先天性ミオパチー

Congenital disorders of glycosylation (CDGs) are rare metabolic diseases characterized by clinical heterogeneity, yet the molecular basis for their tissue-specific manifestations remains poorly understood. Because affected tissues are rarely accessible for biopsy, the baseline transcriptional and regulatory landscape of CDG-causative genes in healthy human tissues offers a valuable, complementary perspective on tissue vulnerability. Here, we performed an in silico study of the expression, allelic regulation, expression quantitative trait loci (eQTLs), and associations with immune cell compositions of 12 CDG-causative genes across healthy human tissues using multi-omics datasets from the Adult GTEx project. The selected panel includes the most prevalent multisystem CDGs (PMM2-, ALG6-, ALG1-, SLC35A2-, ALG13-, SRD5A3-, MAN1B1-, DPAGT1-CDG), three immune-relevant CDGs classified as inborn errors of immunity (MOGS-, PGM3-, VPS13B-CDG), and the autosomal recessive form of GNE-CDG (GNE-CDG (ar); GNE myopathy) as a tissue-restricted contrast. CDG-causative genes were broadly but heterogeneously expressed, with substantial inter-individual variation. Tissues frequently affected in the corresponding disorders did not consistently display the highest baseline gene expression, underscoring that higher gene expression alone is a poor indicator of tissue susceptibility. Allele-specific analyses revealed five distinct allelic expression patterns across individuals and identified tissue-specific deviations from balanced biallelic expression for several genes, most notably SRD5A3, PGM3, VPS13B, and GNE. Tissue-specific eQTLs affecting CDG genes were frequently located in intronic enhancers of unrelated genes or intergenic regions, revealing a complex, predominantly distal regulatory architecture. Several eQTLs overlapped GWAS Catalog traits and ClinVar entries relevant to the corresponding CDG phenotypes, including PMM2 eQTLs associated with reduced PMM2 gene levels. Finally, correlations between CDG-causative gene expression and immune cell composition recapitulated known immune phenotypes from blood and suggested additional tissue-dependent roles for glycosylation in immune modulation, that warrant functional validation. Together, these findings demonstrate that CDG-causative genes operate within diverse transcriptional, allelic, and regulatory contexts across human tissues. Our in silico framework provides an interpretable candidates and foundational reference for interpreting tissue vulnerability in CDG and underscore the need for global analyses to fully understand organ-specific disease mechanisms.

BACKGROUND: Congenital myasthenic syndromes (CMS) are rare genetic disorders caused by pathogenic variants in proteins expressed at the neuromuscular junction. Current literature surrounding adult CMS patients remains limited, primarily derived from Western cohorts. METHODS: We present a Southeast Asian cohort of adult patients with a clinical diagnosis of CMS who were evaluated at a tertiary neuromuscular referral center. Patients with seronegative myasthenic syndrome who did not respond to immunotherapy were suspected of having CMS and underwent genetic testing. Patients with possible inherited myopathy also underwent comprehensive genetic testing which included genes for myopathies and CMS. Patient demographics and clinical features were recorded and analyzed retrospectively. Electrodiagnostic features, autoantibodies, and molecular testing (where available) were also reported. RESULTS: From a single-center neuromuscular disease cohort of 639 adult patients, we identified seven (1.1%) patients with a clinical diagnosis of CMS. Four (57%) had onset of symptoms in adulthood, of whom two manifested in late adulthood. Six were initially misdiagnosed with seronegative myasthenia gravis or congenital myopathy. A genetic diagnosis was achieved in five (71.4%) patients with a median diagnostic delay of 17.8 years (range 1-38 years). Three patients from two families were identified to have COLQ-CMS, one patient with CHRNE-CMS, and one patient with CHRNA1-CMS. Two patients with COLQ-CMS had a multiphasic clinical course; one had no clear precipitants for her exacerbations. We reclassified two variants, COLQ(NM_005677.4): c.1352G > A p.Cys451Tyr and CHRNA1(NM_000079.4):c.823G > A p.Val275Met as likely pathogenic based on the American College of Medical Genetics criteria. We present an algorithm, based on our institution's experience, which may be helpful to facilitate the diagnosis of CMS in clinical practice. CONCLUSIONS: CMS is rare and challenging to diagnose in the adult neurology setting. We present a Southeast Asian cohort of seven adult patients with CMS and discuss their clinical and genotypic features.

CASE: A 4-year-old girl with bilateral arthrogrypotic clubfoot underwent posterior release with bilateral V-Y advancement flaps. At 4 months, the patient ambulated independently over moderate distances. One-year follow-up confirmed pain-free functional ambulation, although persistent toe-walking highlighted ongoing neuromuscular challenges and minor correction loss. CONCLUSION: V-Y advancement flaps provide effective soft tissue coverage after posterior release for arthrogrypotic clubfoot. Early multidisciplinary collaboration integrating orthopedic and plastic surgical planning is essential for optimizing outcomes.

LMNA-associated congenital muscular dystrophy is a currently incurable rare genetic disorder characterized by early-onset muscle weakness, dilated cardiomyopathy, and respiratory failure, resulting from mutations in the LMNA gene. In this study, we assessed the potential of a CRISPR-mediated strategy to eliminate the mutant allele Lmna c.745C>T, p.R249W using a mutation-specific guide (sg745T). Results from R249W-mutation-carrying cellular models showed specific activity of the Cas9/sg745T complex toward the mutant allele. This property varied depending on the concentration of CRISPR components, with a loss of specificity observed with increased dosage. We tested this strategy in vivo using adeno-associated virus delivery in Lmna R249W mice. Despite being associated with a modest CRISPR activity, this therapeutic approach led to a 10% (non-significant) increase in the survival of R249W homozygous mice. Interestingly, a comparable CRISPR activity significantly ameliorated the cardiac pathology observed in Lmna +/R249W animals, resulting in a significant 24.3% extension of their median survival. These results represent the first therapeutic validation of a CRISPR-Cas9-mediated gene editing strategy for the treatment of LMNA-associated congenital muscular dystrophy.

Myopathy with extrapyramidal signs (OMIM #615673) is a rare autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in Mitochondrial calcium uptake protein 1 (MICU1), which encodes the gatekeeper of the mitochondrial calcium uniporter complex. We report a 7-year-old Indian girl with global developmental delay, congenital nonfatiguable right ptosis, proximal-predominant myopathy without calf hypertrophy, multi-system dysmorphism (elongated facies, baggy cheeks, large prominent ears, partial webbed neck, bilateral clinodactyly, fetal finger pads, pes planus, and sandal gap), and thickened corpus callosum on magnetic resonance imaging. Creatine kinase ranged between 4068 and 4732 U/L; electromyography demonstrated a myogenic pattern with normal nerve conduction and nondecremental repetitive nerve stimulation. Whole-exome sequencing identified a novel homozygous missense variant, c.38T>C (p.Leu13Pro), in exon 1 of MICU1, classified as a variant of uncertain significance. To our knowledge, this is the first reported pediatric MICU1 case with congenital ptosis, absence of calf hypertrophy, and a structural corpus callosum abnormality, substantially broadening the phenotypic spectrum of MICU1-related myopathy.