The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies

Abstract

Purpose of review: Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies.

Recent findings: As next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models.

Summary: Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging.

Box 1

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FIGURE 1

Diagrammatic representation for the sites of action for commonly used drugs for congenital myasthenic syndromes AChE, acetylcholinesterase inhibitors (neostigmine, pyridostigmine); 3,4-DAP, 3,4-diaminopyridine; open channel blockers (quinidine, fluoxetine); β2-ADR agonists, β2-adrenergic receptor agonists (salbutamol, ephedrine). VGCC, voltage-gated calcium channel; VGNC, voltage-gated sodium channel.

FIGURE 2

Pathways of synaptic disassembly and assembly at the neuromuscular junctions. Acetylcholine, released from the nerve terminal following a nerve stimulus, activates acetylcholine receptors. In addition to instructing muscle contraction, acetylcholine receptor activation is thought to disperse the tightly packed acetylcholine receptor away from the nerve terminal, which initiates synaptic disassembly. The agrin-induced acetylcholine receptor clustering pathway promotes synaptic assembly and thus counteracts the negative effect of acetylcholine on synaptic structure. Agrin is released from the nerve terminal, then binds LDL receptor-related protein 4, which activates MUSK and DOK7 and ultimately results in aggregation of postsynaptic acetylcholine receptors and maturation of the synaptic apparatus.