Kv3.1 channelopathy: a novel loss-of-function variant and the mechanistic basis of its clinical phenotypes.

Background: KCNC1 encodes Kv3.1, a subunit of the Kv3 voltage-gated potassium channels. It is predominantly expressed in inhibitory GABAergic interneurons and cerebellar neurons.

Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.

Objective: To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy-causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype-phenotype-physiological correlations.

Methods: Ten cases with putative pathogenic variants in KCNC1 were studied.

Lack of response to quinidine in KCNT1-related neonatal epilepsy.

Objective: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro.

Methods: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol.

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

Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset epilepsy.

Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in 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 variants on local diagnostic multiple gene panel testing were also included.

Precision therapy for epilepsy due to mutations: A randomized trial of oral quinidine.

Objective: To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene .

Methods: A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to mutation. Order was block randomized and blinded.

A targeted resequencing gene panel for focal epilepsy.

Objectives: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies.

Methods: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing.

Results: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases.

KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine.

Objective: Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels.