Myasthenic Syndrome, Congenital, 3a, Slow-Channel

A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-3A (CMS3A) is caused by heterozygous mutation in the CHRND gene (100720) on chromosome 2q37. One such patient has been reported.

Mutation in the CHRND gene can also cause fast-channel congenital myasthenic syndrome (CMS3B; 616322) and CMS with acetylcholine receptor (AChR) deficiency (CMS3C; 616323).

Description

Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from 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).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

Gomez et al. (2002) reported a patient who, at 1 month of age, was 'floppy' with poor head control. He also had ptosis and difficulty chewing and swallowing. He had delayed motor development due to muscle weakness and became wheelchair-bound at age 9 years. He had 2 episodes of respiratory insufficiency due to muscle weakness. Electrophysiologic studies showed reduced amplitudes of the miniature endplate potential (MEPP) and current (MECP), repetitive discharges in response to a single nerve stimulus, decremental response to repetitive nerve stimulation, and evidence of prolonged endplate potentials. The findings were consistent with SCCMS. Pathologic studies showed that the number of AChRs at the endplate was not reduced compared to controls. However, serial ultrastructural studies performed at ages 16 months, 9 years, and 15 years showed increasing abnormalities of the NMJ, including shrunken nerve terminals, widened synaptic clefts, and amorphous debris in the clefts, resulting in loss of efficacy of released neurotransmitter and reduced safety factor.

Molecular Genetics

In a patient with SCCMS, Gomez et al. (2002) identified a de novo heterozygous missense mutation in the CHRND gene (S268F; 100720.0001). Functional expression studies showed that the mutation caused delayed closure of AChR ion channels, increasing the propensity for open-channel block, as well as a reduced rate of channel opening. Gomez et al. (2002) suggested that the observations were consistent with steric hindrance on the channel, introduced by the large mutant phenylalanine residue in place of the wildtype serine.