Pharmacological approaches in drug-resistant pediatric epilepsies caused by pathogenic variants in potassium channel genes

作者：Ilaria Filareto, Ilaria Mosca, Elena Freri, Francesca Ragona, Laura Canafoglia, Roberta Solazzi, Barbara Castellotti, Giuliana Messina, Cinzia Gellera, Maria Virginia Soldovieri, Paolo Ambrosino, Maurizio Taglialatela, Jacopo C. DiFrancesco, Tiziana Granata · 发表于：Frontiers in Cellular Neuroscience · 年份：2025 · DOI：10.3389/fncel.2024.1512365 · 被引用次数：4 · 研究领域：Ion channel regulation and function、Epilepsy research and treatment、Cardiac electrophysiology and arrhythmias

Variants in genes encoding for voltage-gated K + (Kv) channels are frequent cause of drug-resistant pediatric epilepsies. Obtaining a molecular diagnosis gives the opportunity to assess the efficacy of pharmacological strategies based on in vitro features of mutant channels. In this retrospective observational study, we selected patients with drug-resistant pediatric epilepsies caused by variants in potassium channel encoding genes, followed at the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, Italy. After the experimental characterization of variants’ functional properties in transiently transfected Chinese Hamster Ovary (CHO) cells, we identified drugs to be used as pharmacological approaches. We recruited six patients carrying different missense variants in four Kv channels (Kv7.2, Kv7.3, Kv3.1, and K Na 1.1). In vitro experiments demonstrated that variants in Kv7 channels induced loss-of-function (LoF) effects, while those affecting Kv3.1 or K Na 1.1 led to gain-of-function (GoF). Moreover, we found that the Kv7 channels activator gabapentin was able to revert the LoF effects caused by Kv7.2/Kv7.3 variants, and the potassium channel-blocker fluoxetine counteracted the GoF effects in Kv3.1 or K Na 1.1 variants. According to experimental data, patients carrying Kv7 variants were treated with gabapentin. While this treatment resulted successful in two patients (#1, Kv7.2 G310S variant; #3, Kv7.3 V359L + Kv7.3 D542N), it resulted detrimental in the remaining cas...