Alternative titles; symbols
ORPHA: 590, 98913; DO: 0110679;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.2 | Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency | 608931 | Autosomal recessive | 3 | CHRNE | 100725 |
A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency is caused by homozygous or compound heterozygous mutation in the CHRNE gene (100725) on chromosome 17p13.
Mutation in the CHRNE gene can also cause slow-channel CMS (CMS4A; 605809) and fast-channel CMS (CMS4B; 616324).
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 with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (summary by Engel et al., 2015).
For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).
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 with 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 increased expression of CHRNG, suggesting compensatory mechanisms.
Sieb et al. (1998) described 2 families in which 5 individuals appeared to have autosomal recessive CMS characterized by deficiency of endplate AChR 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 anticholinesterase 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 reduced expression of utrophin or AChR was unclear.
Nichols et al. (1999) reported 2 sibs from a large consanguineous family who had congenital myasthenic syndrome associated with AChR deficiency. The sibs had a similar phenotype; presentation in childhood 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 compound muscle action potential (CMAP) response, and muscle biopsy showed a decrease in the amplitude of MEPPs and a reduction in the number of endplate AChR.
Croxen et al. (2002) reported 2 sisters diagnosed in childhood with CMS and AChR deficiency. Serum anti-AChR antibody levels were negative in both patients. At the age of 34 years, the younger sister's condition deteriorated, with respiratory failure necessitating tracheostomy and assisted ventilation. Serum anti-AChR titers were elevated, indicating autoimmune myasthenia gravis (MG; 254200), and the patient was successfully treated with plasmapheresis, immunosuppression, and thymectomy. Molecular analysis identified compound heterozygous mutations in the CHRNE gene, consistent with autosomal recessive inheritance. Croxen et al. (2002) suggested that the epsilon-AChR gene mutations may predispose to later development of anti-AChR antibodies. The authors also noted that the younger sister had recently had 3 children and, unlike her sister, was homozygous for the HLA-DR3-B8-A1 phenotype, which is known to associate with autoimmune MG.
Christodoulou et al. (1997) performed linkage studies in 12 families, 7 of them consanguineous, containing 36 patients with a diagnosis of familial infantile myasthenia. A combination of linkage search through the genome, DNA pooling, and homozygosity mapping localized the disorder to the telomeric region of chromosome 17p. A maximum lod score of 9.28 at theta = 0.034 was obtained between the disease locus and marker D17S1537. Haplotype analysis showed that the disease in all families was consistent with linkage to this region, thus providing evidence for genetic homogeneity of familial infantile myasthenia. Multipoint linkage analysis mapped the disease gene in the interval of approximately 4 cM between marker loci D17S1537 and D17S1298 with a maximum multipoint lod score of 12.07. Haplotype analysis and homozygosity by descent in affected individuals of the consanguineous families revealed results in agreement with the confinement of the disease region within the interval between marker loci D17S1537 and D17S1298 on 17p13.
The transmission pattern of CMS associated with AChR deficiency in the family reported by Sieb et al. (1998) was consistent with autosomal recessive inheritance.
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 biallelic mutations in the CHRNE gene (see, e.g., 100725.0004-100725.0005 and 100725.0015-100725.0016).
In 2 sibs with CMS and AChR deficiency, born to consanguineous parents, Nichols et al. (1999) identified homozygosity for a mutation in the CHRNE gene (100725.0011).
In 37 patients from 13 families with CMS associated with AChR deficiency, most of whom were consanguineous and previously reported by Christodoulou et al. (1997), Middleton et al. (1999) identified homozygous mutations in the CHRNE gene (see, e.g., 100725.0012).
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 13 patients from 11 Gypsy families with CMS and acetylcholinesterase deficiency, Abicht et al. (1999) identified a homozygous 1-bp deletion in the CHRNE gene (1267delG; 100725.0012). Genotype analysis indicated that the families 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 Roma population history. 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 for 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.
Richard et al. (2008) identified homozygosity for the CHRNE 1293insG mutation (100725.0014) in 14 (60%) of 23 North African families with AChR deficiency. All 14 families were consanguineous, 9 of which 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 acetylcholinesterase inhibitors.
Miller et al. (1984) demonstrated autosomal recessive inheritance with complete penetrance for congenital myasthenia gravis in smooth fox terrier dogs. In these animals, the trait is lethal; attempts to maintain affected dogs to adulthood were unsuccessful. Affected dogs have a decreased number of acetylcholine receptors in skeletal muscle. Acquired MG due to antibodies against the AChR of the neuromuscular junction occurs most often in adult dogs.
Cossins et al. (2004) generated transgenic mice that constitutively expressed Chrng (100730) in a Chrne-knockout background. These mice, in which neuromuscular transmission is mediated by fetal AChR, lived well into adulthood but showed striking similarities to human AChR deficiency syndrome. They displayed fatigable muscle weakness, reduced MEPPs and endplate potentials, reduced motor endplate AChR number, and altered endplate morphology.
Lecky et al. (1986) reported an 18-year-old girl, born of consanguineous parents, who had negligible postsynaptic alpha-bungarotoxin binding (see 113955), suggesting a deficiency of the acetylcholine receptor. Type 2 muscle fiber atrophy was seen in affected muscles, and endplates were elongated.
Abicht, A., Stucka, R., Karcagi, V., Herczegfalvi, A., Horvath, R., Mortier, W., Schara, U., Ramaekers, V., Jost, W., Brunner, J., Janssen, G., Seidel, U., Schlotter, B., Muller-Felber, W., Pongratz, D., Rudel, R., Lochmuller, H. A common mutation (epsilon1267delG) in congenital myasthenic patients of Gypsy ethnic origin. Neurology 53: 1564-1569, 1999. [PubMed: 10534268] [Full Text: https://doi.org/10.1212/wnl.53.7.1564]
Christodoulou, K., Tsingis, M., Deymeer, F., Serdaroglu, P., Ozdemir, C., Al-Shehab, A., Bairactaris, C., Mavromatis, I., Mylonas, I., Evoli, A., Kyriallis, K., Middleton, L. T. Mapping of the familial infantile myasthenia (congenital myasthenic syndrome type Ia) gene to chromosome 17p with evidence of genetic homogeneity. Hum. Molec. Genet. 6: 635-640, 1997. [PubMed: 9097970] [Full Text: https://doi.org/10.1093/hmg/6.4.635]
Cossins, J., Webster, R., Maxwell, S., Burke, G., Vincent, A., Beeson, D. A mouse model of AChR deficiency syndrome with a phenotype reflecting the human condition. Hum. Molec. Genet. 13: 2947-2957, 2004. [PubMed: 15471888] [Full Text: https://doi.org/10.1093/hmg/ddh320]
Croxen, R., Newland, C., Betty, M., Vincent, A., Newsom-Davis, J., Beeson, D. Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. Ann. Neurol. 46: 639-647, 1999. [PubMed: 10514102] [Full Text: https://doi.org/10.1002/1531-8249(199910)46:4<639::aid-ana13>3.0.co;2-1]
Croxen, R., Vincent, A., Newsom-Davis, J., Beeson, D. Myasthenia gravis in a woman with congenital AChR deficiency due to epsilon-subunit mutations. Neurology 58: 1563-1565, 2002. [PubMed: 12034803] [Full Text: https://doi.org/10.1212/wnl.58.10.1563]
Engel, A. G., Ohno, K., Bouzat, C., Sine, S. M., Griggs, R. C. End-plate acetylcholine receptor deficiency due to nonsense mutations in the epsilon subunit. Ann. Neurol. 40: 810-817, 1996. [PubMed: 8957026] [Full Text: https://doi.org/10.1002/ana.410400521]
Engel, A. G., Shen, X.-M., Selcen, D., Sine, S. M. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 14: 420-434, 2015. Note: Erratum: Lancet Neurol. 14: 461 only, 2015. [PubMed: 25792100] [Full Text: https://doi.org/10.1016/S1474-4422(14)70201-7]
Hantai, D., Richard, P., Koenig, J., Eymard, B. Congenital myasthenic syndromes. Curr. Opin. Neurol. 17: 539-551, 2004. [PubMed: 15367858] [Full Text: https://doi.org/10.1097/00019052-200410000-00004]
Lecky, B. R. F., Morgan-Hughes, J. A., Murray, N. M. F., Landon, D. N., Wray, D., Prior, C. Congenital myasthenia: further evidence of disease heterogeneity. Muscle Nerve 9: 233-242, 1986. [PubMed: 3010100] [Full Text: https://doi.org/10.1002/mus.880090307]
Middleton, L., Ohno, K., Christodoulou, K., Brengman, J., Milone, M., Neocleous, V., Serdaroglu, P., Deymeer, F., Ozdemir, C., Mubaidin, A., Horany, K., Al-Shehab, A., Mavromatis, I., Mylonas, I., Tsingis, M., Zamba, E., Pantzaris, M., Kyriallis, K., Engel, A. G. Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor epsilon-subunit gene. Neurology 53: 1076-1082, 1999. [PubMed: 10496269] [Full Text: https://doi.org/10.1212/wnl.53.5.1076]
Miller, L. M., Hegreberg, G. A., Prieur, D. J., Hamilton, M. J. Inheritance of congenital myasthenia gravis in smooth fox terrier dogs. J. Hered. 75: 163-166, 1984. [PubMed: 6736601] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a109904]
Morar, B., Gresham, D., Angelicheva, D., Tournev, I., Gooding, R., Guergueltcheva, V., Schmidt, C., Abicht, A., Lochmuller, H., Tordai, A., Kalmar, L., Nagy, M., and 10 others. Mutation history of the Roma/Gypsies. Am. J. Hum. Genet. 75: 596-609, 2004. [PubMed: 15322984] [Full Text: https://doi.org/10.1086/424759]
Nichols, P., Croxen, R., Vincent, A., Rutter, R., Hutchinson, M., Newsom-Davis, J., Beeson, D. Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome. Ann. Neurol. 45: 439-443, 1999. [PubMed: 10211467]
Ohno, K., Quiram, P. A., Milone, M., Wang, H.-L., Harper, M. C., Pruitt, J. N., II, Brengman, J. M., Pao, L., Fischbeck, K. H., Crawford, T. O., Sine, S. M., Engel, A. G. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations. Hum. Molec. Genet. 6: 753-766, 1997. [PubMed: 9158150] [Full Text: https://doi.org/10.1093/hmg/6.5.753]
Richard, P., Gaudon, K., Haddad, H., Ben Ammar, A., Genin, E., Bauche, S., Paturneau-Jouas, M., Muller, J. S., Lochmuller, H., Grid, D., Hamri, A., Nouioua, S., and 11 others. The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa. Neurology 71: 1967-1972, 2008. [PubMed: 19064877] [Full Text: https://doi.org/10.1212/01.wnl.0000336921.51639.0b]
Sieb, J. P., Dorfler, P., Tzartos, S., Wewer, U. M., Ruegg, M. A., Meyer, D., Baumann, I., Lindemuth, R., Jakschik, J., Ries, F. Congenital myasthenic syndromes in two kinships with end-plate acetylcholine receptor and utrophin deficiency. Neurology 50: 54-61, 1998. Note: Erratum: Neurology 50: 838 only, 1998. [PubMed: 9443457] [Full Text: https://doi.org/10.1212/wnl.50.1.54]
Sieb, J. P., Kraner, S., Rauch, M., Steinlein, O. K. Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by epsilon-AChR subunit truncating mutations. Hum. Genet. 107: 160-164, 2000. [PubMed: 11030414] [Full Text: https://doi.org/10.1007/s004390000359]