Congenital myasthenic syndromes in a Southeast Asian adult neurology clinic: a long road to diagnosis and therapy

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.