Journal of neuromuscular diseases最新文献

Classic phenotypes of plectinopathies include epidermolysis bullosa simplex and muscular dystrophy with proximal distribution, associated or not with skin blistering. However, in recent years, patients manifesting new muscular phenotypes including lower-limb distal weakness have been described. We aim to expand the phenotypic spectrum of plectinopathies by reporting a case presenting with a pure skeletal myopathy with predominant upper-limb distal weakness. We describe this distal myopathy phenotype providing comprehensive clinical, genetic, myopathological and radiological data. Genetic studies identified two truncating variants in PLEC.

BackgroundB3GALNT2 mutations cause α-dystroglycanopathy (α-DGP), a rare condition characterized by muscular dystrophy, brain malformations, and developmental delay. However, its pathogenic mechanisms remain poorly understood. To date, limited cases have been reported, and the pathogenic mechanisms remain incompletely understood.MethodsClinical and genetic data from 3 newly diagnosed Chinese patients and 28 patients previously diagnosed with B3GALNT2-related α-DGP were analyzed. Using patient-derived fibroblasts, α-dystroglycan (α-DG) glycosylation and laminin-binding capacity were assessed by immunoblotting, laminin overlay and immunofluorescence. B3GALNT2 mRNA and protein levels were quantified by real-time PCR and immunoblotting. Enzymatic activity was measured using purified recombinant B3GALNT2 proteins. Differentially expressed genes were identified via an mRNA microarray.ResultsAll three patients carried compound heterozygous variants involving one truncating and one missense mutation. Two novel mutations (c.657_658insTT and c.1384T > C) were identified. Functional studies confirmed that the missense mutations (Y436C and C462R) impaired enzymatic activity to 40-50% of wild-type levels, while splice variants caused frameshifts and likely complete loss of protein. Despite partial residual activity, all patients showed severely reduced α-DG glycosylation and loss of laminin binding, consistent with a functional threshold effect. Transcriptomic analysis revealed upregulation of CHST10 in two patients.ConclusionsThis study expands the mutational spectrum of B3GALNT2-related α-DGP and provides mechanistic insight into the pathogenicity of novel variants. Our findings support a functional threshold model for B3GALNT2 activity in α-DG glycosylation and suggest CHST10 as a potential transcriptional responder to glycosylation defects. These results deepen the understanding of B3GALNT2-related dystroglycanopathies and may inform future diagnostic and therapeutic strategies.

Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

Objective: The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies.

Methods: The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity.

Results: Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website.

Conclusions: Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.

The Rare Disease Consortium Japan (RDCJ) is a newly formalized cross-sector initiative launched to address the urgent and growing needs of individuals living with rare diseases in Japan, aiming to support a wide range of rare conditions, including-but not limited to-neuromuscular diseases. RDCJ hosted its inaugural symposium on July 18, 2023, at the Shonan Health Innovation Park. This symposium aimed to address the unique challenges of rare diseases through a collaborative approach involving industry, government, academia, patients, and the community. The event brought together these stakeholders to discuss the current state and future directions of rare disease research and treatment in Japan. The event featured a range of speakers and panel discussions on the state of drug development, patient journeys, and the future of patient-centered healthcare services. Highlights included a keynote on antisense oligonucleotide therapeutics and sessions on patient-centered healthcare, human-centered design in healthcare, and innovative approaches to rare disease treatment. This report provides a detailed overview of the symposium, the key takeaways from each session, and the future directions for RDCJ.

BackgroundSpinal muscular atrophy (SMA) is a severe neurodegenerative disease affecting children. Three innovative disease-modifying therapies (DMTs)-nusinersen, risdiplam, and onasemnogene abeparvovec-are available for treatment.ObjectiveTo provide a descriptive overview of patients enrolled in the Registre SMA France until July 22, 2024.MethodsRegistre SMA France is a multicenter, national observational registry that includes patients with SMA-children and adults, treated or untreated. Data collection began retrospectively in 2016 and prospectively in 2020, with a 10-year follow-up plan. The coordinating center is the neuropediatric department of Garches Hospital (AP-HP), while methodological and, regulatory and operational management, are provided by the Clinical Research Unit of AP-HP Paris-Saclay. Financial support is provided through unrestricted grants from Biogen, Novartis, and Roche. Data on patient characteristics, medical and surgical follow-up, treatments, adverse events, and quality of life are recorded via structured forms, with additional modules developed as required (e.g., hematological monitoring post-gene therapy in 2021). Data quality is ensured through routine checks and periodic monitoring.ResultsBy July 22, 2024, 1299 patients from 59 centers were enrolled (299 SMA1, 502 SMA2, 469 SMA3, 19 SMA4, 10 presymptomatic). Of these, 76.2% received DMT (nusinersen: 46.1%, risdiplam: 23.2%, onasemnogene abeparvovec: 9.2%), with 21.5% undergoing sequential or combination therapy. Major complications included ventilatory support (SMA1: 69.9%, SMA2: 64.5%, SMA3: 18.1%), enteral feeding (SMA1: 56.2%SMA1), and spine surgery (SMA2: 24.5%). Survival was significantly higher in treated SMA1 and SMA2 cases.ConclusionThis registry serves as a key resource for understanding the clinical course and treatment outcomes of SMA in the real world, supporting future research and informing clinical and policy decisions in the era of DMTs.Trial registrationNCT04177134.

BackgroundDynactin 1 (DCTN1) mutations are associated with diverse neurological disorders, including distal hereditary motor neuropathy, Perry syndrome, and amyotrophic lateral sclerosis. This study focused on a family with symptoms resembling spinal and bulbar muscular atrophy, showing severe vocal cord paralysis, to understand DCTN1-related neurological disorders in Koreans.MethodClinical examinations revealed variable phenotypes, such as proximal limb weakness, chronic hypercapnia, and gynecomastia, alongside vocal cord paralysis. Whole-exome sequencing identified a missense mutation, c.1175G > A, in DCTN1. Three more Korean families with the same mutation were analyzed to explore a potential founder effect. Microsatellite analysis indicated a shared haplotype, suggesting a common genetic origin.ResultThis study identified a missense mutation, c.1175G > A, in DCTN1 in the initial family with features resembling spinal and bulbar muscular atrophy. The mutation was also present in three other Korean families, indicating a potential founder effect. Microsatellite analysis confirmed a shared haplotype among these families. Meanwhile, the patients also manifested additional clinical features such as peripheral neuropathy and gynecomastia.ConclusionThis study highlights clinical heterogeneity in Korean patients with DCTN1-associated neurological disorders and identifies a potential founder mutation, c.1175G > A, expanding the clinical spectrum of DCTN1 mutations with clinical features of spinal bulbar muscular atrophy. Understanding such genetic and clinical diversity is crucial for accurate diagnoses and management, with implications for future research and therapeutic strategies.

Background: Epidemiological frequency measures serve as reference point for patients, clinicians, researchers, and policymakers. Previously, we published a comprehensive review of the literature with prevalence and incidence rates for thirty neuromuscular disorders frequently encountered in the neuromuscular clinic. No meta-analyses were available at the time.

Objective: We included various new studies and meta-analyses that have been published since 2014, we aim to update our previous review.

Methods: Pubmed was searched for 'incidence' and 'prevalence' in combination with seventeen acquired and inherited neuromuscular disorders to identify peer-reviewed literature from 1990 to 2023. If multiple prevalence and incidence rates were found, these were summarized by providing the mean, the number of the estimates on which the mean was based and the range of these estimates. Additionally, we searched for meta-analyses to compare the found mean prevalence rates based on the summary of individual studies with the pooled prevalence rates based on the meta-analyses.

Results: The mean prevalence estimates for 17 disorders ranged from 0.3/100,000 population for Lambert-Eaton myasthenic syndrome, glycogenosis type V and nemaline myopathy to 20/100,000 for Charcot-Marie-Tooth disease type I. We found annual incidence rates for eight disorders, ranging from 0.3/100,000 population for progressive (spinal) muscular atrophy and facioscapulohumeral muscular atrophy to 1/100,000 for Charcot-Marie-Tooth disease type 1 and myotonic dystrophy type 1. Plotting the mean prevalence estimates from the current study against the pooled prevalence estimates from eight meta-analyses showed reasonable agreement.

Conclusions: Epidemiological frequencies about neuromuscular diseases- and in particular data on incidence are scarce. The mean prevalence estimates based on recently published studies on individual cohorts correspond well with the findings from the sparingly performed meta-analyses.