Genetic Variants of Na+,K+-ATPase Associated With Neurological Disorders: A Systematic Review.

Abstract

Neurological disorders encompass a wide range of severe symptoms and manifestations, many of which are associated with genetic variants that affect ionic homeostasis. Na⁺,K⁺-ATPase, a transmembrane enzyme responsible for maintaining electrochemical gradients in cells, plays a crucial role in neuronal excitability and brain function. The present review aimed to systematically identify and organize published data on Na⁺,K⁺-ATPase variants reported in human studies with neurological outcomes, compiling this information into a structured format. Variants in the ATP1A1 (α1) gene are associated with epilepsy, developmental delay, autism spectrum disorder, and Charcot-Marie-Tooth disease (CMT). Variants in the ATP1A2 (α2) gene are mainly associated with familial hemiplegic migraine type 2 (FHM2) and sporadic hemiplegic migraine (SHM), and epilepsy. Moreover, severe neurodevelopmental phenotypes such as polymicrogyria and microcephaly arise from biallelic ATP1A2 loss-of-function variants. ATP1A3 (α3) variants present the broadest phenotypic diversity, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), cerebellar ataxia, childhood-onset schizophrenia, and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS) syndrome. Furthermore, the Gly41Arg variant in the FXYD2 gene is implicated in isolated dominant hypomagnesemia (IDH) with possible neurological manifestations. The structured compilation presented here consolidates data from 61 studies and covers 123 distinct variants across four Na⁺,K⁺-ATPase subunits, providing an annotated reference that may help future research.