Myasthenic Syndrome, Congenital, 1b, Fast-Channel

A number sign (#) is used with this entry because of evidence that fast-channel congenital myasthenic syndrome-1B (CMS1B) is caused by mutation in the CHRNA1 gene (100690) on chromosome 2q31. Most patients have compound heterozygous mutations, although heterozygous mutations have rarely been reported.

Mutation in the CHRNA1 gene can also cause slow-channel myasthenic syndrome (CMS1A; 601462).

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 acetylcholine receptor (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

Wang et al. (1999) reported 2 brothers with fast-channel CMS. The proband had weakness of the ocular muscles since birth, abnormal fatigability since early childhood, and moderate muscle weakness of the facial, neck, trunk, and limb muscles. EMG showed decremental motor responses, and he responded well to acetylcholinesterase inhibitors and 3,4-diaminopyridine.

Shen et al. (2003) reported a 4-year-old girl who had life-threatening myasthenic symptoms since birth, requiring frequent ventilatory support. She could not hold her head erect, stand, or walk. She had marked eyelid ptosis and facial diplegia, was unable to close her mouth, and could not speak or swallow. Studies of the muscle endplate showed normal amounts and localization of acetylcholinesterase and AChR with preservation of the structural integrity and junctional folds. Electrophysiologic studies showed decremental response to repetitive stimulation and extremely low amplitudes of the miniature endplate potential (MEPP) and current (MEPC). The patient showed a partial response to anticholinesterase drugs and 3,4-diaminopyridine.

Masuda et al. (2008) reported an 18-year-old woman with autosomal recessive inheritance of FCCMS. She had severe symptoms since birth and showed partial response to anticholinesterase medications and 3,4-diaminopyridine. Skeletal muscle biopsy showed reduced numbers of AChRs per endplate (about 20% of normal) and simple postsynaptic regions at nerve terminals. Electron microscopic studies showed a marked decrease in the density and distribution of AChR on the junctional folds. The amplitude of MEPPs was reduced to 23% of normal, and the number of quanta released by nerve impulse was normal. The findings were consistent with mild shortening of the channel-opening events. Heterozygous carriers in the family were unaffected.

Inheritance

The transmission pattern of CMS1B in the family reported by Wang et al. (1999) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 brothers with fast-channel CMS, Wang et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNA1 gene (V285I, 100690.0007 and F233V, 100690.0008).

In a girl with severe FCCMS, Shen et al. (2003) identified compound heterozygosity for 2 mutations in the CHRNA1 gene (V132L, 100690.0010 and a 1-bp deletion, 100690.0011). Functional kinetic expression studies showed that the channels with the V132L mutation had an increased dissociation constant for ACh, decreased ACh binding affinity, shorter burst duration, and resistance to desensitization, culminating in a reduced probability of channel opening over a range of ACh concentrations.

In a patient with FCCMS first reported by Vincent et al. (1981), Webster et al. (2004) identified a heterozygous mutation in the CHRNA1 gene (F526L; 100690.0009). The case was a rare example of autosomal dominant transmission.

In a young woman with symptoms of FCCMS since birth, Masuda et al. (2008) identified compound heterozygous mutations in the CHRNA1 gene (100690.0015 and 100690.0016).