Potassium Channel-Related Developmental and Epileptic Encephalopathies: From Functional Mechanisms to Precision Therapeutics — A Narrative Review Focused on KCNQ2, KCNA2, KCNT1, and KCNB1

Abstract

Potassium channels are central regulators of neuronal resting membrane potential, action-potential repolarization, firing adaptation, and neurotransmitter release. Pathogenic variants in potassium-channel genes can produce a broad neurodevelopmental spectrum, ranging from self-limited epilepsy to severe developmental and epileptic encephalopathies (DEEs). Importantly, the direction of channel dysfunction cannot be inferred reliably from the clinical phenotype alone: loss-of-function, gain-of-function, dominant-negative, and mixed effects may converge on epilepsy through cell-type- and circuit-specific mechanisms. This narrative review examines four potassium channelopathies especially relevant to pediatric DEE and precision neurology—KCNQ2, KCNA2, KCNT1, and KCNB1. We integrate electroclinical phenotypes, functional mechanisms, genotype-phenotype correlations, conventional antiseizure treatment, and emerging mechanism-based therapies. KCNQ2 illustrates the clinical value of early molecular diagnosis, with sodium-channel blockers showing high effectiveness in loss-of-function neonatal epilepsies and recent multicenter data associating earlier treatment with earlier seizure offset and more favorable developmental trajectories. KCNA2 demonstrates the need for functional stratification because gain-of-function variants may respond to 4-aminopyridine. KCNT1-related epilepsy remains therapeutically challenging; quinidine has inconsistent clinical effectiveness, while antisense oligonucleotide strategies are supported by preclinical studies. KCNB1-related disorders combine epilepsy with prominent cognitive, language, and behavioral morbidity and currently lack a validated gene-specific therapy. Across these disorders, functional testing, natural-history cohorts, patient-centered outcomes, and trial-ready registries are essential for moving from gene diagnosis to disease modification. Potassium channelopathies provide a model for precision medicine in pediatric neurology in which treatment selection should increasingly integrate phenotype, variant mechanism, developmental timing, and evidence level rather than gene name alone.