Recent advances in congenital myasthenic syndromes

Congenital myasthenic syndromes ( CMS ) are heterogeneous disorders caused by germline mutations in genes expressed at the neuromuscular junction. Mutations have been identified in 24 genes encoding acetylcholine receptor subunits ( CHRNA 1 , CHRNB 1 , CHRND , CHRNE and CHRNG ), skeletal muscle sodium channel ( SCN 4A ), signaling molecules driving acetylcholine receptor subunits clustering ( AGRN , LRP 4 , MUSK and DOK 7 ), synaptic structural proteins ( COLQ , LAMB 2 and COL 13A1), postsynaptic structural proteins ( RAPSN and PLEC ), presynaptic molecules ( CHAT , SYT 2 ), glycosylation enzymes ( GFPT 1 , DPAGT 1 , ALG 2 , ALG 14 and GMPPB ), and other less characterized molecules ( PREPL and SCL 25A1 ). CMS are recessive disorders, except for slow channel CMS and synaptotagmin 2 (SYT2)‐CMS. Onsets are largely less than 2 years, but adult‐onset is not rare, especially in slow‐channel CMS and limb‐girdle type CMS caused by glycosylation defects and by DOK 7 mutations. Clinical features include fatigable muscle weakness, amyotrophy and minor facial anomalies. Eye, facial and bulbar muscles are frequently affected, but sparing of these muscles is observed, especially in limb‐girdle type CMS . Serum creatine kinase levels are frequently elevated in slow‐channel CMS , glutamine‐fructose‐6‐phosphate aminotransferase 1 (GFPT1)‐ CMS , and guanosine diphosphate mannose pyrophosphorylase B (GMPPB)‐CMS . Electrophysiological findings supporting compromised neuromuscular signal transmission are a prerequisite for diagnosing CMS . Most CMS patients are likely to be underdiagnosed, and recognition of CMS in undiagnosed muscle weakness and/or amyotrophy is critical for diagnosing CMS .