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

Neuromuscul Disord. 2019 Aug;29(8):614-617. doi: 10.1016/j.nmd.2019.07.001. Epub 2019 Jul 5.

Abstract

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.

Keywords: Centronuclear myopathy; Congenital myasthenic syndrome; GMPPB; Glycosylation; Neuromuscular junction.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Guanosine Diphosphate Mannose / genetics*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Myasthenic Syndromes, Congenital / diagnosis
  • Myasthenic Syndromes, Congenital / genetics*
  • Myasthenic Syndromes, Congenital / physiopathology
  • Myopathies, Structural, Congenital / diagnosis
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / physiopathology

Substances

  • Guanosine Diphosphate Mannose