Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Abstract

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.

Keywords: congenital myasthenic syndrome; myopathy; neuromuscular disorder; pathology.

FIGURE 1

Myopathological changes in CMS patients. Patient 1’s biopsy was taken from the left gastrocnemius muscles, and the others were taken from the left biceps brachii muscles. (A) HE staining showing increased fibre size variation and a group of severely atrophic angulated fibres. (B) NADH staining showing multiple and tiny areas of uneven oxidative staining and increased subsarcolemmal activity. (C) ATPase staining (pH 11.0) showing one fascicle composed of type 2 fibres with apparently reduced diameter. (D) HE staining showing increased fibre size variation with perifascicular fibre atrophy and increased endomysial fibrosis. (E) NADH staining showing uneven areas of oxidative reaction in both type 1 and type 2 fibres. (F) APTase staining (pH 11.0) showing type 2 fibre atrophy. (G) HE staining showing the presence of multiple vacuoles with a rim of basophilic material. (H) NADH staining showing multiple hyperintense dotty areas in type 2 fibres corresponding to tubular aggregates. (I) HE staining showing the slightly increased fibre size variation. (J) NADH staining showing multiple hyperintense dotty areas possibly corresponding to tubular aggregates. Scale bar = 50 μm