Congenital myasthenic syndromes

© Springer International Publishing AG, part of Springer Nature 2018. Congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission. Fetal manifestations (hydramnios and arthrogryposis) are sometimes present. The onset occurs usually during the neonatal period but sometimes also in childhood, adolescence, or even adulthood. CMS are characterized by muscle weakness affecting the axial and limb muscles (hypotonia), the ocular muscles (ptosis and ophthalmoplegia), and the facial and bulbar muscles (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. Severe forms are associated with respiratory disease. The diagnostic strategy involves two steps: (1) establishing the diagnosis of a CMS based on its familial occurrence and early onset and (2) identifying the physiopathological type of disease on the basis of the mode of transmission, by detecting a repetitive CMAP after single stimulation upon EMG (characteristic of acetylcholinesterase deficiency and slow-channel syndrome), the response to anticholinesterases, studies of endplate morphology, and molecular analysis. The most frequent forms are postsynaptic CMS, which are caused by mutations leading to reduced amount, or, more rarely, kinetic anomalies of the acetylcholine receptor (slow-channel syndrome and fast-channel syndrome), or by mutations in the RAPSN, MuSK, SCN4A sodium channel, and DOK7 genes (Table 45.1).