Journal of Neuromuscular Diseases

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...

BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease. Clinical evaluation of DMD uses patient-intensive motor function tests, and the recent development of wearable devices allows the collection of a variety of biometric information, including physical activity. OBJECTIVE: In this study, we examined differences in physical activity and heart rate variability (HRV) between patients with DMD and healthy subjects using a wearable device, and investigated any association between these parameters and motor function in patients with DMD...

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a genetic disease in which lack of the dystrophin protein causes progressive muscular weakness, cardiomyopathy and respiratory insufficiency. DMD is often associated with other cognitive and behavioral impairments, however the correlation of abnormal dystrophin expression in the central nervous system with brain structure and functioning remains still unclear. OBJECTIVE: To investigate brain involvement in patients with DMD through a multimodal and multivariate approach accounting for potential comorbidities...

BACKGROUND: NEFL encodes for the neurofilament light chain protein. Pathogenic variants in NEFL cause demyelinating, axonal and intermediate forms of Charcot-Marie-Tooth disease (CMT) which present with a varying degree of severity and somatic mutations have not been described yet. Currently, 34 different CMT-causing pathogenic variants in NEFL in 174 patients have been reported. Muscular involvement was also described in CMT2E patients mostly as a secondary effect. Also, there are a few descriptions of a primary muscle vulnerability upon pathogenic NEFL variants...

BACKGROUND/OBJECTIVE: Myasthenia Gravis (MG) is an autoimmune disorder characterized by pathogenic autoantibodies (AAbs) targeting nicotinic acetylcholine receptors (AChR), disrupting neuromuscular communication. RadioImmunoPrecipitation Assay (RIPA) is recommended to detect AChR AAbs, but its complexity and radioactive requirements limit widespread use. We compare non-RIPA anti-AChR immunoassays, including Cell-Based Assay (CBA) and two ELISA kits, against the gold standard RIPA. METHODS/RESULTS: 145 samples were included with medical indication for anti-AChR testing...

BACKGROUND: Facial weakness is a key feature of facioscapulohumeral muscular dystrophy (FSHD) and may lead to altered facial expression and subsequent psychosocial impairment. There is no cure and supportive treatments focus on optimizing physical fitness and compensation of functional disabilities. OBJECTIVE: We hypothesize that symptomatic treatment options and psychosocial interventions for other neurological diseases with altered facial expression could be applicable to FSHD...

BACKGROUND: Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. OBJECTIVE: In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3...

 Patient-reported outcome measures (PROMs) are valuable in comprehensively understanding patients' health experiences and informing healthcare decisions in research and clinical care without clinicians' input. Until now, no central resource containing information on all PROMS in neuromuscular diseases (NMD) is available, hindering the comparison and choice of PROMs used to monitor NMDs and appropriately reflect the patient's voice. This scoping review aimed to present a comprehensive assessment of the existing literature on using PROMs in children and adults with NMD...

Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60% . We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotype-driven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated...

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated...

BACKGROUND: The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation...

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)...

BACKGROUND: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. METHODS AND RESULTS: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS)...

BACKGROUND: Nusinersen treatment has demonstrated efficacy in improving clinical outcomes for spinal muscular atrophy (SMA), yet its impact on scoliosis progression remains unclear. OBJECTIVE: This study aimed to assess the progression of scoliosis in pediatric patients with SMA undergoing nusinersen treatment. METHODS: In this prospective study, data were systematically collected from Hong Kong pediatric SMA patients receiving nusinersen between 2018 and 2023...

BACKGROUND: Duchenne muscular dystrophy (DMD) and related dystrophinopathies are neuromuscular conditions with great unmet medical needs that require the development of effective medical treatments. OBJECTIVE: To aid sponsors in clinical development of drugs and therapeutic biological products for treating DMD across the disease spectrum by integrating advancements, patient registries, natural history studies, and more into a comprehensive guidance. METHODS: This guidance emerged from collaboration between the FDA, the Duchenne community, and industry stakeholders...

BACKGROUND: Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented. OBJECTIVE: Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic...

Adeno-associated viruses (AAV) are well-suited to serve as gene transfer vectors. Onasemnogene abeparvovec uses AAV9 as virus vector. Previous exposure to wild-type AAVs or placental transfer of maternal AAV antibodies, however, can trigger an immune response to the vector virus which may limit the therapeutic effectiveness of gene transfer and impact safety. We present the case of a female patient with spinal muscular atrophy (SMA) and three survival motor neuron 2 (SMN2) gene copies. The infant had elevated titers of AAV9 antibodies at diagnosis at 9 days of age...

There has been tremendous progress in treatment of neuromuscular diseases over the last 20 years, which has transformed the natural history of these severely debilitating conditions. Although the factors that determine the response to therapy are many and in some instance remain to be fully elucidated, early treatment clearly has a major impact on patient outcomes across a number of inherited neuromuscular conditions. To improve patient care and outcomes, clinicians should be aware of neuromuscular conditions that require prompt treatment initiation...

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness leading to permanent disability. There are no curative treatments, however, there are several upcoming clinical trials testing new therapies in FSHD. OBJECTIVE: This study aimed to explore the disease burden and patient preferences of people with FSHD to ensure that clinical trials can be designed to include outcome measures that are relevant and important to patients...

Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes. By reviewing clinical reports in conjunction with analysis of clinically relevant mouse models, we identify likely causes for the confusion...