Congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are caused by genetic defects of molecules expressed at the neuromuscular junction. Mutations identified to date include (1) MuSK, a receptor for neural agrin that plays a pivotal role in formation of the neuromuscular junction, (2) choline acetyltransferase that resynthesizes acetylcholine at the nerve terminal, (3) collagen Q that anchors acetylcholinesterase at the synaptic basal lamina, (4) rapsyn that clusters acetylcholine receptor (AChR) at the endplate, (5) AChR subunits, and (6) skeletal muscle voltage-gated sodium channel (Na _v1.4). Mutations in the AChR subunit genes cause slow-channel syndrome in which channel opening events are prolonged, fast-channel syndrome that is characterized by short channel opening events, and/or endplate AChR deficiency. Slow channel syndrome is an autosomal dominant disorder, whereas the others are all caused by autosomal recessive mutations. Adult-onset cases of CMS are most commonly observed in slow channel syndrome, but are also observed in other types of CMS. CMS are frequently associated with muscle atrophy, and/or mild orofacial anomalies. CMS should be considered in diagnosing not only myasthenia gravis but also other types of myopathies. Low- and high-frequency repetitive nerve stimulations to any patient that exhibits muscle weakness are highly recommended for diagnosing CMS.