Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction that can be classified by the site of the transmission defect: presynaptic, synaptic, and postsynaptic. FCCMS is an autosomal recessive form of postsynaptic CMS. For a discussion of ... Congenital myasthenic syndromes are genetic disorders of the neuromuscular junction that can be classified by the site of the transmission defect: presynaptic, synaptic, and postsynaptic. FCCMS is an autosomal recessive form of postsynaptic CMS. For a discussion of genetic heterogeneity of CMS, see 608931. In most cases, FCCMS is caused by recessive gain-of-function mutations that decrease activity of the AChR by slowing the rate of opening of the receptor channel, speeding the rate of closure of the channel, or decreasing the number of openings of the channel during ACh occupancy. The result is failure to achieve threshold depolarization of the endplate and consequent failure to fire an action potential. FCCMS is the physiologic opposite of slow-channel CMS (SCCMS; 601462), but the 2 disorders cause similar phenotypes. Sine et al. (2003) provided a detailed analysis of the mechanistic diversity underlying fast-channel congenital CMS. Autosomal dominant inheritance has rarely been described.
Uchitel et al. (1993) reported a 21-year-old woman with moderately severe myasthenic symptoms since birth who responded poorly to acetylcholinesterase inhibitors. No serum antibodies to the AChR were detected. Electrophysiologic studies showed very small miniature endplate potentials (MEPP) ... Uchitel et al. (1993) reported a 21-year-old woman with moderately severe myasthenic symptoms since birth who responded poorly to acetylcholinesterase inhibitors. No serum antibodies to the AChR were detected. Electrophysiologic studies showed very small miniature endplate potentials (MEPP) and currents (MEPC), but the density and distribution of AChRs in the synapse were normal, quantal content was normal, and the junctional folds were intact. Channel conductance studies indicated a kinetic abnormality of the AChR, and the authors postulated a defect in the interaction of ACh with the AChR. In a follow-up study, Ohno et al. (1996) reported favorable response to treatment with 3,4-diaminopyridine, which increases the number of AChR quanta released at the presynaptic membrane by nerve impulses. Ohno et al. (1996) reported a 4-year-old boy and his younger sister who both had myasthenic symptoms from birth. Both patients had negative tests for anti-AChR antibodies and responded incompletely to anticholinesterase drugs. Electrophysiologic studies showed small miniature endplate potentials, normal AChR density, and normal endplate ultrastructure. Patch-clamp studies showed infrequent AChR channel openings, a decrease in channel opening rate, and resistance to desensitization by ACh. The mean opening bursts of the endplate were shorter than normal. Wang et al. (1999) reported 2 brothers with fast-channel CMS. The proband had weakness of the ocular muscles since birth, abnormal fatigability since early childhood, and moderate muscle weakness of the facial, neck, trunk, and limb muscles. EMG showed decremental motor responses and he responded well to acetylcholinesterase inhibitors and 3,4-diaminopyridine. Brownlow et al. (2001) reported a patient who showed decreased fetal movements and was born with CMS and congenital contractures of both hands. Shen et al. (2002) reported 3 Saudi Arabian patients with fast-channel CMS. All 3 patients came from consanguineous unions, and 2 of the patients were first cousins. Three similarly affected sibs died in infancy from muscle weakness and respiratory complications. The course of all 3 patients was similar, with neonatal hypotonia, weak cry, respiratory difficulties, and poor feeding. Later, easy fatigability was noticed, as well as ptosis, ophthalmoplegia, facial weakness, and weakness of the neck flexor muscles. One patient had a high-arched palate, micrognathia, and large ears. EMG showed decremental muscle action potential responses to stimulation and small MEPP and MEPC. Muscle biopsy revealed type 2 fiber atrophy, a reduced number of AChRs, increased numbers of endplate regions, and preserved junctional structure. Functional studies showed abnormally brief AChR-induced ion channel opening events. Masuda et al. (2008) reported an 18-year-old woman with autosomal recessive inheritance of fast-channel CMS caused by compound heterozygous mutations in the CHRNA1 gene (100690.0015 and 100690.0016). She had severe symptoms since birth and showed partial response to anticholinesterase medications and 3,4-diaminopyridine. Skeletal muscle biopsy showed reduced numbers of AChRs per endplate (about 20% of normal), and simple postsynaptic regions at nerve terminals. Electron microscopic studies showed a marked decrease in the density and distribution of AChR on the junctional folds. The amplitude of miniature EP potentials (MEPPs) was reduced to 23% of normal, and the number of quanta released by nerve impulse was normal. The findings were consistent with mild shortening of the channel-opening events. Heterozygous carriers in the family were unaffected. Shen et al. (2012) reported an 8-year-old boy, born of consanguineous parents, with fast-channel congenital myasthenic syndrome caused by a homozygous mutation in the CHRNE gene (W55R; 100725.0021). The patient had severe myasthenic symptoms since birth and was wheelchair-bound. Three similarly affected sibs had died in infancy, and he had 1 similarly affected brother. In vitro functional expression in HEK293 cells showed that the mutant protein was expressed, but patch-clamp recordings indicated 30-fold reduced ACh affinity and 75-fold reduced apparent gating efficiency. The mutation hindered isomerization of the receptor from the closed to the open state, slowed the apparent opening rate, speeded the apparent closing rate, and reduced open channel probability. These altered channel kinetics predicted a short duration and low amplitude of the endplate potential with an inability to activate postsynaptic sodium channels. There was also a low opening probability of the mutant receptor over a range of ACh concentrations, which explained the limited clinical response to pyridostigmine that was observed in this patient.
In 2 unrelated patients with fast-channel congenital myasthenic syndrome, 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene: both patients had a ... In 2 unrelated patients with fast-channel congenital myasthenic syndrome, 1 of whom had been reported by Uchitel et al. (1993), Ohno et al. (1996) identified compound heterozygosity for 2 mutations in the CHRNE gene: both patients had a pro121-to-leu change (P121L; 100725.0003), and each patient had a different second null mutation (100725.0017; 100725.0018). In 2 brothers with fast-channel CMS, Wang et al. (1999) identified compound heterozygosity for 2 mutations in the CHRNA1 gene (100690.0007; 100690.0008). In a patient with fast-channel CMS first reported by Vincent et al. (1981), Webster et al. (2004) identified a heterozygous mutation in the CHRNA1 gene (100690.0009). The case was a rare example of autosomal dominant transmission. In a patient with CMS and congenital contractures of both hands, Brownlow et al. (2001) identified compound heterozygosity for 2 mutations in the CHRND gene: a glu59-to-lys substitution (100720.0003) and a null mutation (100720.0004). In 3 Saudi Arabian patients with fast-channel CMS, Shen et al. (2002) identified a homozygous mutation in the CHRND gene (100720.0002).
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