RYR1-related myopathies (RYR1-RMs) have been reported to exhibit distinct clinical manifestations and muscle pathology. Muscle imaging has gained increasing importance in the diagnosis and the imaging data have also been used in clinical trials for some diseases. This study aims to identify fat replacement patterns among RYR1-RMs and to investigate their relationship with clinical manifestations. A total of 36 patients with RYR1-RMs were examined by quantifying fat replacement in 47 skeletal muscles using the modified Mercuri score (mMS). Patients were classified into 6 diseases: central core disease (CCD), congenital neuromuscular disease with uniform type 1 fiber, central core disease with atypical core, multiminicore disease (MmD), dusty core disease, and myopathy with central nuclei. For data analyses, we employed dimensionality reduction using uniform manifold approximation and projection (UMAP), and hierarchical clustering. The patients with RYR1-RMs were positioned close together on UMAP. Violin plot analysis identified chronological patterns of fat replacement in whole body. Significant correlations were observed between imaging data and clinical symptoms, including respiratory failure, ambulation impairment and scoliosis, and muscle pathology. The patients with RYR1-RMs share a common pattern of fat replacement. Progressive fat replacement was identified, providing a foundation for establishing muscle imaging as a marker for disease progression and treatment efficacy.

The Advanced Cardiac Therapies Improving Outcomes Network formed a dystrophinopathy registry to define cardiac diagnostics, management, and advanced therapies in the current era. Males with dystrophinopathy and one of the following: age ≥10 years, cardiomyopathy, or receipt of gene therapy, were eligible for enrollment. Data collection occurred at enrollment and every 6 months thereafter and includes demographics, neuromuscular, cardiac, and pulmonary endpoints, medications, advanced cardiac therapies, and outcomes. This analysis is of the first 500 males with a mean age of 18.1 years (± 5.38 years), the majority being white (81.2%) with Duchenne Muscular Dystrophy (91.4%), on glucocorticoids (80.2%), non-ambulatory (67.2%), and not requiring respiratory support (54.0%). In this cohort, 58.8% had evidence of cardiac involvement, 54.6% with evidence of ventricular dysfunction. The majority were on cardiac medication: 458 (91.6%) on angiotensin converting enzyme inhibitor or equivalent, 346 (69.2%) on mineralocorticoid receptor antagonist, and 264 (52.8%) on beta-blocker. One-hundred thirteen (22.6%) had an arrhythmia, 8 (1.6%) an implantable cardioverter defibrillator, 6 (1.2%) a ventricular assist device, and 3 (0.6%) underwent heart transplantation. Longitudinal data collection will establish a modern natural history of cardiomyopathy in dystrophinopathy, providing critical information to inform cardiac management and clinical trials.

Pompe disease is a rare disorder characterized by progressive loss of muscle and respiratory function. Data are limited in non-ambulatory patients or those switching from high-dose, high-frequency (HDHF; 40 mg/kg every week) alglucosidase alfa (alg) to cipaglucosidase alfa plus miglustat (cipa+mig). We analyzed outcomes in two non-ambulatory patients in study ATB200-02 who received alg for >13 years (including >2 years' HDHF) before switching to cipa+mig (20 mg/kg + 260 mg every 2 weeks). In both, upper limb quantitative muscle test scores markedly increased over 54 months. Subject and Physician Global Impression of Change scores were improved or unchanged at 6 months and maintained throughout. Fatigue severity improved versus baseline after 12 months. Rotterdam Handicap Scale scores fluctuated over time. Biomarker levels (urine hexose tetrasaccharide and serum creatine kinase) improved versus baseline at all visits. The two patients experienced 11 non-serious adverse events (no infusion-associated reactions). Data provide information for clinicians considering a transition from HDHF alg to cipa+mig.

A 50-year-old man with hypothyroidism was referred for refractory myasthenia gravis (MG). He developed progressive, painless right-sided shoulder and leg weakness, dysphagia, and fatigable diplopia. Acetylcholine receptor (AChR) antibodies were positive. Immunosuppressive therapies provided only transient improvement in oculo-bulbar symptoms, while hemiparesis progressed. Examination showed fatigable ptosis with curtain sign, vertical gaze limitation, and diplopia localizing to left lateral rectus weakness. Upper motor neuron signs included brisk masseteric reflex, right spastic hemiparesis, and hyperreflexia. EMG demonstrated chronic reinnervation in right cervical and lumbosacral regions. MRI revealed T2 hyperintensity in the left upper cervical cord and adjacent medulla without enhancement. A diagnosis of AChR+ MG and Mills' syndrome was made. While MG has previously been reported to coexist with ALS, this is the first known case associated with Mills' syndrome. This highlights the importance of recognizing overlapping autoimmune and neurodegenerative disorders and the need for further research into shared mechanisms.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder marked by progressive muscle weakness and disability throughout life. Affecting about one million people worldwide, FSHD is among the most common forms of muscular dystrophy. To advance global collaboration, the FSHD Society hosted the 32nd International Research Congress (IRC) on June 12-13, 2025, in Amsterdam, the Netherlands. More than 250 researchers, clinicians, patients, and industry representatives attended, highlighting key developments in FSHD research. The Congress comprised six scientific sessions: (1) Population Genetics & Modifiers, (2) Measures of Disease Activity & Progression, (3) Novel Clinical Outcome Measures, (4) Mechanisms of Disease & Interventional Strategies, (5) Clinical Care & Related Issues, and (6) Clinical Studies & Trial Design. Keynote presentations were delivered by Leendert Trouw (Leiden University Medical Center, Netherlands) and Karen Chen (SMA Foundation, USA), who shared perspectives from their respective research domains. Preceding the IRC, the Industry Collaborative (IC) for Therapeutic Development united experts in clinical science, biomarkers, and industry to identify knowledge gaps and strengthen strategies for developing effective FSHD therapies. Following the IRC, the inaugural FSHD Connect Europe meeting brought together patients and families from across Europe to exchange experiences and gain updates on emerging clinical and scientific advances. The FSHD Society continues to foster research and community engagement to accelerate treatment breakthroughs. The next International Research Congress will be held in Chicago, Illinois, on June 25-26, 2026.

We report a case of HMGCR-related limb-girdle muscular dystrophy (LGMD) with neonatal onset and early lethality. The patient, homozygous for the p.Arg641Cys variant in HMGCR, presented with profound hypotonia, respiratory failure by 5 months, and markedly elevated creatine kinase (CK). This case stands out among the 17 previously reported patients for its extremely early onset and rapid clinical deterioration. Functional studies confirmed the pathogenicity of the variant: in vitro assays showed severely impaired HMGCR enzymatic activity, and in vivo modeling using homozygous knock-in mice resulted in embryonic lethality, underscoring its deleterious effect on essential metabolic processes. The patient's early death highlights the urgent need for targeted therapies and early diagnosis. This case expands the clinical and molecular spectrum of HMGCR-related LGMD and supports refining phenotype classification based on genotype-phenotype correlations and age of onset to improve diagnostic precision.

GNE myopathy is a rare autosomal recessive skeletal muscle disorder characterized by progressive distal muscle weakness, typically starting in the lower legs and gradually involving proximal muscle groups. It is an autosomal recessive disease, caused by biallelic variants in GNE. To date, over 350 causative GNE variants have been reported, however, establishing genotype-phenotype correlation remains difficult due to clinical heterogeneity and limited patient numbers. In this study, we describe 20 unrelated European families with a diagnosis of GNE myopathy and biallelic GNE variants identified in either homozygosity or compound heterozygosity. While the majority of variants observed in our cohort have been previously reported, we identified five novel missense variants: p.(G355R), p.(A679T), p.(I709T), p.(V727G), and p.(V744I). Using in silico prediction tools and ACMG/AMP criteria, we classified p.(G355R) and p.(V727G) as likely pathogenic. The clinical features of our cohort were consistent with the classical presentation of GNE myopathy. Our findings contribute new genotype data and support ongoing efforts to refine variant interpretation in GNE myopathy. This study expands the mutational spectrum of GNE and reinforces the phenotypic consistency across diverse populations.

Unlike congenital and adult phenotypes, ChDM1 often involves minimal muscular symptoms with cognitive or behavioral difficulties being the most common early indicator of the disease. These difficulties, often exacerbated by fatigue and slowness, contribute to complex disability scenarios beginning as early as kindergarten but also persisting into early adulthood. This scoping review aims to explore the neuropsychological and behavioral profile associated with ChDM1 throughout the lifespan and seeks to understand how this profile evolves with age. In total, 24 studies were included with 416 individuals identified as having ChDM1. Alongside visuospatial, attentional/executive and social difficulties, neuropsychiatric problems appeared also to be common in this population. Depressive and anxious symptoms were consistently reported in children and adolescents with ChDM1 but appear to be less frequent in adults. The lack of standardized outcome measures for motor, cognitive and behavioral symptoms complicate efforts to determine the true prevalence and severity of impairments across studies. Identifying tools capable of capturing developmental trajectories over a sufficiently long period, from childhood to adulthood, remains a persistent challenge.

The 287th ENMC International Workshop convened experts from ten countries to address the harmonization and federated analysis of Myotonic Dystrophy Type 1 (DM1) registries. With over 10,500 patients enrolled globally, registries remain fragmented, limiting their utility in modeling disease trajectories and supporting clinical trials. As new therapies enter advanced clinical testing, registries must evolve - not only to enable trial readiness but also to support downstream functions like pharmacovigilance. The workshop focused on four objectives: re-defining a core dataset, enabling FAIRification of registries, establishing federated analysis infrastructure, and developing longitudinal modeling strategies. Key outcomes included a revised core set of clinical and patient reported outcome measures that is feasible to collect in a routine care setting, strategies for FAIR data integration, and governance models for federated analysis. Pragmatic and interpretable statistical approaches such as latent variable modeling and unsupervised clustering were discussed, with key prediction targets identified across motor, cardiac, and pulmonary domains. The workshop emphasized the need for sustainable funding, patient-centered design, and international collaboration.

Duchenne muscular dystrophy is a muscle wasting disorder caused by lack of dystrophin protein. Dystrophin is present intracellularly at the sarcolemma and is enriched at the postsynaptic membrane of the neuromuscular junction. Morphological and functional neuromuscular junction deficits have been shown in mdx mice, a model lacking dystrophin. Antisense oligonucleotide-mediated exon skipping has been approved in several countries. It is however unclear whether the partial dystrophin restoration achieved is sufficient to rescue muscle functioning. Despite being well investigated at a myofiber level, it is unknown if the exon skipping therapy holds potential to ameliorate or restore neuromuscular junction deficits. This study investigated the effects of exon skipping on the structure and function of the neuromuscular junction in the mdx mouse. On average, restoration of 16 % of wild type dystrophin protein level was achieved in diaphragm muscle following treatment with a 2'-O-methyl phosphorothioate antisense oligonucleotide. This partially improved neuromuscular junction functioning, evidenced by enhanced amplitudes of miniature endplate potentials and endplate potentials, and reduced sensitivity of neuromuscular transmission to the acetylcholine receptor blocker d-tubocurarine, indicating improved synaptic strength. Additionally, aberrant acetylcholine receptor cluster geometry improved.

This Patients' Forum centers on the testimonial of visual artist Marion Sellenet, who lives with facioscapulohumeral muscular dystrophy (FSHD). In her film Marion or the metamorphosis, co-created with Laëtitia Moreau, she documents her dual journey: coping with the physical manifestations of FSHD and overcoming a "second illness" of fear, despair, and stigma induced by the diagnosis. By relinquishing the hope of cure, she found renewed meaning and a sense of wholeness, advocating for collaborative approaches that integrate medical, philosophical, and experiential knowledge. Her account is complemented by reflections from Alexandra Belayew, who underscores the importance of patient education and accessible communication of research; Baziel van Engelen, who highlights the need to bracket biomedical knowledge to address lived experience; and Ria de Haas and Nicol Voermans, who emphasize patient engagement in care and research. Together, these perspectives illustrate the transformative potential of patient narratives and underline the value of patient-centered, holistic approaches in 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.

Spinal muscular atrophy is a multisystem neuromuscular condition which crosses a spectrum of paediatric care. With disease modifying therapies demonstrating a range of clinical responses, effectively monitoring change is vital. The need for a respiratory longitudinal outcome measure is important due to the large impact on patient quality of life and cost to healthcare. The International Spinal Muscular Atrophy Consortium is developing a global scale for assessing the overall status of patients with SMA. We report the process of creating and piloting the pulmonary module. 10 respiratory specialists, with experience managing patients with SMA, developed a single module to be used across the developmental spectrum. Modules included Clinical History, Physical Exam, and Pulmonary Function Testing. The module was piloted at three institutions, demonstrating the module was easy to use and produced data in 51 subjects representing SMA types 1, 2 and 3. The data demonstrated differences between the three types: patients with SMA1 had the lowest score, and increasing scores for patients with SMA2 and SMA3, respectively. Designing the module to assess the respiratory status in SMA is both feasible and allows for discrimination between SMA subtypes. While results are encouraging, more data is needed to validate the module and determine its precision.

Around the world, epidemiological data on neuromuscular disorders (NMD) in the pediatric population are very limited. Through medical and genetic hospital records in expert NMD centers (Toulouse, Montpellier, Bordeaux), from May 2001 to June 2022, NMD pediatric prevalence and the epidemiological profile of these disorders were investigated. We performed a retrospective cohort study with data from the French National Rare Disease Databank, which gathers a minimal dataset on all patients. The prevalence by diagnosis and age group or by year and survival from birth for muscular disorders by sub-group were analyzed. 1621 children were included with 62 % males. We estimated the regional prevalence at 37.9 (CI95 % = 35.3 - 40.7)/100,000 inhabitants under 18 years old. For the muscular disorder sub-cohort analysis, we estimated regional prevalence for Duchenne, Becker, Charcot-Marie-Tooth type 1 and Spinal Muscular Atrophy at 5 (CI95 % = 4.1 - 6.1), 1.3 (CI95 % = 0.9 - 1.9), 6.2 (CI95 % = 0.1 - 7.3) and 3.2 (CI95 % = 2.5 - 4.1), respectively. Our findings seem in accordance with other previous but scarce data. Together, these data may reflect a consensus across countries. This epidemiological study is the first robust estimation of the French pediatric prevalence of neuromuscular disorders and presents a strong starting point to be confirmed by analyses extended to all French expert centers.

LAMA2-related dystrophies (LAMA2-RDs) are among the most frequent congenital muscular dystrophies, caused by pathogenic variants in the LAMA2 gene. They typically present in infancy with severe muscle weakness but span a wide clinical spectrum, from neonatal onset to milder, later-onset forms. Complications include respiratory insufficiency, nutritional difficulties, joint contractures, scoliosis, and central nervous system involvement. No specific internationally agreed standards of care (SoC) exist, leading to variability in diagnosis, monitoring, and access to multidisciplinary management and care. The 283rd ENMC International Workshop gathered international stakeholders to review current evidence, suggest expert care recommendations and reach an agreement on the best methods to develop diagnostic and care guidelines for LAMA2-RD. Key outcomes included consensus care recommendations across major clinical domains, strategies for dissemination through a dynamic, open-access resource, and a framework to guide development of SoC for other genetic forms of congenital muscular dystrophies.

The 288 ENMC workshop (16-18 May 2025) brought together a group of 26 healthcare professionals, researchers, and patient representatives to advance understanding and clinical management of gastrointestinal (GI) manifestations in individuals with myotonic dystrophy (DM). GI symptoms are common in DM but are not systematically addressed in clinical care and are frequently left untreated or treated incorrectly. This workshop highlighted the breadth and impact of GI manifestations in DM, addressing symptoms in the oropharynx, oesophagus, liver, gallbladder, stomach, small and large intestines, and pelvic floor muscles. Attention was given to nutritional, cognitive, and behavioural influences on these symptoms and differences across males and females. Developments in genetic and animal studies that contribute to an increased understanding of the pathophysiology and potential treatment of GI manifestations were discussed, and recommendations are provided for their use. Building on these discussions, this report extends and substantiates the workshop content by incorporating additional literature and expert interpretation. Practical clinical recommendations to optimise the care and treatment of GI symptoms in DM were provided and, together with patient representatives, a list of 10 questions has been developed that can be used in the consultation room to identify whether a patient is experiencing GI symptoms. Next steps include the development of a DM-specific assessment instrument for GI symptoms and the selection of outcome measures to monitor changes in symptoms over time, during treatment, or in clinical trials.

In anticipation to clinical trials in pediatric DM1, the 284th ENMC workshop aimed to establish diagnostic and management protocols for CNS involvement based on international expert-consensus by 1) reviewing existing translational research findings on CNS involvement in pediatric DM1, 2) sharing current clinical and diagnostic approaches to CNS involvement in the international pediatric DM1 population and 3) discuss protentional CNS biomarkers relevant to future clinical and research applications in pediatric DM1. Patient and family perspectives on the impact on quality of life were considered. The workshop highlighted the complexity of the spectrum of CNS involvement from a research and clinical care perspective and confirmed the need for international harmonization of clinical assessment of cognitive-behavioral abnormalities. Consensus was reached on 1) disease classification based on age of symptom-onset and 2) a core neuropsychological assessment protocol to be used in clinical practice. Implications for trial design and further research are discussed.

The role of muscle excitability in the underlying mechanism of contraction-induced strength loss and the recovery processes in those with Duchenne muscular dystrophy is unknown. Strength loss of wrist extensor muscles was induced by an intermittent, submaximal, isometric contraction exercise protocol in males with (n = 10) and without Duchenne muscular dystrophy (n = 10). Muscle strength was measured by torque from isometric maximum voluntary contractions. Muscle excitability was measured by compound muscle action potential evoked by transcutaneous magnetic stimulation. Central component of electromyogram was measured by integral electromyogram during isometric maximum voluntary contractions. Significant reductions in muscle excitability were observed in both groups along with reduced maximum voluntary contractions torque after exercise. Muscle excitability was positively correlated with maximum voluntary contractions torque and did not show between-group differences before or immediately after exercise. However, this correlation showed significant between-group differences during recovery. Results indicate that in males with Duchenne muscular dystrophy, muscle strength loss was accompanied by reduced muscle excitability. Importantly, the difference in excitability-torque correlation between groups during recovery suggests that DMD muscle function was affected by the ability to recover from strength loss more than during the contraction-induced strength loss.

Immune-mediated necrotizing myopathy (IMNM) is a rare but treatable inflammatory myopathy characterized by severe muscle necrosis with minimal inflammatory infiltration. IMNM typically presents with progressive proximal muscle weakness and markedly elevated serum creatine kinase (CK) levels. Here, we report a unique case of IMNM associated with anti-signal recognition particle (SRP) antibody, in which hyperCKemia persisted for 40 years before the onset of muscle symptoms. The extremely prolonged asymptomatic course initially suggested a hereditary myopathy; however, the absence of selective fatty replacement on muscle MRI pointed toward an inflammatory etiology. This imaging finding guided the diagnosis toward IMNM, a treatable condition, and led to successful immunotherapy with normalization of CK levels and marked improvement in muscle strength over 12 months.

The non-dystrophic myotonias are rare genetic conditions characterised by delayed muscle relaxation, muscle stiffness, pain and fatigue. This study examines the experience of the UK National Referral Centre in using lamotrigine to treat non-dystrophic myotonias. A prospective cohort of 37 patients with genetically confirmed non-dystrophic myotonias (23 with CLCN1 variants and 14 with SCN4A variants) who were prescribed lamotrigine as part of routine clinical care were followed for a mean of 26 months. Treatment efficacy was assessed using the Myotonia Behaviour Score. 26 participants were included in the efficacy analysis where lamotrigine was found to reduce the mean Myotonia Behaviour Score from 3.3 to 1.8 (p < .001, Cohen's d = 1.2), demonstrating significant symptom improvement. Side effects, mainly rash and headache, led to discontinuation in nine out of 37 patients, but no severe adverse events occurred. In most cases, lamotrigine was chosen due to prior side effects with mexiletine or cardiac contraindications to mexiletine and proved to be an effective alternative. This study provides real-world evidence supporting the long-term use of lamotrigine and the integration of lamotrigine into personalised treatment strategies for non-dystrophic myotonias.