Myasthenic Syndrome, Congenital, 9, Associated With Acetylcholine Receptor Deficiency

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-9 (CMS9) associated with acetylcholine receptor (AChR) deficiency is caused by homozygous or compound heterozygous mutation in the MUSK gene (601296), which is critical for synaptic differentiation, on chromosome 9q31.

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. Patients may show a favorable response to amifampridine (summary by Engel et al., 2015).

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

Clinical Features

Chevessier et al. (2004) reported a 27-year-old French woman with congenital myasthenic syndrome. Her similarly affected brother died at 1.5 years of age. Muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the NMJ and severe decreases in CHRNE (100725) and MUSK expression.

Mihaylova et al. (2009) reported 5 sibs, born of consanguineous Sudanese parents, with congenital myasthenic syndrome. Between ages 1 and 3 years, all patients were noted to have ptosis and easy fatigability when walking long distances. At the time of the report, the patients ranged in age from 9 to 20 years. Features included ophthalmoparesis, mild facial weakness, Gowers sign, and proximal muscle weakness in the upper and lower limbs. One patient had a waddling gait, and 2 had lordosis. One patient experienced respiratory insufficiency at age 20.

Maselli et al. (2010) reported a 19-year-old woman with severe CMS. She had been born full-term to nonconsanguineous parents. She was hypotonic at birth, and during the first month of life, she experienced respiratory failure that required tracheotomy and mechanical ventilation. While weakness continued throughout infancy, no motor milestones were delayed. She underwent corrective surgery for patent ductus arteriosus at age 2. Respiratory infections were recurrent. She underwent surgery for severe scoliosis at age 12. Neurologic examination revealed normal cognition, bilateral ptosis, and intact external ocular movements except for mild reduction of upward gaze. She had facial, bulbar, neck, and proximal limb weakness with intact deep tendon reflexes, and required continuous respiratory support with positive airway pressure during night sleep. Intracellular microelectrode recordings and microscopy studies of the NMJ in a muscle biopsy revealed decreased MEPPs, reduced endplate size, and simplification of secondary synaptic folds, consistent with a postsynaptic deficit. consistent with additional presynaptic failure.

Molecular Genetics

In a 27-year-old French woman with CMS, Chevessier et al. (2004) identified compound heterozygosity for mutations in the MUSK gene (601296.0001 and 601296.0002).

In 5 sibs, born of consanguineous Sudanese parents, with CMS, Mihaylova et al. (2009) identified a homozygous missense mutation in the MUSK gene (P344R; 601296.0003).

In a 19-year-old woman with CMS9, Maselli et al. (2010) identified compound heterozygous missense mutations in the MUSK gene (M605I, 601296.0004 and A727V, 601296.0005). Expression studies in mouse Musk-deficient myotubes revealed that A727V caused severe impairment of agrin (AGRN; 103320)-dependent Musk phosphorylation, aggregation of AChRs, and interaction of Musk with Dok7 (610285). In contrast, M605I resulted in only moderate impairment of agrin-dependent Musk phosphorylation, aggregation of AChRs, and interaction of Musk with Dok7.