Kcnt2, also known as Slick, encodes for pore-forming alpha subunits of the sodium-activated potassium (KNa) channel [2]. This channel is rapidly gating, weakly voltage-and sodium-dependent, and is involved in processes like limiting peptidergic nociceptor excitability and hyperalgesia [3]. It is expressed in small-sized and medium-sized calcitonin gene-related peptide (CGRP)-containing dorsal root ganglia (DRGs) neurons [3].

Pathogenic variants in Kcnt2 are rare causes of developmental epileptic encephalopathy (DEE). In a study of 25 patients with Kcnt2 variants, phenotypes included intellectual disability/developmental delay, epilepsy, neurological impairment, and dysmorphisms [1]. Nineteen pathogenic variants were found, with some showing gain-of-function (GoF) and some loss-of-function (LoF) in vitro [1]. Quinidine and fluoxetine blocked GoF variants, while loxapine and riluzole had variable effects on LoF variants [1]. Also, Kcnt2 variants have been associated with Lhermitte-Duclos disease, and in a deeply phenotyped neuropathy cohort, the KCNT2 locus was linked with pain intensity [2,4].

In conclusion, Kcnt2 plays a crucial role in maintaining normal neuronal excitability as seen through its functions in nociceptor regulation and its association with DEE. The study of Kcnt2-related disorders through patient-based research has provided insights into the genotype-phenotype correlations and potential targeted therapies for these rare neurological conditions.