A neurocutaneous Na_V1.8 channelopathy underlies a genetic subtype of primary idiopathic hyperhidrosis.

Abstract

Primary idiopathic hyperhidrosis (PIH) is a poorly understood disorder characterized by excessive sweating. We identify a genetically defined subset of PIH associated with rare coding changes in voltage-gated Na⁺ (Na_V) channels. Whole-exome sequencing of hereditary PIH families revealed gene-level enrichment within the Na_V channel family, with <i>SCN10A</i> (Na_V1.8) most strongly implicated. A knock-in mouse carrying the clinically observed Na_V1.8^p.R14L substitution recapitulated excessive sweating. Na_V1.8 was detected in a subset of postganglionic neurons in thoracic sympathetic ganglia in humans and mice, where p.R14L produced a gain-of-function profile that enhanced cholinergic responsiveness. Excessive sweating in mutant mice was reversible with Na_V channel inhibition, including clinically used agents and a Na_V1.8-preferential compound. Together, these findings define a targetable neurocutaneous channelopathy underlying a subset of PIH and support a model in which excessive sweating arises from either gland-intrinsic dysfunction or altered sympathetic drive, motivating stratified therapeutic approaches.