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CHRNA1 – Postsynaptic Congenital Myasthenic Syndrome

CHRNA1 encodes the α1 subunit of the muscle nicotinic acetylcholine receptor, and pathogenic variants cause an autosomal recessive postsynaptic congenital myasthenic syndrome characterized by slow-channel gating defects. A 36-year-old woman presented in infancy with excessive daytime somnolence (HP:0001262), facial dysmorphism (HP:0000271), and limb muscle weakness (HP:0003690). Genetic testing at age 30 revealed a homozygous c.1396G>A (p.Gly466Arg) in CHRNA1, and treatment with pyridostigmine partially improved strength, with further gains upon addition of 3,4-diaminopyridine ([PMID:39677241]). No other affected relatives were reported, consistent with autosomal recessive inheritance.

Multiple in vitro functional assays in heterologous systems confirm that slow-channel CHRNA1 variants cause gain-of-function defects. The p.Phe253Val change in the M3 domain reduces endplate current amplitude and accelerates decay kinetics ([PMID:10195214]). The p.Cys438Trp substitution in M4 increases channel open probability ~26-fold without affecting agonist affinity ([PMID:16685696]). These concordant results support a slow-channel mechanism rather than receptor deficiency, and antisense oligonucleotide strategies demonstrate restoration of functional receptor expression. Together, clinical response to cholinergic therapies and mechanistic data robustly implicate CHRNA1 in postsynaptic CMS.

Key take-home: Early genetic diagnosis of CHRNA1-mediated postsynaptic CMS enables precision therapy with pyridostigmine and 3,4-diaminopyridine.

References

  • Cureus • 2024 • Slow-Channel Congenital Myasthenic Syndrome Due to the Novel Variant c.1396G_A in CHRNA1 That Responds Favorably to 3,4-Diaminopyridine: A Case Report. PMID:39677241
  • Nature neuroscience • 1999 • Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating. PMID:10195214
  • Annals of neurology • 2006 • Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown. PMID:16685696

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single homozygous proband with postsynaptic CMS and no additional familial segregation ([PMID:39677241]).

Genetic Evidence

Limited

One proband with a homozygous pathogenic variant; no segregation data.

Functional Evidence

Moderate

Multiple heterologous expression studies demonstrating gain-of-function channel gating defects consistent with slow-channel syndrome ([PMID:10195214]; [PMID:16685696]).