Congenital myasthenic syndromes (CMS) represent a heterogeneous group of disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region of the motor endplate. The disease proteins identified to date include the acetylcholine receptor, acetylcholinesterase, choline acetyltransferase, rapsyn, and Na(v)1.4, muscle-specific kinase, agrin, β2-laminin, downstream of tyrosine kinase 7, and glutamine-fructose-6-phosphate transaminase 1. Analysis of electrophysiologic and biochemical properties of mutant proteins expressed in heterologous systems have contributed crucially to defining the molecular consequences of the observed mutations and have resulted in improved therapy of most CMS.
"Congenital myasthenic syndromes (CMS) comprise a group of hereditary disorders characterized by a neuromuscular transmission defect. In recent years, disease-associated mutations have been identified in several genes that encode different presynaptic, synaptic, and postsynaptic proteins of the neuromuscular junction   . Postsynaptic CMS caused by mutations identified in RAPSN, DOK7, AGRN, and MUSK further underlined the key role of the agrin–MuSK–rapsyn pathway for the organization and maintenance of the postsynaptic scaffold   . "
[Show abstract][Hide abstract] ABSTRACT: Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders characterized by a neuromuscular transmission defect. In recent years, causative mutations have been identified in atleast 15 genes encoding proteins of the neuromuscular junction. Mutations in MUSK are known as a very rare genetic cause of CMS and have been described in only three families, world-wide. Consequently, the knowledge about efficient drug therapy is very limited. We identified a novel missense mutation (p.Asp38Glu) heteroallelic to a genomic deletion affecting exons 2-3 of MUSK as cause of a limb-girdle CMS in two brothers of Turkish origin. Clinical symptoms included fatigable limb weakness from early childhood on. Upon diagnosis of a MUSK-related CMS at the age of 16 and 13years, respectively, treatment with salbutamol was initiated leading to an impressive improvement of clinical symptoms, while treatment with esterase inhibitors did not show any benefit. Our findings highlight the importance of a molecular diagnosis in CMS and demonstrate considerable similarities between patients with MUSK and DOK7-related CMS in terms of clinical phenotype and treatment options.
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