Editorial: Pathogenic Potassium Channel Variants in Neurological Disorders: From Functional Analysis to Personalized Pharmacological Approaches

Ilenio Servettini^1*Luca Guglielmi²Luigi Sforna³Luigi Catacuzzeno^3*

• ¹Department of Medicine and Health Sciences Vincenzo Tiberio, University of Molise, Campobasso, Italy
• ²MRC Laboratory of Molecular Biology (LMB), University of Cambridge, Cambridge, England, United Kingdom
• ³Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Umbria, Italy

The well-established link between specific K⁺ channel mutations and neurological disorders like epilepsy, ataxia, intellectual disability, neurocognitive delay and autism spectrum disorders has been extensively studied (Sicca et al., 2016;D' Adamo et al., 2020;Guglielmi et al., 2015;Ambrosini et al. 2014;Allen NM et al., 2020;Cheng P et al.,2021). Initial discoveries focused on a limited number of mutations, enabling detailed functional characterization in terms of the changes in the biophysical properties of the channel as well as their consequence on physiopathological processes. However, the advent of advanced genetic sequencing and increased awareness of K⁺ channel relevance in neuronal physiology have dramatically expanded the list of pathogenic variants. These studies have highlighted how the phenotype associated to the neurological disease is often variable and likely dependent on the nature of the genetic mutation and the functional consequences produced on K + channel expression and activity (Soldovieri et al., 2024;Wei AD et al., 2022;Cioclu MC et al., 2023;Bar C et al. 2020). Thus, understanding the functional effects of novel disease-linked variants is key to better stratify patients, with the final aim of providing personalized therapies. Furthermore, an in-depth characterization of K⁺ channel disfunction in disease would ease drug repurposing, which has already yielded promising, albeit limited, clinical results (Hedrich UBS et al, 2021;Ambrosino P et al, 2023). Despite these advances, the pace of variant discovery has outpaced our ability to functionally characterize them, creating a widening knowledge gap. With this Research Topic, we aim to help close this gap by highlighting eight key studies providing significant new insights into the consequences of K⁺ channels mutations in neurological disorders. 2024) identified a gain-of-function (GoF) S937G variant in the KCNT1 gene (encoding the KNa1.1 channel) in a girl with drug-resistant focal seizures, developmental delay, and behavioural disorders. Functional analysis using patch-clamp on transfected CHO cells confirmed the GoF phenotype. In vitro electrophysiology demonstrated that fluoxetine significantly reduced the aberrant current. Subsequently, fluoxetine administration in the patient led to sustained EEG improvement and seizure cessation, alongside behavioural and cognitive benefits, suggesting its potential as a precision therapy for KCNT1-related GoF epilepsies. 2024) explored donepezil, an acetylcholinesterase inhibitor, as a potential therapy for developmental encephalopathy and autism caused by GoF mutations in KCNQ2/3 genes (Kv7 channels). In vitro studies on mouse hippocampal neurons showed donepezil reduced M-current density and increased firing frequency. A 12-month trial in four children with KCNQ2/3 GoF variants demonstrated improvements in cognitive and autistic features, suggesting donepezil repurposing as a novel treatment. Evidence from animal models suggests the involvement of multiple K + channel families in PTSDlike phenomena, suggesting that developing effective and safe channel modulators could significantly advance PTSD management.Although there is still much work to be done, we can consider the articles published in this research topic a step towards a translational approach based on the functional characterization of K + channel pathogenic variants, aiming at both a better genotype-phenotype correlation and a targeted therapeutic approach. In addition, the relevance of identifying specific modulators of K + channels is highlighted, both for Mendelian and non-Mendelian pathologies.