CHRNA4 – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

CHRNA4 encodes the α4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), and pathogenic variants in CHRNA4 underlie autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), also known as sleep-related hypermotor epilepsy. ADNFLE is characterized by clusters of brief hypermotor seizures during sleep, often beginning in childhood or adolescence, with variable penetrance and occasional neuropsychiatric comorbidities.

Clinical Validity

Overall classification: Definitive
Justification: Six independent pedigrees across diverse ethnic groups—Australian–Norwegian insertion (c.776_778insGCT), Japanese Ser284Leu, Spanish Ser280Phe, Korean Ser284Leu, de novo Ser284Leu, and other families—show co-segregation of CHRNA4 variants with ADNFLE and concordant functional data confirming altered receptor properties (6 families) (PMID:9175743, PMID:10563623, PMID:10448807, PMID:14623738, PMID:10939581, PMID:9339675).

Genetic Evidence

Inheritance is autosomal dominant. Segregation analysis across pedigrees identifies at least 28 additional affected relatives with CHRNA4 variants (PMID:10448807; PMID:14623738). Case series include over 50 probands harboring missense and small-insertion variants, predominantly clustering in the M2 transmembrane domain. Recurrent missense variants Ser252Leu, Ser280Phe, and Ser284Leu account for the majority of familial cases, with evidence for independent mutational events rather than founder effects (PMID:10448807; PMID:10802757). De novo Ser284Leu mutations have been reported in sporadic NFLE, confirming pathogenicity outside large families (PMID:10939581).

Functional / Experimental Evidence

Electrophysiological studies of M2-domain variants demonstrate increased acetylcholine sensitivity and altered calcium permeability consistent with a gain-of-function mechanism (PMID:9175743; PMID:10771020). Pharmacogenomic profiling of patients with Ser280Phe shows marked seizure reduction and cognitive improvement upon transdermal nicotine administration, underscoring mechanistic treatment potential (PMID:32097883).

Conflicting Evidence

Screening in large cohorts of idiopathic generalized epilepsy and sporadic NFLE indicates that CHRNA4 mutations are rare outside familial ADNFLE, supporting locus heterogeneity but not disputing the gene–disease link in classic pedigrees (PMID:11121188; PMID:10450598).

Integration and Clinical Utility

CHRNA4-related ADNFLE demonstrates a clear autosomal dominant inheritance with high penetrance in core families, a well-defined variant spectrum of gain-of-function alleles in the M2 domain, and robust electrophysiological and therapeutic validation. Genetic testing for CHRNA4 variants is recommended in patients presenting with nocturnal hypermotor seizures, with potential precision therapy via nicotinic agents.

Key Take-home: CHRNA4 pathogenic variants cause ADNFLE through gain-of-function effects on α4β2 nAChRs; genetic diagnosis enables targeted treatment and family counseling.

References

• Human molecular genetics • 1997 • An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. PMID:9175743
• Neurology • 1999 • A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. PMID:10563623
• Archives of neurology • 1999 • Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene. PMID:10448807
• Archives of neurology • 2003 • A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. PMID:14623738
• Annals of neurology • 2000 • A de novo mutation in sporadic nocturnal frontal lobe epilepsy. PMID:10939581
• European journal of pharmacology • 2000 • Neuronal nicotinic receptors in human epilepsy. PMID:10771020
• Epilepsy & behavior : E&B • 2020 • Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy. PMID:32097883

Evidence Based Scoring (AI generated)