Chapter 26 - Congenital Myasthenic Syndromes

Abstract

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, morphologic, and molecular genetic studies have paved the way for defining phenotypic features of the different syndromes, identifying disease genes and proteins, and recommending appropriate therapy. Disease proteins reside in the nerve terminal, the synaptic basal lamina, or the postsynaptic region of the neuromuscular junction, or are distributed in many tissues including the junction. Those identified to date include choline acetyltransferase, the endplate species of acetylcholinesterase β2-laminin, each subunit of the acetylcholine receptor, rapsyn, plectin, Nav1.4, MuSK, agrin, Dok-7, GFPT1, DPAGT1, ALG2, and ALG14. Analyses of properties of expressed mutant proteins contribute to finding improved therapy for most CMS. Despite these advances, the molecular basis of some phenotypically characterized CMS remains elusive. Moreover, other types of CMS and disease genes likely exist and await discovery.