Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction. Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003). Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic NMJ characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). Genetic Heterogeneity of Congenital Myasthenic Syndromes Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13. CMS5 (603034) is caused by mutation in the COLQ gene (603033) on 3p25; CMS6 (254210) is caused by mutation in the CHAT gene (118490) on 10q; CMS7 (616040) is caused by mutation in the SYT2 gene (600104) on 1q32; CMS8 (615120) is caused by mutation in the AGRN gene (103320) on 1p; CMS9 (616325) is caused by mutation in the MUSK gene (601296) on 9q31; CMS10 (254300) is caused by mutation in the DOK7 gene (610285) on 4p; CMS11 (616326) is caused by mutation in the RAPSN gene (601592) on 11p11; CMS12 (610542) is caused by mutation in the GFPT1 gene (138292) on 2p14; CMS13 (614750) is caused by mutation in the DPAGT1 gene (191350) on 11q23; CMS14 (616228) is caused by mutation in the ALG2 gene (607905) on 9q22; CMS15 (616227) is caused by mutation in the ALG14 gene (612866) on 1p21; CMS16 (614198) is caused by mutation in the SCN4A gene (603967) on 17q; CMS17 (616304) is caused by mutation in the LRP4 gene (604270) on 11p12; CMS18 (616330) is caused by mutation in the SNAP25 gene (600322) on 20p11; CMS19 (616720) is caused by mutation in the COL13A1 gene (120350) on 10q22; CMS20 (617143) is caused by mutation in the SLC5A7 gene (608761) on 2q12; CMS21 (617239) is caused by mutation in the SLC18A3 gene (600336) on 10q11; CMS22 (616224) is caused by mutation in the PREPL gene (609557) on 2p21; CMS23 (618197) is caused by mutation in the SLC25A1 gene (190315) on 22q11; CMS24 (618198) is caused by mutation in the MYO9A gene (604875) on 15q22; and CMS25 (618323) is caused by mutation in the VAMP1 gene (185880) on 12p13.