MYASTHENIC SYNDROME, CONGENITAL, 4C, ASSOCIATED WITH ACETYLCHOLINERECEPTOR DEFICIENCY
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Synonyms, Signs:
MYASTHENIC SYNDROME, CONGENITAL, POSTSYNAPTIC, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY
CMS1E, INCLUDED
CMS1D
CMS Ie, INCLUDED
MYASTHENIC SYNDROME, CONGENITAL, Ie, INCLUDED
MYASTHENIC SYNDROME, CONGENITAL, TYPE Id
CMS Id MYASTHENIC SYNDROME, CONGENITAL, WITH FACIAL DYSMORPHISM, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY, INCLUDED
Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction and can be classified by the site of the transmission defect: presynaptic, synaptic, or postsynaptic. Presynaptic CMS with episodic ataxia (254210) is caused by mutation in the CHAT ... Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction and can be classified by the site of the transmission defect: presynaptic, synaptic, or postsynaptic. Presynaptic CMS with episodic ataxia (254210) is caused by mutation in the CHAT gene (118490), and synaptic acetylcholinesterase (AChE) deficiency (603034) is caused by mutation in the COLQ gene (603033). Postsynaptic disorders can be divided into 2 kinetic defects, fast-channel (608930) and slow-channel (601462) CMS, and a third disorder, AChR deficiency. Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003). See also CMS caused by mutation in the SCN4A sodium channel gene (603967); familial limb-girdle myasthenic syndrome (254300), caused by mutation in the DOK7 (610285) or agrin (AGRN; 103320) genes; and limb-girdle myasthenia with tubular aggregates (610542), caused by mutation in the GFPT1 gene (138292) on chromosome 2p13. See also NOMENCLATURE below.
Lecky et al. (1986) reported an 18-year-old girl, born of consanguineous parents, who had negligible postsynaptic alpha-bungarotoxin binding (113955), suggesting a deficiency of the acetylcholine receptor. Type 2 muscle fiber atrophy was seen in affected muscles, and endplates ... Lecky et al. (1986) reported an 18-year-old girl, born of consanguineous parents, who had negligible postsynaptic alpha-bungarotoxin binding (113955), suggesting a deficiency of the acetylcholine receptor. Type 2 muscle fiber atrophy was seen in affected muscles, and endplates were elongated. Nichols et al. (1999) reported 2 sibs with congenital myasthenic syndrome associated with AChR deficiency. They were part of a large consanguineous family. The sibs had a similar phenotype; presentation in childhood age with ptosis and mild proximal limb weakness. Antibodies to AChR were absent and response to anticholinesterase inhibitors was favorable. EMG showed a decrement in the CMAP, and muscle biopsy showed a decrease in the amplitude of miniature endplate potentials (MEPP) and a reduction in the number of endplate AChR. Ohno et al. (1997) reported 3 patients with CMS and AChR deficiency. The first patient was an 11-year-old male who had decreased movements in utero, a weak cry and a feeble suck at birth, ptosis of the eyelids beginning at 5 months of age, and ophthalmoparesis beginning at 2 years of age. He always fatigued easily, could never run well, and had difficulty climbing steps. The second patient, an 8-year-old female, had a weak cry at birth, ptosis since age 18 months, easy fatigability, and inability to run. The third patient was a 31-year-old woman who had weakness since infancy and numerous episodes of impaired respiration and fatigue on exertion. All 3 patients had absence of AChR antibodies, a decremental EMG response on stimulation of motor nerves, and a favorable response to anticholinesterase inhibitors. Two of the 3 patients had an increase of the fetal AChR gamma subunit (CHRNG; 100730), suggesting compensatory mechanisms. Sieb et al. (1998) described 2 families in which 5 individuals appeared to have an autosomal recessive CMS characterized by deficiency of end-plate acetylcholine receptor and utrophin (UTRN; 128240). All 5 patients suffered from ptosis and slowly progressive limb-girdle muscle weakness. All had abnormal decremental response on low frequency nerve stimulation, but there were no repetitive responses to single stimuli. The patients improved on antiacetylcholinesterase drugs. Three brothers in 1 family and a brother and sister in the other were affected. They were all young adults. Studies suggested that the patients had a defect in the development or maintenance of the postsynaptic clefts; whether this defect resulted from or caused a reduced expression of utrophin or AChR was unclear. Quiram et al. (1999) reported 3 sibs with CMS and severe AChR deficiency. The proband, 8 years of age at the time of report, had severe myasthenic symptoms from birth, requiring frequent ventilation and enteric alimentation through a gastrostomy. She had a decremental electromyographic response on stimulation of motor nerves and responded partially to cholinesterase inhibitors. Tests for anti-AChR antibodies were negative. The parents were unaffected. Electrophysiologic studies showed that the MEPP and miniature endplate current (MEPC) were both decreased, with normal quantal release. Analysis of affected muscle fibers showed an increased number of small endplate regions distributed over a 3-fold increased span of the muscle fiber surface. Nerve terminal size and the postsynaptic area of folds and clefts were both decreased compared to normal. Ohno et al. (2002) reported 4 unrelated patients with CMS and AChR deficiency caused by mutations in the RAPSN gene (601592.0001-601592.0003). All patients had a similar disease course with weak fetal movements in utero, hypotonia with poor suck and cry, and ptosis at birth. They 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. Mihaylova et al. (2009) reported 5 sibs, born of consanguineous Sudanese parents, with congenital myasthenic syndrome due to a homozygous mutation in the MUSK gene (P344R; 601296.0003). 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. At birth she was hypotonic and during the first month of life experienced respiratory failure, for which she 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 bilevel positive airway pressure during night sleep. - Congenital Myasthenic Syndrome Ie 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. Satisfactory response to cholinesterase inhibitors was observed. Laboratory studies showed absence of antibodies to the AChR and decremental response on repetitive stimulation at 3 Hz, but no repetitive compound muscle action potential (CMAP) in response to a single nerve stimulus. Goldhammer et al. (1990) suggested that the facial abnormalities may be secondary to the neuromuscular defect. Despite the early onset, half the patients had been diagnosed between the ages of 18 and 42 years. Zlotogora (1995) reviewed hereditary disorders among Jewish persons originating from Iran and Iraq.
In a patient with CMS associated with AChR deficiency, Engel et al. (1996) identified compound heterozygosity for two 1-bp insertions in the CHRNE gene (100725.0013; 100725.0014). In 3 patients with CMS and AChR deficiency, Ohno et al. (1997) ... In a patient with CMS associated with AChR deficiency, Engel et al. (1996) identified compound heterozygosity for two 1-bp insertions in the CHRNE gene (100725.0013; 100725.0014). In 3 patients with CMS and AChR deficiency, Ohno et al. (1997) identified 6 mutations in the CHRNE gene (see, e.g., 100725.0004;100725.0005; 100725.0015; 100725.0016). In 2 sibs with CMS and AChR deficiency, born of consanguineous parents, Nichols et al. (1999) identified homozygosity for a mutation in the CHRNE gene (100725.0011). In 3 sibs with CMS and AChR deficiency, Quiram et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNB1 gene (100710.0003; 100710.0004). In 2 affected members of 1 of the families reported by Sieb et al. (1998), Sieb et al. (2000) identified compound heterozygosity for 2 mutations in the CHRNE gene (100725.0006-100725.0007). In 4 patients with CMS and AChR deficiency, Ohno et al. (2002) identified 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. Thirteen of the patients, 5 of whom were homozygous for N88K, 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 of the patients, including 2 who were homozygous for N88K, had a late 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 groups of patients, early- and late-onset, responded well to anticholinesterase therapy. Chevessier et al. (2004) reported a 27-year-old French woman with congenital myasthenic syndrome in whom they identified compound heterozygosity for mutations (601296.0001 and 601296.0002) in the MUSK gene (601296). Her similarly affected brother died at 1.5 years of age. Muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in CHRNE and MUSK expression. 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 exons, middle exons, 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. - Congenital Myasthenic Syndrome Ie 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.
In 13 patients from 11 Gypsy families with CMS and AChE deficiency, Abicht et al. (1999) identified a homozygous 1-bp deletion in the CHRNE gene (1267delG; 100725.0012). Genotype analysis indicated that they derived from a common ancestor. Croxen ... In 13 patients from 11 Gypsy families with CMS and AChE deficiency, Abicht et al. (1999) identified a homozygous 1-bp deletion in the CHRNE gene (1267delG; 100725.0012). Genotype analysis indicated that they derived from a common ancestor. Croxen et al. (1999) identified the 1267delG mutation in patients from India and Pakistan. Morar et al. (2004) used the 1267delG mutation and 4 other private mutations among the Roma Gypsies to infer some of the missing parameters relevant to the comprehensive characterization of the population history of the Gypsies. Sharing of mutations and high carrier rates supported a strong founder effect. The identity of the congenital myasthenia 1267delG mutation in Gypsy and Indian/Pakistani chromosomes provided strong evidence of the Indian origins of the Gypsies. Hantai et al. (2004) reported a carrier rate of 3.74% for the 1267delG mutation in these ethnic groups. Dunne and Maselli (2004) stated that all previously reported patients with postsynaptic CMS carried the N88K (601592.0001) mutation. They 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 and 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 and that this may have implications in the phenotypic expression of the disease. By haplotype analysis of 21 CMS patients of European and Indian origin with the RAPSN N88K mutation (601592.0001), Muller et al. (2004) identified a core founder haplotype of 10 SNPs encompassing a region of 0.36 Mb flanking the mutation and concluded that N88K derived from a single founder event in an ancient Indo-European population. Richard et al. (2008) identified homozygosity for the 1293insG mutation (100725.0014) in 14 (60%) of 23 North African families with AChR deficiency. All families were consanguineous, and 9 families originated from Algeria, 3 from Tunisia, and 1 each from Morocco and Libya. Haplotype analysis indicated a founder effect that occurred about 700 years ago. The phenotype was relatively homogeneous without fetal involvement and with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors.