Chapter 4 - Mutations affecting muscle nicotinic acetylcholine receptors and their role in congenital myasthenic syndromes

Abstract

Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders that have in common the defective transmission of the signal from nerve to muscle and consequent fatigable muscle weakness. Nerve to muscle transmission depends principally on acetylcholine (ACh) release from the nerve terminal and its reaction with the muscle nicotinic acetylcholine receptor (AChR), a pentameric ligand-gated ion channel. This chapter focuses on the disorders that result from the mutations in the AChR subunit genes and briefly describes CMS that arises from mutations affecting acetylcholinesterase (AChE). The principal clinical congenital myasthenic syndromes involving AChR mutations are AChR deficiency (AChRdef), the slow channel syndrome (SCS), and the low-affinity fast channel syndrome (FCS). Each of these can arise from mutations at a number of different sites, and can show distinctive and electromyographic features. Endplate acetylcholinesterase deficiency (EAD) results from mutations at various sites in the ColQ gene that encodes the collagenlike tail that attaches AChE to the basal laminar at the neuromuscular junction. The chapter illustrates case histories of AChRdef and SCS. The chapter describes the clinical features of AChRdef, SCS, and FCS; their genetics, pathogenesis, and phenotypic consequences of AChR mutations. AChR deficiency is nonprogressive, presents in the first two years of life, responds to anticholinesterase medication, and is caused by heteroallelic or homozygous mutations in the ɛ- subunit including its promoter region. The FCS has a similar phenotype to AChRdef but is much rarer. Mutations at different sites lead to fewer and shorter channel activations. The SCS is progressive; presents in childhood, adolescence, or adult life; and does not respond to anticholinesterase medications.