CHRNA2 – sleep-related hypermotor epilepsy

Sequencing of CHRNA2 in a cohort of 150 probands (73 sporadic NFLE, 77 familial ADNFLE) with video-EEG–confirmed diagnosis revealed a heterozygous c.889A>T (p.Ile297Phe) variant in one large family (≈0.6% of the cohort; 1.2% of familial cases), segregating in all six living affected relatives (PMID:25770198). A second heterozygous missense variant, c.754T>C (p.Tyr252His), was identified in a sporadic case and inherited from an asymptomatic parent (PMID:30809122). Both variants were absent in screens of 46 unrelated Italian NFLE patients (PMID:18226955) and in 11 paroxysmal hypnogenic dyskinesia patients (PMID:27123484), underscoring the overall rarity of CHRNA2 mutations. These findings support an autosomal dominant mode with reduced penetrance and limited allelic heterogeneity in sleep-related hypermotor epilepsy.

Electrophysiological assays of the p.Ile297Phe and p.Tyr252His mutants in α2β4 and α2β2 nAChR subtypes demonstrated ~60–80% reduction in whole-cell currents without affecting receptor assembly or surface expression (PMID:25770198; PMID:30809122). These data establish a loss-of-function mechanism consistent with haploinsufficiency and correlate with nocturnal hypermotor seizures recorded by video-EEG. The absence of gain-of-function CHRNA2 variants and negative mutation screens in multiple NFLE and PHD cohorts further delineate the limited contribution of CHRNA2 to disease. Overall, current genetic and experimental evidence achieves Limited clinical validity. Key Take-home: CHRNA2 mutations are a rare cause of autosomal dominant sleep-related hypermotor epilepsy and should be considered in diagnostic panels despite low diagnostic yield.

References

• Sleep medicine | 2009 | CHRNA2 mutations are rare in the NFLE population: evaluation of a large cohort of Italian patients. PMID:18226955
• Neurology. Genetics | 2016 | Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene. PMID:27123484
• Neurology | 2015 | Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. PMID:25770198
• Frontiers in molecular neuroscience | 2019 | CHRNA2 and Nocturnal Frontal Lobe Epilepsy: Identification and Characterization of a Novel Loss of Function Mutation. PMID:30809122

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