Myasthenic Syndrome, Congenital, 4b, Fast-Channel

A number sign (#) is used with this entry because of evidence that fast-channel congenital myasthenic syndrome-4B (CMS4B) is caused by homozygous or compound heterozygous mutation in the CHRNE gene (100725) on chromosome 17p13.

Mutation in the CHRNE gene can also cause slow-channel myasthenic syndrome (CMS4A; 605809) and CMS with acetylcholine receptor (AChR) deficiency (CMS4C; 608931).

Description

Fast-channel congenital myasthenic syndrome (FCCMS) 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 abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (summary by Sine et al., 2003 and Engel et al., 2015).

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

Clinical Features

Uchitel et al. (1993) reported a 21-year-old woman with moderately severe myasthenic symptoms since birth who responded poorly to acetylcholinesterase inhibitors. No serum antibodies to the AChR were detected. Electrophysiologic studies showed very small miniature endplate potentials (MEPPs) and currents (MEPCs), but the density and distribution of AChRs in the synapse were normal. Quantal content was also normal, and the junctional folds were intact. Channel conductance studies indicated a kinetic abnormality of the AChR, and the authors postulated a defect in the interaction of ACh with the AChR. In a follow-up study, Ohno et al. (1996) reported favorable response to treatment with 3,4-diaminopyridine, which increases the number of AChR quanta released at the presynaptic membrane by nerve impulses.

Ohno et al. (1996) reported a 4-year-old boy and his younger sister who both had myasthenic symptoms from birth. Both patients had negative tests for anti-AChR antibodies and responded incompletely to anticholinesterase drugs. Electrophysiologic studies showed small MEPPs, normal AChR density, and normal endplate ultrastructure. Patch-clamp studies showed infrequent AChR channel openings, a decrease in channel-opening rate, and resistance to desensitization by ACh. The mean opening bursts of the endplate were shorter than normal, consistent with FCCMS.

Shen et al. (2012) reported an 8-year-old boy, born of consanguineous parents, with fast-channel congenital myasthenic syndrome. The patient, who had severe myasthenic symptoms since birth, was wheelchair-bound. Three similarly affected sibs died in infancy, and he had 1 similarly affected brother.

Inheritance

The transmission pattern of CMS4B in the family reported by Shen et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients with FCCMS, 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene: both patients had a pro121-to-leu change (P121L; 100725.0003), and each patient had a different null mutation (G8R, 100725.0017; S143L, 100725.0018).

In 4 affected patients from 3 unrelated families with FCCMS, Wang et al. (2000) identified a missense mutation in the CHRNE gene (A411P; 100725.0019). The mutation was found in homozygosity in 2 patients and in compound heterozygosity with a null mutation in 2 patients. Functional expression studies showed that the A411P mutation caused an increase in the distribution rates for channel opening and closing, increasing the range of activation kinetics.

In an 8-year-old boy, born of consanguineous parents, with FCCMS, Shen et al. (2012) identified a homozygous missense mutation in the CHRNE gene (W55R; 100725.0021). In vitro functional expression in HEK293 cells showed that the mutant protein was expressed, but patch-clamp recordings indicated 30-fold reduced ACh affinity and 75-fold reduced apparent gating efficiency. The mutation hindered isomerization of the receptor from the closed to the open state, slowed the apparent opening rate, speeded the apparent closing rate, and reduced open channel probability. These altered channel kinetics predicted a short duration and low amplitude of the endplate potential with an inability to activate postsynaptic sodium channels. There was also a low opening probability of the mutant receptor over a range of ACh concentrations, which explained the limited clinical response to pyridostigmine that was observed in this patient.