Myasthenic Syndrome, Congenital, 3c, Associated With Acetylcholine Receptor Deficiency

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-3C (CMS3C) associated with acetylcholine receptor (AChR) deficiency is caused by compound heterozygous mutation in the CHRND gene (100720) on chromosome 2q37. One such patient has been reported.

Mutation in the CHRND gene can also cause slow-channel congenital myasthenic syndrome (CMS3A; 616321) and fast-channel congenital myasthenic syndrome (CMS3B; 616322).

Description

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. Treatment with acetylcholinesterase inhibitors or amifampridine may be helpful (summary by Engel et al., 2015).

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

Clinical Features

Muller et al. (2006) reported a 7-year-old German boy with early-onset congenital myasthenic syndrome. He presented at birth with a high-arched palate and difficulty feeding. Additional features included intermittent ptosis, facial weakness, hypotonia, and moderately delayed motor development. During a viral infection, he developed respiratory insufficiency requiring assisted ventilation. Electrophysiologic studies showed a decremental response to repetitive stimulation. Treatment with pyridostigmine resulted in clinical improvement. At age 7, he had mild exercise-induced generalized limb muscle weakness predominantly affecting the proximal muscles as well as mild facial muscle weakness. Muscle biopsy from the patient was not available.

Inheritance

The transmission pattern of CMS3C in the family reported by Muller et al. (2006) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a German boy with CMS3C, Muller et al. (2006) identified compound heterozygosity for a missense mutation (E381K; 100720.0010) and an intragenic deletion (100720.0011) in the CHRND gene. In vitro functional expression studies in HEK293 cells showed that the E381K mutation resulted in decreased expression of the AChR at the cell surface (about 70% of wildtype). The mutant protein impaired normal clustering of the AChR channel with rapsyn (RAPSN; 601592), which stabilizes the AChR at the cell surface.