The Therapy of Congenital Myasthenic Syndromes

Therapeutic Strategies in Congenital Myasthenic Syndromes

“…Affected are several proteins or enzymes involved in the cascade leading to a normal formation of synapses, and also clustering of AChRs, and the Na v 1.4 channel. [1][2][3][4] The CMS are classified in terms of the located defect: presynaptic, postsynaptic, and synaptic. These are inherited disorders, caused by various genetic defects, and all but the slow-channel CMS by recessive inheritance.…”

“…These are inherited disorders, caused by various genetic defects, and all but the slow-channel CMS by recessive inheritance. [1][2][3][4][5] To date, mutations in 10 different genes have been found to cause a CMS: CHAT, coding for the presynaptic choline acetyltransferase 6 ; COLQ, coding for the endplate acetylcholine esterase 7,8 ; CHRNA1, CHRNB1, CHRND, and CHRNE coding for four different AChR subunits 9,10 ; RAPSN, coding for the postsynaptic protein rapsyn 11 ; MUSK, coding for the muscle-specific kinase 12 ; DOK7, coding for the downstream of kinase 7 protein 13 ; and SCN4A, coding for the postsynaptic voltage-gated sodium channel Na v 1.4. 14…”

“…[1][2][3][4]15 The combination of these symptoms is suggestive for a CMS and calls for further work-up; data of the patient's history, the critical clinical examination, and electrophysiologic studies often disclose clinical clues to diagnosis of a specific CMS (Table 1). 2,3,16 Therapy in CMS depends on the structural defect of the neuromuscular junction and the underlying genetic defect.…”

“…3,4,13,15,[17][18][19][20][21] Although there are no double-blind, placebo-controlled clinical trials for CMS, several drugs have shown convincingly positive clinical effects.…”

“…The safety margin of the neuromuscular transmission is a function of the difference between the depolarization caused by the endplate potential and the depolarization necessary to activate Na v 1.4. This complex cascade, which is induced by a single nerve impulse, depends on normal and orchestrated activity of all pre-and postsynaptic steps. [1][2][3][4] The most important disorders affecting the neuromuscular junction are autoimmune-induced myasthenia gravis (in most cases caused by antibodies against the AChR, or the muscle-specific tyrosine kinase receptor [MuSK]) and the growing number of congenital myasthenic syndromes (CMS). This review addresses therapeutic strategies in CMS.…”