Duchenne muscular dystrophy (DMD) is a muscle wasting disease where patients lose muscle tissue and function. The disease is caused by pathogenic variants that abolish the production of functional dystrophin protein. There are many therapeutic approaches in clinical development for DMD patients, but so far showing clinical benefit in trials has proven challenging. On May 6, 2025, the World Duchenne Organization convened a multistakeholder drug development round table meeting to discuss pertinent aspects of drug development in the DMD field: trial design, the impact of variable doses and regimen of glucocorticoids on disease trajectory, gene therapy and the use of real world evidence. Herein the most important discussion points, realizations and recommendations are summarized. As current therapeutic approaches for DMD patients aim to slow down disease progression, measuring benefit will likely be challenging. The trial design should consider the mechanism of action of the therapeutic approach, the expected therapeutic effect, and the exposure to glucocorticoids could be considered as a stratification factor (regimen and when glucocorticoids were initiated). For gene therapy there are many uncertainties yet, and in hindsight trials were not all properly designed. Looking forward, additional data needs to be collected to assess the therapeutic effect and its longevity. Finally, real world data can only be used if it has sufficient quantity and quality. This will require global alignment and collaboration.

We evaluated the safety and effectiveness of onasemnogene abeparvovec (OA) for 34 patients with spinal muscular atrophy (SMA) and tracheostomies enrolled in the RESTORE registry. Most patients (76.5%) received other SMA treatments before and/or after OA. Safety findings were consistent with OA's established profile. There were four fatalities, three caused by respiratory events unrelated to OA, one of unknown cause. Overall, patients exhibited positive motor outcomes, even in cases where the need for tracheostomy emerged after treatment. These real-world data support OA treatment for patients with SMA and tracheostomies and can inform future access, treatment, and care decisions.: Clinicaltrials.gov NCT identifier NCT04174157, registration date September 12, 2019.

BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial - gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of in undiagnosed cases of sporadic or maternally inherited HSP.

Homozygous variants have been described to cause congenital myopathy, myofibrillar myopathy type 7, and hereditary spastic paraplegia. We report the findings in two families harboring the homozygous missense NM_178554.4:c.727T > C p.(Cys243Arg) and splice site NM_178554.4:c.710 + 1G > A variants leading to early-onset myopathy with equinovarus deformity, lateral tongue atrophy, kyphoscoliosis, and contractures. Myopathological examination showed a myopathic pattern in conjunction with fibers containing eosinophilic sarcoplasmic inclusions positive for kyphoscoliosis peptidase and filamin-C but not desmin, myofibrillar degeneration, and focal mitochondrial loss. Kyphoscoliosis peptidase protein expression levels were markedly reduced, and analysis of the predicted protein variants suggested impairment of the kyphoscoliosis peptidase catalytic triad.

Pathogenic variants in the gene are associated with congenital myopathy We report 13 unrelated patients and a systematic review of published cases through 30 October 2024, supplemented by HGMD Pro (2024.2) and LOVD (https://www.lovd.nl/) databases. In the case series, most patients (n = 11/13, 84.6%) exhibited clinical symptoms from early childhood to middle adulthood. The mean age of onset was 22.8 years (vs 7.73 years in literature review), likely because of absence of birth contractures, described in early reports. External ophthalmoparesis, though not a defining feature, should raise suspicion of MYH2-related myopathy in patients with a CPEO-like presentation and limb-girdle weakness. Notably, two patients presented with postural tremor of the upper limbs as their first symptom. Although rimmed vacuoles were a characteristic feature in initial reports of MYH2-related myopathy, they were absent in our case series. The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres. Electron microscopy revealed additional features, such as the presence of cores associated with rods in one patient and pathological subsarcolemmal mitochondrial accumulations in 2 patients. Fifteen novel variants were identified amongst the 13 patients of this study, expanding the current genetic landscape for MYH2-related muscle diseases. The phenotypic and histological diversity observed can not be fully accounted for by genetic factors alone, suggesting the presence of additional contributing factors. This wide variability may lead to under-recognition of this disease, thus the importance of clinicians' awareness on the topic.

BackgroundDuchenne muscular dystrophy (DMD) is a severe muscle disease with an unmet therapeutic need. Despite ongoing research efforts, only a few medicines have achieved marketing authorisation in the EU to date. We present a regulatory science overview summarising the insights obtained from the evaluation by the Paediatric Committee (PDCO) of the European Medicines Agency (EMA) of paediatric investigation plans (PIPs) for this condition, with the primary objective of providing recommendations for future developments.MethodsWe reviewed the PIPs approved by the PDCO and related regulatory procedures analysimg the available information in our own databases completing it with a search in the EU Clinical Trials Register (EudraCT) and Clinical Trials Information System (CTIS) databases to provide context.ResultsBetween January 2005 and December 2024, 16 PIPs were agreed. By 2024, 1 PIP has been completed, the remaining ones are ongoing. So far, 3 medicines for the treatment of DMD have received a positive opinion by EMA's Committee for Medicinal Products for Human Use (CHMP). Main characteristics and critical factors contributing to successful developments are outlined.ConclusionsThis study presents the first in-depth evaluation of PIPs approved within the EU for DMD offering insights into potential strategic approaches for clinical development of investigational medicinal products. It highlights the accumulated experience of regulators and stakeholders, particularly regarding pivotal trials that establish clinical efficacy in key patient subgroups. Furthermore, it underscores the emerging value of innovative methodologies - such as extrapolation of efficacy and integration of real-world evidence - while acknowledging persistent challenges related to data quality.

BackgroundSince the approval of onasemnogen abeparvovec (OA) for gene addition therapy in children with spinal muscular atrophy (SMA), there has been a considerable increase of evidence regarding its effectiveness and safety. Consequently, the previous recommendations needed to be revised.ObjectiveThe primary objective was to develop an evidence- and expert-based best practice protocol ensuring optimal patient safety and comprehensive support for affected families. The harmonization of treatment algorithms is expected to facilitate the collection of standardized real-world data, laying the foundation for future evidence-based adjustments.MethodsA modified, two-part Delphi process was selected as a standardized methodology. Experts specializing in SMA from all 31 neuromuscular treatment centers within Germany, Austria and Switzerland, and patient advocacy groups participated in an industry-independent Delphi panel. Existing evidence concerning effectiveness, safety, and guidelines of OA was analyzed in a systematic literature followed by development of consensus statements regarding its effectiveness.ResultsStrong consensus was reached regarding the following statements on effectiveness: (1) OA gene addition therapy for SMA demonstrates a clear advantage compared to the natural progression of the disease. (2) Superiority of any of the three approved disease-modifying therapies has not been proven. (3) Earlier initiation of therapy with fewer symptoms and shorter disease duration leads to better outcomes. (4) There is no clinical evidence supporting the superiority of combining two treatments over monotherapy.Conclusions: The systematic literature analysis constitutes the basis for the subsequent part 2, which involves the generation of expert-based recommendations for the surveillance of SMA gene addition therapy.

This scoping review aims to explore and map the most frequently reported limitations in activities of daily living (ADLs) among individuals with spinal muscular atrophy (SMA), with the goal of informing clinical assessment and multidisciplinary care strategies.

Congenital disorders are a significant contributor to neonatal intensive care unit (NICU) admissions and neonatal mortality, adding to substantial healthcare costs and emotional burden for families. The introduction of rapid next-generation sequencing (NGS), also known as massively parallel sequencing (MPS), in the NICU has advanced neonatal care by enabling rapid and precise diagnoses. This review explores various NGS technologies utilized in the NICU, their clinical utility, and their role in newborn screening (NBS). It also highlights several challenges hindering its widespread adoption. Addressing these barriers will require a combined effort from all the different stakeholders to ensure fair and responsible integration of NGS into neonatal care.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease resulting from biallelic pathogenic variants of the () gene that leads to motor neuron degeneration, progressive muscle atrophy, and weakness. In its most severe form and without timely initiation of treatment, SMA can be fatal or lead to a requirement for permanent ventilation by 2 years of age. Approved treatments for SMA target an increase in SMN protein production. These include nusinersen and risdiplam, which modify splicing of the pre-mRNA, and onasemnogene abeparvovec, a viral-mediated gene therapy. In 2020, an expert panel provided recommendations and practical considerations regarding onasemnogene abeparvovec administration. As more countries have approved onasemnogene abeparvovec and new data have emerged from clinical trials and real-world use, a similar expert panel provides updated recommendations along with additional guidance. Specific recommendations are centered around family preparation prior to and immediately following dosing to minimize risk of infectious illness, timing of anti-adeno-associated virus serotype 9 antibody titer testing for those patients with exclusionary titers, modifying immunization schedules, avoiding potential complications with long-term corticosteroid administration, safety monitoring, considerations for combination therapy, implementing newborn screening, and emphasizing the need for ongoing multidisciplinary care and adherence to standard-of-care guidelines.

The Western Canadian Neuromuscular Conference (WCNMC) is a conference focused on neuromuscular medicine that was held in Calgary, Alberta from September 27-29, 2024. Although WCNMC has a history going back to 2010 as a regional event, the most recent iteration of the conference aimed to expand this as a national meeting. A collaboration with Muscular Dystrophy Canada and the Neuromuscular Network for Canada (NMD4C) helped to achieve this goal and encourage participation from across Canada. Other goals for this event were to increase the opportunities for trainees, showcase new research, and integrate new topics into the program. The sessions included a clinicopathologic case series for the first time, which was led by neuromuscular fellows from across Canada. Sessions covering topics in neuromuscular disease focused on challenging diagnostic situations, and therapeutic developments for diseases including spinal muscular atrophy, Pompe disease, and TTR amyloidosis. A separate session covered genetic neuromuscular diseases, with a focus on conditions with genetic founder effects in western Canada. Finally, a transdisciplinary session was included, which discussed patient-focused issues in neuromuscular care, as well as preliminary results from the Burden of Inherited Neuromuscular Disease (BIND) study, on the indirect costs of living with a neuromuscular disorder. A research symposium at the conclusion of the event focused on trainee-led research but also included lectures regarding antisense therapies in neuromuscular disease and updates in research on amyotrophic lateral sclerosis.

IntroductionMyotonic dystrophy type 1 (DM1) is characterized by a lifelong progressive muscular weakness associated with life-threatening events such as chronic respiratory failure (CRF). Early identification of patients at risk remains challenging.ObjectiveTo identify clinical and biological markers predictive of CRF onset and survival in a large DM1 cohort.MethodsWe conducted a retrospective cohort study of 126 DM1 adult patients followed from 2000 to 2024 at Rouen University Hospital. The primary outcome was the first forced vital capacity (FVC) ≤ 70% of predicted value. Prognostic factors were analyzed using Cox proportional hazards models with the start of follow-up at the time of diagnosis of DM1 and were followed until the outcome occurred, or death (censorship according to Kalbfleisch & Prentice approach to competing risks).ResultsDuring a median follow-up of 12.5 years, 45 patients developed FVC ≤ 70%. Muscular impairment rating scale (MIRS) (HR: 1.85, 95%CI:1.30-2.63) and conduction/rhythm disorders (HR: 3.13, 95%CI: 1.37-7.31) at diagnosis were independent predictors of FVC ≤ 70% adjusted on age, female sex (HR: 1.54, 95%CI: 0.82-2.91) and cataract at diagnosis (HR: 0.50, 95%CI: 0.22-1.16). CTG repeats ≥400 was associated with a doubled risk of respiratory decline but did not reach statistical significance. The 20-year mortality rate was 32%. MIRS (HR: 2.34, 95%CI:1.22- 4.51), male sex and older age at diagnosis significantly predicted death.ConclusionsMuscular impairment and cardiac rhythm/conduction disorders at diagnosis were strong predictors of respiratory complications. MIRS, male sex and older age at diagnosis were predictors of mortality in DM1. These prognostic markers should inform clinical management strategies to improve survival in DM1 patients.

Slowly progressive proximal muscle weakness in an otherwise healthy male posed particular challenges for the treating physicians, considering the wide range of possible differentials. Here we present a case of a 52-year-old male with paraparesis, elevated creatine kinase-levels, antibodies against the Mi-2 antigen and subtle skin lesions, leading to subsequent treatment for dermatomyositis. Beyond that, exome sequencing revealed biallelic variants in the gene encoding acid alpha-glucosidase with concordant reduced enzymatic activity in fibroblasts, indicating late onset Pompe disease. Subsequently performed magnetic resonance imaging revealed a pattern of involvement typical for LOPD, but histological workup from the vastus lateralis muscle was more indicative of an immune-mediated myopathy. After treatment for dermatomyositis and Pompe disease the patient showed an improvement in skin changes and a halt in muscular weakness. In conclusion, both entities could be seen in the patient. However, early and prolonged subclinical hyper-CK-emia hinted at Pompe disease as the primary entity.

BackgroundWeakness associated with facioscapulohumeral muscular dystrophy (FSHD) impacts daily activities. Impact is often measured using standardized clinical assessments, documenting activity capacity, and only captures a snapshot of function. Wearable sensors may enable assessments of real-world activity performance.ObjectiveTo examine activity performance (actigraphy) and its relationship with capacity (clinical measures of strength and function) in adults with FSHD.MethodsRemote assessments were piloted in a subgroup from Motor Outcomes to Validate Evaluations in FSHD. Participants wore waist-worn activity monitors for 7 days. Activity metrics included moderate-to-vigorous intensity physical activity (MVPA), time in activity levels, and step counts. Descriptive statistics summarized activity, Mann Whitney U tests compared groups, and correlation analyses examined relationships between activity performance and capacity.ResultsThirteen subjects wore the device for a median of 7 days. Most time was sedentary, with minimal vigorous activity. Participants spent a median of 23.1 min daily (IQR: 23.8) and 161.7 min weekly (IQR: 157.9) in MVPA. Median daily step count was 4245 (IQR: 2892), with a median maximum step count of 20 (IQR: 7) within a 10-second epoch. Correlations were found between total MVPA and 10mw/r (ρ=-0.720, p = 0.006) and TUG-comfortable (ρ=-0.720, p = 0.006), and between maximum step count and several functional measures.ConclusionThis pilot study provides insights into activity performance and its relationship with capacity in a small cohort of adults with FSHD. Total MVPA and maximum step count appear most informative for evaluating activity performance; larger studies are needed to confirm findings and assess psychometric properties of these metrics.

Spinal muscular atrophy (SMA) is a neuromuscular disease that affects patients and caregivers worldwide, including in India, with a significant economic burden.

Idiopathic inflammatory myopathies (IIM), also known as myositis, are a group of heterogeneous autoimmune diseases characterized by muscle inflammation and frequent involvement of extramuscular organs. Autoantibodies are present in approximately 70% of the patients. Despite treatment advances, management of IIM largely relies on empirical approaches and current treatment options lack robust evidence, with the exception of intravenous immunoglobulin (IVIg). Even with immunosuppressive therapy, up to 80% of the patients continue to experience ongoing disease activity, functional impairment and a significant reduced quality of life. Several challenges complicate the management of IIM, including rare occurrence, heterogeneity of the disease, systemic manifestations, higher prevalence of malignancies and the complexity of conducting large-scale clinical trials in rare diseases. Along with this, therapeutic development has long been hindered by an incomplete understanding of the disease pathogenesis. However, recent insights into the molecular and cellular mechanisms of IIM have revealed novel therapeutic targets. In this review, we will discuss the underlying immunopathogenesis of IIM, including the role of potentially pathogenic autoantibodies, B and T cells, the interferon (IFN) pathway and the complement system. We will also review current treatment strategies and provide an overview of emerging and promising new treatments tested in recently published clinical trials or ongoing clinical trials, including chimeric antigen receptor (CAR) T-cell therapy, T-cell engagers, T-cell targeting therapies, neonatal Fc receptor (FcRn) inhibitors, and small-molecule inhibitors targeting intracellular signaling molecules such as Janus kinases (JAKs), IFNs, and complement.

Nusinersen is a designer drug for spinal muscular atrophy (SMA) and was the first approved treatment for this once deadly disease. It is an antisense oligonucleotide that pairs with a specific locus of the gene, to modify splicing and generate an increase in full-length transcript. This in turn increases expression of survival motor neuron protein, deficiency of which results in motor neuron dysfunction and reduced cellular survival, the principal cause of SMA. Pre-clinical studies of nusinersen in animal models of SMA demonstrated substantial clinical responses and proof-of-concept, leading to successful clinical trials in symptomatic children and then in infants. Nusinersen's favorable safety profile after repeated lumbar intrathecal delivery as well as improvement in motor function and survival resulted in US regulatory approval for SMA in 2016. Other countries have followed with variable coverage policies depending upon age, weight, genotype and/or clinical severity. In the current treatment era, two populations of individuals with SMA exist: symptomatic patients identified in the clinic and pre-symptomatic patients (having no or few early clinical features of disease) largely identified by newborn screening. Real-world experience with nusinersen, the topic of this focused review, presents post-approval data in a broad range of patients beyond those studied in clinical trials. The favorable clinical response and safety profile are discussed, as well as the emerging new phenotypes of disease. Nusinersen, one of three FDA-approved drugs for SMA (as of 2025) remains an important therapeutic consideration for infants, children and adults with SMA.

ObjectiveTo describe the disease burden in patients with Pompe disease treated with enzyme replacement therapy (ERT) in the US as defined by comorbid conditions, supportive services, and treatment patterns.MethodsA retrospective cohort study (01/01/2012-09/30/2022) was conducted using the Merative™ MarketScan Research Databases. Inclusion criteria were: ≥ 2 outpatient or ≥1 inpatient claims of Pompe disease, ≥ 1 claim of ERT, and continuous enrollment in medical/prescription coverage for ≥90 days before diagnosis date for patients ≥2 years and ≥1-month post-index date. Patients were stratified into infantile-onset Pompe disease (IOPD) or late-onset Pompe disease (LOPD) cohorts based on age at diagnosis and clinical presentation. Key comorbidities, supportive services, and treatment modifications were presented as cumulative incidence.ResultsA total of 105 patients were included (IOPD: n = 50; LOPD: n = 55). For IOPD and LOPD groups, the 12-month cumulative incidence was 84.5% and 79.4% for respiratory, 57.4% and 54.3% for ambulatory, 67.8% and 33.4% for gastrointestinal, and 16.9% and 28.7% for cardiovascular comorbidities, respectively; 12-month cumulative incidence was 66.9% and 31.8% for physical therapy, 59.5% and 3.9% for speech therapy, 48.6% and 1.8% for immune tolerance induction or intravenous immunoglobulin, 47.3% and 11.2% for nutritional therapy, 15.1% and 17.0% for respiratory support, 27.8% and 3.7% for occupational therapy, and 8.3% and 11.1% for ambulatory support, respectively. Fourteen (IOPD: n = 2; LOPD: n = 12) patients switched ERT therapy, and 21 (IOPD: n = 14; LOPD: n = 7) had ≥1 dose modification.ConclusionsPatients with Pompe disease demonstrate substantial comorbidity burden and utilization of supportive services despite ERT treatment.

To investigate how parents of children with SMA who are treated with disease modifying therapies cope with hopes and worries related to disease progression, and to investigate their needs for counseling and rehabilitation initiatives.