Myasthenic Syndrome, Congenital, 3b, Fast-Channel

A number sign (#) is used with this entry because of evidence that fast-channel congenital myasthenic syndrome-3B (CMS3B) is caused by homozygous or compound heterozygous mutation in the CHRND gene (100720) on chromosome 2q37.

Mutation in the CHRND gene can also cause slow-channel congenital myasthenic syndrome (CMS3A; 616321) and congenital myasthenic syndrome associated with acetylcholine receptor (AChR) deficiency (CMS3C; 616323).

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 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

Brownlow et al. (2001) reported a 6-year-old girl who showed decreased fetal movements and was born with CMS and congenital contractures of both hands. She showed breathing and eating difficulties soon after birth and had mildly delayed walking. At age 6, while on pyridostigmine, she had ptosis, limitation of eye movements, intermittent swallowing difficulty, and fatigable muscle weakness of the upper and lower limbs. Single-fiber EMG showed increased jitter with blocking. A brother had reduced fetal movements and hand contractures, and died at age 5 months.

Shen et al. (2002) reported 3 Saudi Arabian patients with FCCMS. All 3 patients came from consanguineous unions, and 2 of the patients were first cousins. Three similarly affected sibs died in infancy from muscle weakness and respiratory complications. The disease course of all 3 patients was similar, with neonatal hypotonia, weak cry, respiratory difficulties, and poor feeding. Later, easy fatigability was noticed, as well as ptosis, ophthalmoplegia, facial weakness, and weakness of the neck flexor muscles. One patient had a high-arched palate, micrognathia, and large ears. EMG showed decremental muscle action potential responses to stimulation and small miniature endplate potential (MEPP) and current (MEPC). Muscle biopsy revealed type 2 fiber atrophy, a reduced number of AChRs, increased numbers of endplate regions, and preserved junctional structure. Functional studies showed abnormally brief AChR-induced ion channel-opening events.

Shen et al. (2008) reported a 20-year-old woman with moderately severe to severe myasthenic symptoms since birth, no anti-AChR antibodies, and a decremental compound muscle action potential (CMAP) response on repetitive stimulation. She responded poorly to pyridostigmine alone, but improved markedly after the addition of 3,4-diaminopyridine. A similarly affected sibling died at age 11 months. There was decreased expression of the AChR at the endplate, with numerous and small endplate regions. Electrophysiologic studies showed decreased MEPP and MEPC amplitudes. Shen et al. (2008) concluded that the safety margin of neuromuscular transmission was compromised by the combined effects of endplate AChR deficiency, altered endplate geometry, reduced opening probability of the available AChRs, and abnormally fast decay of the synaptic current.

Inheritance

The transmission pattern of CMS3B in the families reported by Shen et al. (2002) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with FCCMS, Brownlow et al. (2001) identified compound heterozygosity for 2 mutations in the CHRND gene: a glu59-to-lys substitution (E59K; 100720.0003) and a null mutation (100720.0004).

In 3 Saudi Arabian patients with FCCMS, Shen et al. (2002) identified a homozygous missense mutation in the CHRND gene (P250Q; 100720.0002). In vitro functional expression studies showed that the opening burst duration of the AChR was decreased and that disassociation of ACh was increased, resulting in brief channel-opening episodes.

In a 20-year-old woman with CMS3B, Shen et al. (2008) identified compound heterozygosity for 2 missense mutations in the CHRND gene (L42P, 100720.0008 and I58K, 100720.0009). In vitro functional expression studies showed that the I58K substitution prevented expression of the delta subunit and was a null mutation. The L42P substitution resulted in reduced gating efficiency, slower opening of the channel, and decreased probability that the channel would open in response to ACh. Further studies showed that the L42P-mutant protein altered the intersubunit linkage of the adjacent delta subunit asn41 with the juxtaposed alpha subunit (CHRNA1; 100690) residue tyr127.