A homozygous mutation in GMPPB leads to centronuclear myopathy with combined pre- and postsynaptic defects of neuromuscular transmission.

Mutations in GMPPB cause a wide spectrum of neuromuscular syndromes, including muscular dystrophies and congenital myasthenic syndrome. The mechanisms by which GMPPB mutations impair neuromuscular transmission however remain incompletely understood. We expand here upon a previous report of one such patient presenting with a myopathy-congenital myasthenic syndrome overlap phenotype. Fatigable proximal muscle weakness developed gradually between 13 and 25 years of age, with subsequent stabilization. Low-frequency repetitive nerve stimulation showed a decrement, while a muscle biopsy demonstrated the presence of a centronuclear myopathy. Genetic testing identified a homozygous c.458C > T (p.Thr153Ile) variant in GMPPB. In-vitro microelectrode recordings and ultrastructural studies showed impairment of both pre- and postsynaptic neuromuscular transmission, thus demonstrating the presence of not only postsynaptic, but also presynaptic pathology in GMPPB-related disorders.