KCNT1 – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a focal epilepsy characterized by stereotyped nocturnal motor seizures and cognitive comorbidities. ADNFLE follows an autosomal dominant inheritance pattern with high penetrance and is associated with pathogenic variants in KCNT1 among other genes. Early onset and refractory night‐time convulsions underscore the need for molecular diagnosis to guide treatment and genetic counseling.

Initial linkage and sequencing studies identified a heterozygous KCNT1 missense mutation in a pedigree with ADNFLE and psychiatric features, with KCNT1 variants found in two additional families and one sporadic case (total 4 probands) (PMID:23086396). Segregation in these families and a later report of a novel c.2797C>T (p.Arg933Cys) in a father–daughter pair (2 probands) confirmed co-segregation across four independent families (PMID:36117860).

In ADNFLE cohorts, KCNT1 variants are exclusively missense, clustering in the C-terminal regulatory domains. Recurrent alleles include c.2686A>G (p.Met896Val) and c.2782C>T (p.Arg928Cys) in multiple families, indicating mutational hotspots at CG dinucleotides. Phenotypic variability ranges from isolated nocturnal seizures to broader developmental delay and behavioral disturbances, with an estimated carrier prevalence of ~1 in 100 000 based on diagnostic panels.

Functional analyses in Xenopus oocytes and mammalian cells demonstrate that ADNFLE-associated KCNT1 variants cause a marked gain of function, increasing KNa1.1 current amplitude and shifting activation to more hyperpolarized potentials. Quinidine and other channel blockers partially reverse this gain of function, establishing a genotype-directed therapeutic avenue (PMID:24591078; PMID:28366665). Animal and induced pluripotent stem cell models recapitulate hyperexcitability and respond to targeted blockade, supporting translational relevance.

The proposed pathogenic mechanism is a gain-of-function effect of KCNT1 variants leading to increased neuronal excitability and sleep‐related seizure susceptibility. Electrophysiological studies consistently show enhanced channel open probability and increased potassium conductance at subthreshold voltages, driving network hyperexcitability.

No studies to date have refuted the KCNT1–ADNFLE association. Together, genetic and functional data fulfill ClinGen criteria for a Strong gene–disease relationship.

Key take-home: KCNT1 missense gain-of-function variants cause autosomal dominant nocturnal frontal lobe epilepsy, and functional assays provide targets for personalized therapy.

References

• Nature Genetics | 2012 | Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. PMID:23086396
• Translational Neuroscience | 2022 | Autosomal dominant sleep-related hypermotor epilepsy associated with a novel mutation of KCNT1. PMID:36117860
• Annals of Neurology | 2014 | KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. PMID:24591078
• Neuroscience | 2017 | The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype. PMID:28366665

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