KCNT1 – Malignant Migrating Partial Seizures of Infancy

Malignant migrating partial seizures of infancy (MMPSI) is a rare early-onset epileptic encephalopathy characterized by pharmacoresistant migrating focal seizures and profound developmental delay. Patients typically present within the first months of life with focal seizures that shift location across cortical regions, often evolving into bilateral tonic–clonic events and refractory status epilepticus. The condition leads to severe neurodevelopmental arrest and high mortality. Genetic studies have identified KCNT1, encoding the sodium-activated potassium channel Slo2.2 (Slack), as a predominant cause of MMPSI.

Exome sequencing in three unrelated MMPSI probands revealed de novo missense variants in KCNT1, prompting targeted analysis in nine additional patients; mutations were found in 6 of 12 unrelated individuals (12 unrelated probands) ([PMID:23086397]). A subsequent screening of 362 patients with early-onset epileptic encephalopathies identified KCNT1 mutations in 9 of 18 MMPSI cases (50%) and one transmitted via somatic mosaicism ([PMID:26140313]). Autosomal dominant inheritance with de novo occurrence predominates.

All pathogenic KCNT1 variants reported in MMPSI are heterozygous missense changes clustering in the intracellular C-terminal and transmembrane domains. Recurrent hotspots include c.862G>A (p.Gly288Ser) identified in two sporadic cases, suggesting mutational hot spots (recurrent in 2 patients) ([PMID:24029078]). Other examples span p.Arg428Gln, p.Ala934Thr, p.Arg474Cys and p.Arg474Leu among unrelated probands.

Functional assays in Xenopus oocytes and mammalian cells demonstrate that MMPSI-associated KCNT1 variants produce a marked gain-of-function phenotype, with increased channel currents and leftward shifts in activation gating. Quinidine and bepridil effectively block both wild-type and mutant channels in vitro, with mutant channels showing heightened sensitivity to blockade ([PMID:26784557], [PMID:23086397]).

Targeted therapy with quinidine has been correlated with significant reduction in seizure frequency and improved psychomotor development in a KCNT1-positive MMPSI patient ([PMID:25042079]). Ketogenic diet therapy also yielded seizure amelioration in a case with a KCNT1 mutation, leading to hospital discharge without adverse effects ([PMID:26785903]).

Conflicting evidence arises from a study of six MMPSI patients in whom sequencing of KCNT1 (and other loci) did not reveal pathogenic variants, indicating genetic heterogeneity or undiscovered loci (6 patients) ([PMID:24315024]).

Collectively, autosomal dominant de novo missense KCNT1 mutations are a definitive cause of MMPSI, supported by multiple unrelated probands, robust segregation data, and concordant gain-of-function functional studies. Genetic testing of KCNT1 is essential for diagnosis, prognostication, and guiding precision therapy, including quinidine trials.

Key Take-home: KCNT1 gain-of-function mutations underlie MMPSI, and targeted blockade of hyperactive Slo2.2 channels offers a promising precision-medicine avenue.

References

• Nature Genetics • 2012 • De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy PMID:23086397
• Epilepsia • 2015 • De novo KCNT1 mutations in early-onset epileptic encephalopathy PMID:26140313
• Gene • 2013 • A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy PMID:24029078
• Molecular and Cellular Neurosciences • 2016 • Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy PMID:26784557
• Annals of Neurology • 2014 • Targeted treatment of migrating partial seizures of infancy with quinidine PMID:25042079
• Brain & Development • 2016 • Usefulness of ketogenic diet in a girl with migrating partial seizures in infancy PMID:26785903
• Epilepsy Research • 2014 • Lack of pathogenic mutations in six patients with MMPSI PMID:24315024

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