遠位型ミオパチー

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: Agrin-congenital myasthenic syndrome (AGRN-CMS) is a rare, heterogeneous genetic disorder of the neuromuscular transmission that can present from infancy to adulthood. The clinical phenotype includes distal weakness mimicking distal myopathies. Additionally, electromyography and muscle biopsy may demonstrate myopathic features, increasing the diagnostic challenge. Mitochondrial dysfunction has not been reported in the muscle of AGRN-CMS patients. METHODS: We report the clinical, electrophysiological, radiological, myopathological, and genetic findings of a patient with AGRN-CMS. RESULTS: A 47-year-old male presented at age 18 with sudden onset of eyelid ptosis, weakness, and fatigue, followed by dysphagia, dyspnea on exertion, exercise intolerance, and myalgias. Three sisters had similar symptoms. Neurological examination showed lower limb weakness, predominantly affecting the calf muscles with associated atrophy. Tendon reflexes were normal but absent at the ankles. Creatine kinase levels were normal. Electromyography demonstrated myopathic changes in distal muscles with fibrillation potentials in the gastrocnemius. 2 Hz-Repetitive nerve stimulation of the fibular nerve revealed a 32% decrement in the extensor digitorum brevis without facilitation. Tibialis anterior biopsy showed non-specific myopathic changes, neurogenic features, and histological evidence of mitochondrial dysfunction, as suggested by the scattered cytochrome c oxidase-negative fibers. Whole exome sequencing detected a homozygous pathogenic AGRN variant (c.5012G>A, p.Arg1671Gln). No pathogenic or suspected pathogenic variants were detected in muscle mitochondrial DNA or in nuclear genes affecting mitochondrial function. CONCLUSIONS: This patient expands the pathological spectrum of AGRN-CMS to include mitochondrial dysfunction and highlights the importance of low-frequency repetitive nerve stimulation in the assessment of patients with distal weakness for differentiating myopathies from CMS.

Arthrogryposis multiplex congenita (AMC) is a diverse group of conditions characterized by multiple joint contractures. Although individually rare, these disorders are estimated to affect 1 in 3000-5000 live births. Their common pathophysiological mechanism is fetal akinesia, a sustained reduction of fetal movement that may arise from intrinsic disturbances-such as central nervous system malformations, motor neuronopathies, neuropathies, neuromuscular junction defects, congenital myopathies, muscular dystrophies, or metabolic diseases-or from extrinsic factors including uterine constraint, maternal illness, infections, or toxic exposures. Reduced fetal motion leads to relatively uniform clinical manifestations, known as the fetal akinesia deformation sequence (FADS), which is characterized by craniofacial anomalies, pulmonary hypoplasia, growth restriction, and contractures. Currently, AMC is classified by clinical features, such as distal arthrogryposis or lethal congenital contracture syndromes. However, advances in molecular genetics have shown wide variability among conditions classified into the same category. Prognosis is widely variable, ranging from lethal perinatal forms to non-progressive mild conditions. This review discusses AMC etiologies from a topographic standpoint, considering the different levels of the motor system involved, by combining current clinical, genetic, and pathophysiological information.

BackgroundDistal myopathies (DMs) comprise a heterogeneous group of hereditary muscle diseases characterized by predominant distal muscle weakness and atrophy overlapping with hereditary neuropathies, leading to diagnostic delays or misclassification.ResultsWe conducted a retrospective analysis of 125 patients from 103 families with DMs revealed at a federal genetics referral center in Russia from 2010 to 2025, representing the largest Russian DM cohort. Causative variants were identified in 20 genes, most commonly in the GNE (30.1%), DYSF (13.6%), and TTN (9.7%) genes. Although distal muscle involvement predominated, lower limb muscle magnetic resonance imaging (MRI) showed proximal involvement in 93.4% (71/76) of cases regardless of disease stage. Across the cohort, gracilis, rectus femoris, and tibialis posterior were relatively spared. Referral misdiagnosis as hereditary neuropathy occurred in 32.8% (41/125) of cases. To characterize diagnostic pitfalls, we compared patients initially referred with neuropathy to those referred with DM. We demonstrated that group differences were evident solely in the needle electromyography (EMG) reports, while clinical features and lower limb muscle MRI data were broadly comparable. We analyzed the probable causes of EMG misinterpretations, which most commonly included severe spontaneous activity being mistaken for active denervation, high-amplitude motor unit potentials being misclassified as neurogenic, and, in some cases, the wrong choice of muscle for the study.ConclusionAccording to our data, one-third of patients with DM were initially referred for suspected neuropathy. In many cases, misclassification was likely due to pitfalls in EMG interpretation, highlighting the need for careful EMG analysis in patients with myopathies.