Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review

Int J Mol Sci. 2023 Feb 13;24(4):3730. doi: 10.3390/ijms24043730.

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

Keywords: amifampridine; cholinesterase inhibitors; congenital myasthenic syndromes; ephedrine; muscle nicotinic acetylcholine receptor; neuromuscular junction; salbutamol (albuterol).

Publication types

  • Review

MeSH terms

  • Albuterol
  • Amifampridine
  • Cholinesterase Inhibitors
  • Humans
  • Mitochondrial Proteins / genetics
  • Mutation
  • Myasthenic Syndromes, Congenital* / genetics
  • Myasthenic Syndromes, Congenital* / pathology
  • NAV1.4 Voltage-Gated Sodium Channel / genetics
  • Neuromuscular Junction / pathology
  • Receptors, Cholinergic / genetics
  • Symporters* / genetics
  • Synaptic Transmission

Substances

  • Albuterol
  • Amifampridine
  • Cholinesterase Inhibitors
  • CHRND protein, human
  • Mitochondrial Proteins
  • MYO9A protein, human
  • NAV1.4 Voltage-Gated Sodium Channel
  • Receptors, Cholinergic
  • SCN4A protein, human
  • Slc25a1 protein, human
  • SLC5A7 protein, human
  • Symporters