were homozygous for the c.826C>A variant tended to be older, to be composed of a higher percentage of females, to have had less time since diagnosis, and to be composed of a greater percentage of ambulatory participants than those who had other FKRP genotypes. Glycosylated ⍺DG levels were consistently lower in LGMD2I/R9 participants than in the control at baseline (median 8.5% of control, interquartile range [IQR] 10.8%) and reflected disease severity by genotype, with c.826C>A homozygotes showing higher median glycosylated ⍺DG levels (10.5% of control, IQR 10.9%, n = 54) than participants with other FKRP genotypes (4.6% of control, IQR 4.3%, n = 17). Glycosylated αDG levels remained stable over 6-12 months. Discussion:Glycosylated ⍺DG was consistently lower in participants with LGMD2I/R9 than in the unaffected control, reflected disease severity by genotype, and remained stable over 6-12 months, suggesting that it may be an appropriate biomarker for assessing the effect of potential therapies for LGMD2I/R9. Trial Registration Information:ClinicalTrials.gov ID NCT04202627, first posted 17 Dec 2019.

Reports of clinical characteristics of FSHD in childhood have often focused on the most severely affected. To include children in clinical trials, it is important to understand the full pediatric spectrum. The Muscular Dystrophy Surveillance, Tracking, and Research Network provides a population-based, cross-sectional cohort of children diagnosed with FSHD. Children diagnosed before 19 years of age during 2008-2019 were included (n=93). Clinical characteristics abstracted from the medical record included motor symptoms, genetic test results, and family history. Of those with known FSHD type (n=73 of 93, 78.8%), 72 (98.6%) had FSHD1. Among those with FSHD1, the most frequent D4Z4 repeat category was 1-3 repeats (n=33, 45.8%) and few had 7-10 repeats (n=7, 9.7%). Among those with FSHD1 and known symptom onset age (n=70), 22 (31.4%) had early onset disease. Overall, most (88.2%) were ambulatory at last visit. The number of children diagnosed increased steadily across childhood, suggesting a continuous spectrum of age at onset. The most common co-morbidity was hearing loss (n=19 of 93, 20.4%); most commonly among children with FSHD1 and 1-3 D4Z4 repeats (n=13 of 33, 39.4%). Our series provides data to support the design of pediatric FSHD trials, critical to ensure timely access to future effective treatments.

Introduction Omaveloxolone est approuvé dans le traitement de l’AF chez des patients ≥16 ans. Après complétion de l’étude MOXIe (NCT02255435), les patients éligibles poursuivaient dans l’extension en ouvert MOXIe OLE. Objectifs Évaluer l’efficacité, la sécurité et la tolérance à long terme d’omaveloxolone (omav) chez des patients atteints d’ataxie de Friedreich traités ∼4 ans dans MOXIe OLE. Méthodes L’analyse de MOXIe OLE, au 27 février 2025, rapporte les données sur ∼4 ans, du jour 1 de l’extension (baseline (BL)) à la semaine 216. Nous rapportons la variation moyenne des scores mFARS et FA Activities of Daily Living (FA-ADL) dans les groupes placebo-omav ; omav-omav, et la population globale. La sécurité et la tolérance ont été évaluées de manière continue. Résultats Au total, 149 patients étaient inclus dans cette analyse (43 omav-omav, 106 placebo-omav). Les patients traités par omav ont présenté une variation moyenne (ET) par rapport à BL de 4,40 (6,26) (+1,1 point/an) pour les scores mFARS et de 2,79 (3,04) (+0,7 point/an) pour les scores FA-ADL sur une période de 4 ans, avec des résultats comparables dans les groupes omav-omav et placebo-omav. Les résultats en matière de sécurité concordaient avec les rapports précédents. Discussion Les résultats de MOXIe OLE, plus longue étude menée sur un traitement modificateur de la maladie en AF, montrent une progression lente de la maladie sur ∼4 ans de traitement omav (+1,1 vs ∼2,0 points mFARS/an dans les études d’histoire naturelle). Aucune progression significative de la maladie n’était observée au niveau de la fonction bulbaire et coordination des membres supérieurs. Conclusion Les résultats de MOXIe OLE ont montré une progression lente de la maladie avec ∼4 ans de traitement par omaveloxolone, soulignant son potentiel pour modifier l’évolution de l’AF.

Identifying clinical outcome assessments (COAs) that are able to detect change in functional abilities over time in the limb girdle muscular dystrophy (LGMD) population is critical for managing disease progression in addition to determining drug efficacy in the context of anticipated therapeutic trials. Through the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Consortium, 42 participants with LGMDR1 were enrolled in a 12-month natural history study across 11 international sites. Each participant completed a battery of COAs, including the North Star Assessment for Limb Girdle-Type Muscular Dystrophies (NSAD), 100-meter timed test (100 m), Performance of the Upper Limb (PUL), and 4-Stair Climb (4SC) in addition to several patient-reported outcome measures (PROM) across three time points in this year-long study. Participants with LGMDR1 demonstrate significant decline in the 100 m, NSAD, PUL, and 4SC over a 12-month time period. The rate of decline was greater in those considered to be higher functioning (10-meter time <12 s) while genetic variant types did not appear to significantly influence the rate of decline in our cohort. A combination of COAs is determined to be the best approach at measuring functional change over time in patients with LGMDR1.

BACKGROUND:Duchenne muscular dystrophy (DMD) is an X-linked genetic disease of skeletal and cardiac muscle that leads to loss of ambulation and premature death due to progressive myopathy and cardiomyopathy. Deramiocel, a heart-derived cellular therapy consisting of human allogeneic cardiosphere-derived cells, improved cardiac and skeletal muscle function in phase 1-2 studies of DMD. Our aim was to assess the efficacy and safety of deramiocel in advanced DMD and support the findings of HOPE-2. METHODS:HOPE-3, a phase 3, multicentre, randomised (1:1), double-blind, placebo-controlled study, included participants aged 10 years or older with DMD. Investigational product was infused intravenously every 3 months in outpatient settings. Skeletal and cardiac function was evaluated at 12 months. The primary endpoint was total Performance of the Upper Limb 2.0 (PUL2.0) percentage change from baseline. The trial is registered with ClinicalTrials.gov (NCT05126758). FINDINGS:Between June 22, 2022, and May 28, 2024, 139 participants were screened, of whom 106 were randomly assigned to deramiocel (n=54) or placebo (n=52), and included in the intention-to-treat population. The primary endpoint showed significant improvements in the deramiocel group versus placebo. For total PUL2.0, least-squares mean percentage change at 12 months favoured deramiocel by 4·55% (95% CI 0·47-8·63; p=0·029). The safety profile of deramiocel was similar to that of placebo. INTERPRETATION:Deramiocel safely slows disease progression in advanced DMD, preserving skeletal muscle function. Administered quarterly in a simple outpatient regimen, deramiocel is a promising treatment for DMD, agnostic to the precise underlying genetic lesion. FUNDING:Capricor Therapeutics.

BACKGROUND:Limb girdle muscular dystrophy type R9 (LGMDR9) results from biallelic variants in FKRP. There is limited data to predict loss of ambulation (LOA) among those with LGMDR9. METHODS:Participants in an ongoing dystroglycanopathy natural history study (NCT00313677) with FKRP variants who had achieved ambulation and were more than 3 years old were included (n = 97). LOA was defined as self-reported full-time wheelchair use, weakness preventing completion of the 10-m walk-run test (10MWT) or 10MWT time > 30 s. Interval-censored time-to-event analysis was used to determine median age at LOA. Receiver operating characteristic curves were used to examine the ability of 10MWT and 4-stair climb (4SC) times to predict LOA. RESULTS:Of 97 participants, 55 (57%) were homozygous for the c.826C>A founder variant. Thirty-one participants lost ambulation; 15 (49%) were homozygous for c.826C>A. Earliest age at LOA was 9 years (non-homozygous for c.826C>A). Median age at LOA for the cohort was 46.0 years. Performances on 10MWT and 4SC were highly predictive of LOA within 3 years, with areas under the ROC curve of 0.89 (10MWT) and 0.87 (4SC) when genotype was included in analysis. Optimal cutoffs for predicting LOA within 3 years differed by genotype and had acceptable sensitivity and specificity. DISCUSSION:LOA among those with LGMDR9 is strongly predicted by performance on 10MWT and 4SC. These results demonstrate the real-world significance of standardized motor function tests used in LGMDR9 clinical trials and aid in anticipatory guidance.

Limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that generally result in weakness and loss of limb-girdle muscles, leading to severe disability and early mortality due to cardiac and respiratory complications. Heterogeneity across and within individual LGMD subtypes in addition to variability in progression rates presents significant challenges to traditional drug development approaches for these diseases. In an effort to discuss these challenges, as well as opportunities in support of advancing drug development for LGMD, on February 8, 2024, The Speak Foundation assembled a multistakeholder group consisting of academic medical experts, patients and caregivers, patient advocacy organizations, senior leaders from the US Food and Drug Administration, and commercial drug developers. This review will provide an overview of the broad range of topics discussed at the workshop, including LGMD pathophysiology, natural history studies, clinical outcomes, patient-focused drug development, surrogate end points, the Accelerated Approval pathway, and future directions for LGMD drug development.

UDP-glucose dehydrogenase (UGDH) variants have been associated with hypotonia, developmental delay, and epilepsy. We report the first pathologic evidence of dystroglycanopathy in siblings with UGDH variants. Both presented around 6 months with developmental delay and elevated creatinine kinase. Sibling A developed epilepsy at age 9 years. Muscle biopsy from sibling A showed necrotizing myopathy with reduced matriglycan immunostaining. Western blot revealed α-dystroglycan with abnormally low molecular weight. The siblings shared pathogenic UGDH variants in trans: c.305G>A p.(R102Q) is predicted to disrupt protein structure and function; c.265-6C>G is deleterious to splicing. We propose that UGDH is an additional dystroglycanopathy gene.

ABSTRACTIntroduction/AimsProphylactic treatment of left ventricular dysfunction (LVD) in Duchenne muscular dystrophy (DMD) delays onset of LVD, but there is limited data showing impact on survival. Our aim was to describe survival among treated and untreated individuals with DMD.MethodsRetrospective, population‐based surveillance data from the Muscular Dystrophy Surveillance, Tracking and Research Network (MD STARnet) were used. We analyzed 327 males with DMD born between 1982 and 2009 who were at least 6 years old at the last visit and who initiated cardiac prophylactic medication before age 14 years. Death status was ascertained through vital record linkages and medical record review. Prophylaxis was defined as cardiac medication use at least 1 year before LVD onset (ejection fraction < 55% or shortening fraction < 28%). Age at first visit, corticosteroid use, scoliosis surgery, initiation of noninvasive ventilation, and loss of ambulation were also coded. Cox Proportional Hazard modeling with time‐varying covariates describes associations.ResultsProphylactic cardiac treatment was documented for 27.7% (n = 90); corticosteroids were used by 60.9% (n = 157). Adjusting for age at first visit and MD STARnet site, prophylactic treatment was associated with a 54% lower hazard of death (HR = 0.46, 95% CI = 0.22–0.93) compared to no prophylaxis. Adjusting for selected clinical covariates did not appreciably change the estimate (HR = 0.46, 95% CI = 0.22–0.99).DiscussionInitiation of cardiac medication when left ventricular function is normal was associated with prolonged survival in this study of males with DMD. Only one‐quarter of individuals received this treatment, however, indicating a topic of focus for improving care.

INTRODUCTION/AIMS:Pain is a recognized symptom of muscular dystrophy (MD), but little is known about prescription pain medications in this population. We describe pain experiences and pain medications prescribed for individuals with selected MDs using population-based surveillance data collected by the Muscular Dystrophy Surveillance, Tracking, and Research Network. METHODS:Pain and prescription data were abstracted from medical records for 1282 individuals with Duchenne and Becker (DBMD) MD during 2000-2015 and congenital (CMD), distal (DD), Emery-Dreifuss (EDMD), facioscapulohumeral (FSHD), limb-girdle (LGMD), and myotonic (DM) MDs during 2008-2016. Percentages of individuals prescribed pain medications for ≥ 6 weeks during follow-up were estimated. Logistic regression was used to examine associations with selected demographic and clinical characteristics. RESULTS:Moderate pain was observed among 34% of all people with available pain scores and varied by MD type (13%-53%). Pain medications were prescribed for 31.1%-40.2% of people 20 years and older, but less frequently (< 15%) among people less than 20 years old. Among people prescribed pain medications, the first medication was typically a non-opioid (57%), but both non-opioid and opioid medication classes were prescribed during follow-up (34%). Pain medications were typically prescribed for longer than 1 year (> 85%). Impaired mobility had the strongest association with prescription pain medication. DISCUSSION:The prescription of pain medication is common for people with symptomatic MD. Most people were prescribed only non-opioids. These data highlight pain management as a frequent component of MD care. Understanding modifiable factors associated with MD-related pain and effective interventions may help improve care.

OBJECTIVE:Identifying functional measures that are both valid and reliable in the limb girdle muscular dystrophy (LGMD) population is critical for quantifying the level of functional impairment related to disease progression in order to establish clinical trial readiness in the context of anticipated therapeutic trials. METHODS:Through the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Consortium, 42 subjects with LGMDR1 were enrolled in a 12-month natural history study across 11 international sites. Each subject completed a battery of clinical outcome assessments (COA), including the North Star Assessment for Limb Girdle-Type Dystrophies (NSAD), 10-m walk/run, and Performance of the Upper Limb (PUL), in addition to several patient-reported outcome measures (PROM). RESULTS:In this baseline cross-sectional analysis, significant correlations were found between COAs and PROMs, with significant differences in the performance of assessments based on subjects' ambulatory status and genetic variant classification. INTERPRETATION:The study has determined that the NSAD and other assessments are valid and reliable measures for quantifying the level of disease impairment in individuals with LGMDR1.

INTRODUCTION/AIMS:Few studies describing comorbidities in individuals with facioscapulohumeral muscular dystrophy (FSHD) are available. We used data from the Muscular Dystrophy Surveillance, Tracking and Research Network (MD STARnet) to identify and describe the prevalence of three comorbidities-hearing loss, retinal abnormalities, and seizures-in individuals with FSHD. METHODS:We analyzed retrospective population-based data from 548 individuals diagnosed with FSHD who had at least one health visit during 2008-2019. The primary variables of interest were the presence of one or more of the three comorbidities and the age at diagnosis of the comorbidity. We calculated percentages of each comorbidity by population characteristics. RESULTS:Among the study cohort, 17.2% (n = 94) had at least one comorbidity, with 1.5% (n = 8) having multiple comorbidities. Hearing loss (13%; n = 71) was the most frequently reported comorbidity, followed by retinal abnormalities (3.6%; n = 20) and seizures (2.0%; n = 11). Median age at diagnosis for hearing loss, retinal abnormalities, and seizures was 46.5 [interquartile range (IQR):11.8-65.3 years], 58.7 (IQR: 41.5-66.5 years), and 16.5 years (IQR: 3.0-34.7 years), respectively. DISCUSSION:This study demonstrated that a substantial minority of the study cohort had hearing loss, while fewer had retinal abnormalities and seizures. Age at diagnosis varied widely; hearing loss and retinal disease tended to occur in adults, while for seizures, half were ≤ 10 years old. Our results on the prevalence of comorbid conditions among individuals living with FSHD help provide a better understanding of disease burden and support recommendations for ophthalmological and hearing screenings.

Using data from the US population-based, multisite Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet), we describe respiratory testing and insufficiency among people with facioscapulohumeral muscular dystrophy (FSHD) diagnosed during 2008-2016. We calculated frequencies and proportions for selected outpatient respiratory assessments (pulmonary function tests [PFTs], forced vital capacity (FVC), inspiratory/expiratory pressure, and polysomnograms) and abnormal test results. We examined frequencies by disease characteristics (FSHD type, ages of onset, non-ambulatory status, scoliosis, lordosis), obesity, and number of health encounters. Of 170 people with FSHD, 20.0% underwent PFTs during 2008-2016. Polysomnograms were infrequent (14.1%). FVC <80% predicted was recorded for 64.7% of people tested; additional respiratory outcomes were rare (<5%). Frequency of evaluations and respiratory insufficiency were higher among those with known risk factors and longer follow-up. We observed low proportions of respiratory testing among all confirmed cases of FSHD, but relatively high proportions of mild respiratory insufficiency among those tested. The higher proportions of testing among people with conditions that increase risk of respiratory complications suggest targeted monitoring. Broad implementation of the FSHD guidelines recommending all individuals receive baseline respiratory evaluation at diagnosis could identify respiratory insufficiency as a complication of FSHD.

The 279th ENMC workshop on childhood-onset facioscapulohumeral dystrophy (FSHD) was held on November 1-3, 2024. The workshop aimed to standardize classification based on disease severity, address implications for clinical trials and patient access, and improve clinical management of children and adolescents with FSHD. Key priorities included establishing a working party to address knowledge gaps in clinical management and outcome measures, defining a standardized minimal dataset in both research and clinical environments, and enhancing pharmaceutical engagement. Childhood-onset FSHD presents a spectrum, from early-onset progressive cases to later adolescent onset with a classical phenotype. Standardized care, including psychological support and transition planning, is needed. Challenges in trial design, such as disease heterogeneity and ethical considerations, were highlighted. Consensus that childhood-onset FSHD forms part of a disease continuum was reached. Two task forces were established to define minimal outcome measure datasets and paediatric-specific care guidelines, marking a crucial step toward improved clinical care and trial readiness.

To examine the frequency, onset, and duration of the treatment-emergent adverse events (TEAEs) in MOXIe Part 2 that occurred more often in patients with Friedreich ataxia treated with omaveloxolone as compared to those treated with placebo.

Spinal muscular atrophy (SMA) severity generally correlates with SMN2 gene copy number. Patients with only one SMN2 copy are at risk for the most severe SMA phenotype, characterized by profound hypotonia and respiratory insufficiency at birth and a rapidly progressive and fatal course. Clinical trials of onasemnogene abeparvovec (OA), a one-time gene therapy for SMA, did not include patients with one SMN2 copy. Therefore, little is known about treatment outcomes in these patients, who may receive treatment in real-world practice. We sought to describe outcomes following OA for patients with SMA and one SMN2 copy enrolled in RESTORE, a multinational, noninterventional SMA registry. As of May 23, 2023, RESTORE enrolled three OA-treated patients with one SMN2 copy. Patients had either SMA type 0 or 1. All were treated in the USA and identified by newborn screening. One patient was bridged to OA with nusinersen from 1–3 months of age, and also received add-on therapy with risdiplam, which was initiated at 13 months of age. One patient was male, and two females, all >30 weeks gestational age at birth. All patients were alive at data cutoff. All three patients received ventilatory support: two patients before OA and the third patient after OA. Post-OA CHOP INTEND was recorded for all patients, and all achieved scores >40 or significant (≥4 points) improvements during the observation period. Greatest motor milestones achieved were: one patient stood with support; one patient sat independently and stood with support; and one patient rolled from side-to-side on three separate visits. Adverse events were recorded for one patient. None were serious or treatment-related, and event types were consistent with the established safety profile of OA. Investigation of potential gene modifier is ongoing. SMA patients with one SMN2 copy survived and achieved motor improvements after OA, indicating positive benefit:risk in these particularly vulnerable children.

Background:The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. Methods/design:The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). Discussion:To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. Trial registration:clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

BACKGROUND:Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene.OBJECTIVE:Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec.METHODS:An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing.RESULTS:Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested.CONCLUSIONS:The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.