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Alternative titles; symbolsCONGENITAL MYASTHENIC SYNDROME TYPE Ia1, FORMERLY; CMS1A1, FORMERLYCMS Ia1, FORMERLY▼ DescriptionSlow-channel congenital myasthenic sy...

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▼ Description
Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from 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).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

▼ Clinical Features
Oosterhuis et al. (1987) reported a young woman (case 2) who developed mild ptosis in her late teens and progressive muscle weakness in her twenties. AChR antibodies were absent, and there was no response to anticholinesterase medication. Electrophysiologic studies showed a prolonged rise and decay of miniature endplate potentials (MEPPs). Ultrastructural studies showed degeneration of junctional folds and diffusely thickened endplate basal lamina. Two asymptomatic first-degree relatives had similar abnormal electrophysiologic findings. The findings suggested prolonged open time of the ACh-induced ion channel, consistent with slow-channel myasthenic syndrome.

Chauplannaz and Bady (1994) reported a woman (case 3) with SCCMS who had onset of symptoms in her twenties. She first noted weakness of the finger extensor muscles, and later developed weakness in other muscle groups, including the neck muscles. Single nerve stimulation elicited a repetitive compound muscle activation potential (CMAP) response, and repetitive nerve stimulation induced a myasthenic decremental response in finger extensor muscles. Her mother and son were similarly affected.

Ohno et al. (1995) reported a 20-year-old woman with myasthenic symptoms since the neonatal period, a decremental electromyographic response on stimulation of motor nerves, negative tests for anti-AChR antibodies, and no history of similarly affected relatives. Studies of an intercostal muscle specimen from this patient at age 17 revealed signs of severe endplate myopathy, and patch-clamp studies showed markedly prolonged AChR channel openings.

Engel et al. (1996) reported a 16-year-old boy with slow-channel congenital myasthenic syndrome. He had myasthenic symptoms since early infancy involving ocular, truncal, and limb muscles. He also experienced intermittent episodes of respiratory insufficiency requiring ventilatory support. Electrophysiologic studies showed prolonged endplate currents and prolonged AChR channel-opening episodes, and muscle biopsy showed endplate myopathy with loss of AChR from degenerating junctional folds.

Croxen et al. (2002) reported a rare example of a patient, born to consanguineous parents, with autosomal recessive inheritance of SCCMS. She presented at age 29 years with failure to breathe after administration of an anesthetic. She had bilateral ptosis, limitation of eye movements, and weakness of facial, neck, shoulder, hip, and small muscles of the hand. She first became aware of weakness in her early twenties. Electrophysiologic studies showed a decremental response to repetitive stimulations, consistent with a defect in neuromuscular transmission.

▼ Molecular Genetics
In a patient with SCCMS, Ohno et al. (1995) identified a heterozygous missense mutation in the CHRNE gene (T264P; 100725.0001) that resulted in prolonged channel opening.

In a 16-year-old boy with SCCMS, Engel et al. (1996) identified a heterozygous missense mutation in the CHRNE gene (L269F; 100725.0002).

Croxen et al. (2002) reported 2 unrelated families with a mild form of SCCMS confirmed by heterozygous missense mutation in the CHRNE gene (L221F; 100725.0010). In 1 family, all members with the mutation were affected, whereas in the other family, 2 members with the mutation were clinically unaffected, indicating incomplete penetrance. The patients had previously been reported by Oosterhuis et al. (1987) and Chauplannaz and Bady (1994).

In a patient, born of consanguineous parents, with SCCMS, Croxen et al. (2002) identified compound heterozygous mutations in the CHRNE gene (100725.0022-100725.0023).

▼ Animal Model
Kraner et al. (2002) determined the genetic defect in 4 previously reported related Brahman calves with severe myasthenia weakness (Thompson, 1998). They demonstrated homozygosity for a 20-bp deletion in exon 5 of the CHRNE gene that caused a frameshift followed by a premature stop codon. Survival was limited to only a few months, indicating that the effect on neuromuscular transmission was more pronounced in the calves than that observed in humans homozygous for truncating CHRNE mutations. Kraner et al. (2002) speculated that this might be due to a different capacity to express the fetal-type AChR after birth.

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. Mutant mice displayed fatigable muscle weakness, reduced MEPPs and endplate potentials, reduced motor endplate AChR number, and altered endplate morphology.

Groshong et al. (2007) found that mice with the L269F mutation in the Chrne gene (100725.0002) showed muscle weakness, fatigability, and impaired neuromuscular transmission, similar to the human disorder. Muscle fibers from mutant mice showed significantly increased levels of the calcium-activated cysteine protease calpain (see, e.g., CAPN3; 114240) at the NMJ. Calpain levels were dependent on synaptic activity and activation of mutant AChR, and diminished with blockade of AChR. Transgenic expression of the natural calpain inhibitor calpastatin (CAST; 114090) reduced calpain to baseline, normalized the size of the NMJ and the endplate current frequency, and improved strength and neuromuscular transmission. The protective effect of Cast appeared to be due to a strengthening of synaptic connections, rather than a protective effect on mutant AChRs. There was persistent endplate myopathy in Cast-null/L269F double-mutant mice associated with ongoing activation of caspase family proteases, such as Casp3 (600636), that are not inhibited by calpastatin.

Tags: 17p13.2