Clinical and molecular characterization of KCNT1 -related severe early-onset epilepsy

Abstract

ObjectiveTo characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy.MethodsWe identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system.ResultsWe identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.ConclusionsGain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

“…The most commonly involved gene was KCNT1 (36/135, 27% cohort, including 20 reported cases). We identified KCNT1 variants in 16 new patients: 5 with novel KCNT1 variants (2 with p.R356W, 1 each with p.M267T, p.F909L, and p.F932L), and 11 previously described (see Supplementary Table 2).…”

The expanding spectrum of movement disorders in genetic epilepsies

“…Mutations in FHF1 (R52H), have been reported in patients with early onset epilepsy associated with progressive cerebellar atrophy and ataxia. 43 Moreover, some patients present with an early-onset choreiform movement disorder or generalized dystonia. 26,42 Axial hypotonia is frequently present though the majority of patients do not have other pyramidal tract signs.…”

“…[39][40][41] Potassium channel genes Autosomal dominant mutations in KCNT1, which encodes the sodium-activated potassium channel, are identified in a wide range of epileptic disorders from benign familial neonatal-infantile seizures and autosomal dominant nocturnal frontal lobe epilepsy to severe DEE syndromes, such as Ohtahara syndrome, West syndrome, and EIMFS. 26,43 KCNQ2, encoding the voltage-gated potassium channel (KQT-like subfamily), has been associated with benign familial neonatal-infantile seizures and more recently with DEE, including Ohtahara syndrome, 44 and West syndrome. 43 Moreover, some patients present with an early-onset choreiform movement disorder or generalized dystonia.…”

Lack of response to quinidine in KCNT1‐related neonatal epilepsy

“…The discovery that the class I antiarrhythmic drug quinidine can reverse channel overactivity in vitro led to its rapid clinical application in a patient with EIMFS and an R428Q (c1283G>A, pArg428Gln) variant with reported in vivo efficacy . Subsequently, reductions in seizure frequency have been observed in few patients, some with functionally milder gain‐of‐function mutations in KCNT1 , but treatment failures in other patients were also reported . A dissociation with regard to in vitro efficacy of quinidine on potassium current and in vivo responsiveness has been noted, with a distinct patient with an R428Q variant demonstrating the least effective seizure reduction with quinidine .…”