Myasthenic Syndrome, Congenital, 11, Associated With Acetylcholine Receptor Deficiency

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-11 (CMS11) associated with acetylcholine receptor (AChR) deficiency is caused by homozygous or compound heterozygous mutation in the RAPSN gene (601592), which plays an essential role in the clustering of AChR at the endplate, on chromosome 11p11.

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 cholinesterase 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

Ohno et al. (2002) reported 4 unrelated patients with CMS and AChR deficiency. All patients had a similar disease course with weak fetal movements in utero, hypotonia with poor suck and cry, and ptosis at birth. They all learned to walk at ages 15 to 18 months but had frequent falls, and most could never walk fast or run. Other features included easy fatigability, positive Gowers sign, and high-arched palate. On several occasions, respiratory infections or other intercurrent illnesses precipitated generalized weakness, often requiring assisted ventilation. One patient was born with multiple joint contractures, although her mother was unaware of decreased fetal movement in utero. All patients had type 1 fiber predominance on muscle biopsy and markedly attenuated numbers of AChR.

Burke et al. (2003) reported 16 patients with CMS11. Thirteen patients had an early onset, with arthrogryposis multiplex congenita, hypotonia, bulbar and/or respiratory difficulties at birth, and episodic crises and/or apnea. Most patients improved later in life. Three patients had a later onset, at 13, 21, and 48 years, with proximal and ankle dorsiflexion weakness and mild ptosis in 2. All 3 late-onset patients were initially diagnosed with seronegative myasthenia gravis (see 254200). Both early- and late-onset patients responded well to anticholinesterase therapy.

Das et al. (2014) reported a male infant with severe CMS11 who presented at birth with weak cry, hypotonia, joint contractures, limited spontaneous movement, and severe respiratory insufficiency. He also had prominent occiput, low-set ears, hypertelorism with small palpebral fissures, micrognathia, broad nasal bridge, and high-arched palate. Skeletal muscle biopsy showed mild myofiber atrophy consistent with denervation. The child remained hypotonic with decreased muscle bulk, but cognitive function progressed normally. Treatment with pyridostigmine at age 16 months resulted in dramatically improved motor strength and movement.

Clinical Variability

In 14 Jewish patients from 10 families of either Iraqi or Iranian origin, Goldhammer et al. (1990) described congenital myasthenia associated with facial malformations, which included an elongated face, mandibular prognathism with class III malocclusion, and a high-arched palate. Muscle weakness was restricted predominantly to ptosis, weakness of facial and masticatory muscles, and fatigable speech. The course was mild and nonprogressive. Patients showed satisfactory response to cholinesterase inhibitors. Laboratory studies showed absence of antibodies to AChR and decremental response on repetitive stimulation at 3 Hz, but there was no repetitive compound muscle action potential (CMAP) in response to a single nerve stimulus. Goldhammer et al. (1990) suggested that the facial abnormalities observed in these patients could be secondary to the neuromuscular defects. Despite the early onset associated with this phenotype, half of the patients had been diagnosed between the ages of 18 and 42 years.

Mapping

Menold et al. (1998) studied DNA from 5 consanguineous families of Iranian Jewish origin in which several members had CMS beginning in infancy. The disease followed a nonprogressive course with muscle weakness confined mainly to the facial and masticatory muscles. Linkage studies excluded regions of chromosomes 2 and 17 where CMS had previously been mapped. Affected members of these families were later found to have mutations in the RAPSN gene on 11p (Ohno et al., 2003).

Molecular Genetics

In 4 patients with CMS and AChR deficiency, Ohno et al. (2002) identified homozygous or compound heterozygous mutations in the RAPSN gene (601592.0001-601592.0003).

Burke et al. (2003) reported 16 patients with CMS caused by the RAPSN N88K mutation (601592.0001): 7 were homozygous and 9 were compound heterozygous.

Gaudon et al. (2010) found that 3 (15%) of 20 unrelated patients with CMS due to RAPSN mutations were compound heterozygous for the common N88K mutation and an intragenic multiexonic deletion in the RAPSN gene. The 3 different deletions, which encompassed the first, middle, and last exons, respectively, were detected by SNP analysis and gene dosage studies. Two of the deletions occurred between repeated sequences within the RAPSN gene, and Gaudon et al. (2010) suggested that RAPSN may be particularly prone to genomic recombination because it contains numerous repeated sequences.

In a patient with severe CMS11, Das et al. (2014) identified compound heterozygous mutations in the RAPSN gene: the common N88K mutation and a 2-bp duplication (c.1083_1084dupCT; 601592.0015). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. Functional studies of the variants were not performed.

Population Genetics

In 6 Iraqi/Iranian patients with CMS and AChR deficiency associated with facial dysmorphism originally reported by Goldhammer et al. (1990), Ohno et al. (2003) identified a homozygous mutation in the promoter region of the RAPSN gene (601592.0006). Haplotype analysis showed a founder effect for the mutation. Zlotogora (1995) reviewed hereditary disorders among Jewish individuals originating from Iran and Iraq.

Dunne and Maselli (2004) stated that all previously reported patients with postsynaptic CMS carried the N88K mutation in the RAPSN gene. The authors used 7 intragenic SNPs spanning 8 kb to characterize the haplotype associated with N88K. In 3 affected N88K homozygous individuals, they identified a common haplotype present in all heterozygous carriers of N88K. Of note, in 2 asymptomatic N88K homozygous individuals, a second haplotype was present that differed at 3 SNP sites downstream from the N88K mutation. The finding of a common haplotype associated with N88K supported a founder effect. The discordant haplotype in homozygous individuals suggested that recombination events may have occurred within the RAPSN gene, which could have implications for the phenotypic expression of the disease.

By haplotype analysis of 21 CMS patients of European and Indian origin with the RAPSN N88K mutation, Muller et al. (2004) identified a core founder haplotype of 10 SNPs encompassing a region of 0.36 Mb flanking the mutation. The authors concluded that N88K derived from a single founder event in an ancient Indo-European population.