KCNT1 – Epilepsy of Infancy with Migrating Focal Seizures

Epilepsy of infancy with migrating focal seizures (EIMFS) is a severe early-onset developmental epileptic encephalopathy characterized by polymorphous focal seizures and profound neurodevelopmental impairment. Heterozygous de novo missense variants in KCNT1, encoding the sodium-activated potassium channel KNa1.1, underlie a majority of EIMFS cases, typically manifesting within the first month of life with refractory focal motor seizures PMID:31618474.

In large multicenter cohorts, KCNT1 mutations were identified in 36 of 135 unrelated EIMFS probands (27%), with 90% occurring de novo and one pedigree demonstrating paternal mosaic transmission and segregation in two affected uncles PMID:31618474; PMID:31872048. Affected relatives (n=2) exhibited overlapping nocturnal frontal lobe epilepsy phenotypes, confirming autosomal dominant inheritance.

The spectrum of pathogenic KCNT1 alleles is dominated by gain-of-function missense changes clustering in the channel’s C-terminus and pore-forming regions. A recurrent de novo variant, c.1420C>T (p.Arg474Cys), has been reported in multiple sporadic cases, reinforcing a hotspot for pathogenicity PMID:27081515.

Functional studies in Xenopus oocytes and human iPSC-derived neurons consistently demonstrate marked increases in KNa1.1 current amplitude and altered activation gating for EIMFS-associated mutants. Quinidine and other small-molecule blockers reverse gain-of-function currents in vitro, supporting a haploinsufficiency-rescue therapeutic approach PMID:24591078; PMID:31350261.

No studies have refuted the KCNT1–EIMFS link, and experimental concordance across models underscores a unified gain-of-function mechanism. Ongoing ASO and targeted drug screening efforts aim to refine precision treatments for this pharmacoresistant epilepsy.

Key Take-home: KCNT1 gain-of-function variants are a well-validated, autosomal dominant cause of EIMFS; early genetic diagnosis enables targeted pharmacotherapy and informs prognosis.

References

• Annals of Neurology • 2019 • The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures PMID:31618474
• Neurology: Genetics • 2019 • Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability PMID:31872048
• Annals of Neurology • 2014 • KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine PMID:24591078
• The Journal of Neuroscience • 2019 • An Epilepsy-Associated KCNT1 Mutation Enhances Excitability of Human iPSC-Derived Neurons by Increasing Slack KNa Currents PMID:31350261
• Human Genome Variation • 2014 • A novel KCNT1 mutation in a Japanese patient with epilepsy of infancy with migrating focal seizures PMID:27081515

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