Myasthenic Syndrome, Congenital, 1a, Slow-Channel

A number sign (#) is used with this entry because of evidence that slow-channel congenital myasthenic syndrome-1A (CMS1A) is caused by heterozygous mutation in the CHRNA1 gene (100690) on chromosome 2q31. There are rare reports of recessive inheritance.

Mutation in the CHRNA1 gene can also cause fast-channel CMS1B (608930).

Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). 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).

Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic NMJ characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015).

Genetic Heterogeneity of Congenital Myasthenic Syndromes

Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13.

CMS5 (603034) is caused by mutation in the COLQ gene (603033) on 3p25; CMS6 (254210) is caused by mutation in the CHAT gene (118490) on 10q; CMS7 (616040) is caused by mutation in the SYT2 gene (600104) on 1q32; CMS8 (615120) is caused by mutation in the AGRN gene (103320) on 1p; CMS9 (616325) is caused by mutation in the MUSK gene (601296) on 9q31; CMS10 (254300) is caused by mutation in the DOK7 gene (610285) on 4p; CMS11 (616326) is caused by mutation in the RAPSN gene (601592) on 11p11; CMS12 (610542) is caused by mutation in the GFPT1 gene (138292) on 2p14; CMS13 (614750) is caused by mutation in the DPAGT1 gene (191350) on 11q23; CMS14 (616228) is caused by mutation in the ALG2 gene (607905) on 9q22; CMS15 (616227) is caused by mutation in the ALG14 gene (612866) on 1p21; CMS16 (614198) is caused by mutation in the SCN4A gene (603967) on 17q; CMS17 (616304) is caused by mutation in the LRP4 gene (604270) on 11p12; CMS18 (616330) is caused by mutation in the SNAP25 gene (600322) on 20p11; CMS19 (616720) is caused by mutation in the COL13A1 gene (120350) on 10q22; CMS20 (617143) is caused by mutation in the SLC5A7 gene (608761) on 2q12; CMS21 (617239) is caused by mutation in the SLC18A3 gene (600336) on 10q11; CMS22 (616224) is caused by mutation in the PREPL gene (609557) on 2p21; CMS23 (618197) is caused by mutation in the SLC25A1 gene (190315) on 22q11; CMS24 (618198) is caused by mutation in the MYO9A gene (604875) on 15q22; and CMS25 (618323) is caused by mutation in the VAMP1 gene (185880) on 12p13.

Nomenclature

An international workshop (Middleton, 1996) classified the congenital myasthenia syndromes on the basis of their genetic and clinical features: type Ia (254210); Ib, limb-girdle myasthenia (254300); Ic, endplate AChR deficiency (603034); Id, AChR deficiency; and Ie, CMS with facial dysmorphism, which has since been shown to be caused by AChR deficiency. Type IIa is autosomal dominant slow-channel syndrome, and type III is sporadic. These designations have largely been replaced by a classification according to the location of the defect (presynaptic, synaptic, or postsynaptic), as well as by pathologic mechanism (i.e., AChR deficiency) (Engel et al., 2003) and genetic defect (Engel et al., 2015).

Lambert-Eaton myasthenic syndrome is a distinct, acquired disorder in which patients develop autoantibodies against several putative antigens associated with P/Q-type voltage-gated calcium channels (see, e.g., CACNA1A, 601011 and CACNB2, 600003).

Clinical Features

Engel et al. (1982) reported 5 patients from 2 families and 1 sporadic patient who had a congenital myasthenic syndrome characterized by selective involvement of cervical, scapular, and finger extensor muscles and ophthalmoparesis from infancy or early childhood. Laboratory studies showed a decremental compound muscle action potential (CMAP) response to stimulus, prolonged endplate potentials, and prolonged miniature endplate potentials (MEPPs) and endplate currents (MEPCs). Quantal content and acetylcholinesterase activity were normal. Muscle biopsy showed predominance of type I fibers, atrophic type 2 fibers, and abnormal endplate configuration. Electron microscopy showed a decrease in the size of nerve terminals, a reduction in the length of postsynaptic membranes, and focal degeneration of junctional folds with loss of acetylcholine receptors. Engel et al. (1982) suggested that the defect was a prolonged open time of the acetylcholine-induced ion channel.

Whiteley et al. (1976) described 2 brothers, aged 19 and 29, with myasthenic symptoms beginning within the first 2 years of life. Ptosis and ophthalmoplegia responded poorly to oral anticholinesterase therapy and to thymectomy. The brothers had 2 different HLA haplotypes, and neither had the A1-B8-Dw3 haplotypes commonly associated with adult-onset myasthenia gravis (MG; 254200).

Oosterhuis et al. (1987) reported a woman (case 1) who developed weakness of the upper arm in the eighth month of her first pregnancy at age 23 years. She showed generalized myasthenic weakness and mild hand muscle wasting. Antibodies to AChR were absent, and she reacted adversely to anticholinesterase drugs. Electrophysiologic studies showed a repetitive muscle response to a single nerve stimulation, and in vitro microelectrode studies showed a prolonged decay time of MEPPs. The authors concluded that there was prolonged open time of the ACh-induced ion channel.

Chauplannaz and Bady (1994) reported 2 unrelated women (cases 1 and 2) with SCCMS who had onset of symptoms in childhood and at age 16 years, respectively. They had generalized weakness and prominent wasting and weakness of the finger extensor muscles. One patient also had marked weakness and atrophy of the cervical muscles and developed respiratory problems. A single nerve stimulus elicited repetitive CMAP responses, and repetitive nerve stimulation showed a myasthenic decrement in finger extensor muscles. Similar symptoms were noted in first-degree relatives of both women. Croxen et al. (1997) noted that both women reported by Chauplannaz and Bady (1994) had deterioration of symptoms during or after pregnancy.

Engel et al. (1996) reported a 30-year-old woman with SCCMS who had ocular muscle weakness since early childhood, limb muscle weakness with difficulty climbing stairs since age 8, and scoliosis since age 10. Family history was consistent with autosomal dominant inheritance spanning 3 generations. Electrophysiologic studies showed prolonged endplate currents and prolonged AChR channel-opening episodes, with a repetitive CMAP response to a single nerve stimulus. Ultrastructural studies of muscle biopsies showed an endplate myopathy with loss of AChR from degenerating junctional folds.

Croxen et al. (1997) reported a 34-year-old man who became aware of lower limb weakness at the age of 14. He later developed facial, neck, and upper limb weakness, with wasting of the forearm and hand muscles, and slight difficulty with chewing and swallowing. Serum antibodies to AChR were absent.

Shen et al. (2006) reported a 24-year-old man with SCCMS who had lid ptosis since birth, high-arched palate, pectus carinatum, and moderate limitation of eye movements. As a young adult, he developed fatigable weakness of the lower extremities with selective severe distal upper and lower limb weakness. EMG studies showed a decremental response on repetitive stimulation, and single nerve stimuli showed a repetitive CMAP, consistent with slow-channel CMS. He had no family history of a similar disorder.

Clinical Management

Engel et al. (1996) noted that acetylcholinesterase inhibitors would not be an effective treatment for SCCMS because they would result in exacerbated desensitization of mutant AChRs. The authors suggested that long-lived AChR channel blockers would be of greater benefit.

Fukudome et al. (1998) noted that quinidine is a long-lived open-channel blocker of the endplate AChR. In vitro, quinidine shortened the AChR channel-opening burst in cells expressing mutant SCCMS AChRs. Harper and Engel (1998) reported successful treatment of 6 SCCMS patients with quinidine sulfate. After 30 days of therapy, patients showed an improvement in muscle strength and in decrement of the CMAP.

Harper et al. (2003) found that fluoxetine significantly shortened the prolonged opening bursts of SCCMS AChR expressed in fibroblasts. Treatment of 2 SCCMS patients, who were allergic to quinidine, with fluoxetine resulted in marked subjective and objective improvement in muscle strength.

Movaghar and Slavin (2000) studied the effects of heat versus ice application on eyelid ptosis in 4 patients with ocular or systemic myasthenia. Transient complete improvement of ptosis was found in 3 patients and marked improvement in 1 patient after each test. The results of heat, ice, and modified sleep tests were identical. The authors concluded that the common denominator among these 3 tests, rest, seemed to be the relevant factor in the study.

Pathogenesis

In studies of muscle tissue from patients with SCCMS, Engel et al. (1996) found a decrease in the rate of AChR ion channel closure and an increase in apparent affinity of the receptor for ACh, resulting in a prolonged channel-opening time. Cationic overloading of the postsynaptic region results in an endplate myopathy with loss of AChR due to destruction of the junctional folds. The temporal summation of endplate potentials predicted a depolarization block, also suggesting desensitization in the presence of acetylcholinesterase inhibitors.

Zhou et al. (1999) found that mutant AChRs that cause SCCMS were activated by serum choline and by transient exposure to synaptically released transmitter. The high frequency of openings in serum was reduced by treatment with choline oxidase. Single-channel kinetic analysis indicated that the increased response to choline is caused by a reduced intrinsic stability of the closed channel. The results suggested that a mutation that destabilizes the inactive conformation of the AChR, together with the sustained exposure of endplates to serum choline, results in continuous channel activity that contributes to the pathophysiology of the disease.

Molecular Genetics

In 5 members of a family and another unrelated individual with SCCMS (Engel et al., 1982), Sine et al. (1995) identified a heterozygous missense mutation in the CHRNA1 gene (G153S; 100690.0004). Electrophysiologic analysis of endplates revealed prolonged decay of miniature endplate currents and prolonged activation episodes of single AChR channels. Single-channel kinetic analysis of engineered alpha-G153S AChR showed a markedly decreased rate of acetylcholine dissociation, indicating an increased affinity for ACh and causing the mutant AChR to open repeatedly during ACh occupancy. In addition, ACh binding measurements combined with the kinetic analysis indicated increased desensitization of the mutant AChR. Sine et al. (1995) concluded that ACh binding affinity can dictate the time course of the synaptic response.

In a 30-year-old woman with SCCMS, Engel et al. (1996) identified a heterozygous missense mutation in the CHRNA1 gene (N217K; 100690.0001).

In 4 patients with SCCMS, 3 of whom were previously reported by Oosterhuis et al. (1987) and Chauplannaz and Bady (1994), Croxen et al. (1997) identified different heterozygous missense mutations in the CHRNA1 gene (100690.0002-100690.0005).

In a 24-year-old man with SCCMS, Shen et al. (2006) identified a de novo heterozygous missense mutation in the CHRNA1 gene (C418W; 100690.0012). Functional kinetic expression studies in HEK cells showed that the AChR with the mutant alpha-subunit increased the channel-opening equilibrium as well as the mean duration of open durations and bursts characteristic of a slow-channel mutation.

Associations Pending Confirmation

For discussion of a possible association between congenital myasthenic syndrome and variation in the UNC13A gene, see 609894.0001.

For discussion of a possible association between presynaptic congenital myasthenic syndrome and variation in the LAMA5 gene, see 601033.0001.