先天性筋無力症候群

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.

The vesicular acetylcholine transporter knockdown (VAChT-KD) mouse is a genetic model of congenital myasthenic syndrome (CMS) characterized by impaired cholinergic transmission at the neuromuscular junction, resulting in presynaptic neuromuscular dysfunction. Here, we performed a longitudinal behavioral analysis to determine the onset and progression of motor deficits across development and adulthood, including potential sex-dependent effects. VAChT-KD mice exhibited early and persistent motor impairments. Neonatal animals showed reduced strength, impaired coordination, and delayed motor development compared to controls, and these deficits persisted into adulthood. Motor performance was consistently impaired in tests of global strength, while other behavioral measures revealed age- and sex-dependent differences. Notably, repeated exposure to motor tasks improved performance in mutant mice, indicating a learning component that partially compensates for underlying deficits. Across behavioral paradigms, genotype and age emerged as the primary determinants of motor performance. Importantly, the identification of early disease onset and measurable functional deficits across development highlights a critical window for therapeutic intervention. These findings support the use of VAChT-KD mice as a translational platform for testing early-stage therapies and underscore the importance of considering behavioral adaptation when designing preclinical studies for neuromuscular disorders.

Purine-rich element-binding protein A (PURA) syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the PURA gene and is characterized by neonatal hypotonia, feeding difficulty, respiratory dysregulation, and severe developmental impairment. The PURA gene has recently been identified as a cause of congenital myasthenic syndrome. We report two unrelated infants with genetically confirmed PURA syndrome who were treated with neuromuscular junction-directed therapy and reviewed three additional published cases. All five patients had neonatal hypotonia and apnea or respiratory failure requiring respiratory support. Pyridostigmine was used in four of the five infants included with heterogeneous response, while salbutamol, used in three patients, was associated with clinical benefit in all. These findings suggest that neuromuscular junction dysfunction may contribute to the respiratory and motor phenotype in patients with PURA syndrome. Early consideration of salbutamol, with careful monitoring and objective outcome measurement, may help stabilize severe infantile respiratory failure and improve motor function.

Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to glycosylation of a wide array of proteins. Biallelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants as well as missense variants from the individuals reported in this study. Investigations of the Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a Bona fide CDG. These findings may guide evaluation of future individuals with suspected ALG14-CDG and future targeted therapeutics such as those being used in other CDG.

Urinary dysfunction has been reported in association with myasthenic syndromes, including myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS), but evidence regarding its prevalence, clinical impact, pathophysiology, and management remains limited. This scoping review synthesizes the available evidence on urinary symptoms, diagnostic approaches, pathophysiological features, treatment-related associations, and sex-specific findings in these disorders. A literature search was conducted in PubMed, LIVIVO, Epistemonikos, and the Cochrane Library in accordance with PRISMA guidelines. Of 774 records identified, eight studies met the inclusion criteria, comprising two case reports, three case-control studies, one prospective study, and two retrospective observational studies. Seven studies addressed MG and one addressed LEMS; no eligible studies were identified for CMS. Reported urinary symptoms were predominantly storage lower urinary tract symptoms (LUTS), including urinary incontinence, urgency, nocturia, and increased frequency, whereas voiding and bladder-emptying abnormalities were described less consistently. Diagnostic approaches were heterogeneous and included questionnaires, clinical examination, urodynamic testing, imaging, and autonomic assessments. Proposed mechanisms remain uncertain, with limited evidence supporting contributions from pelvic floor weakness, autonomic dysfunction, and cholinesterase inhibitor exposure. Treatment-related associations were largely observational and most consistently implicated pyridostigmine in symptom worsening, while evidence for specific treatment of urinary symptoms was sparse. Sex-specific analyses were limited and did not identify consistent sex-related patterns. Current evidence indicates that urinary symptoms have been reported in myasthenic syndromes and have been associated with reduced quality of life in the included studies, but the available data remain insufficient to define prevalence, mechanisms, or optimal management.