ATP1A3-related neurological disorders: updated insights into clinical heterogeneity, molecular mechanisms and...

ATP1A3-related neurological disorders comprise a rapidly expanding spectrum of rare neurogenetic diseases characterized by remarkable clinical heterogeneity and complex genotype-phenotype relationships. Since the publication of previous comprehensive reviews, the identification of novel ATP1A3-associated phenotypes, refinement of genotype-phenotype correlations, and advances in molecular pathogenesis and precision therapeutic strategies have substantially expanded current understanding of these disorders, highlighting the need for an updated synthesis. This narrative review summarizes recent advances in the clinical spectrum of ATP1A3-related disorders and discusses current insights into genotype-phenotype correlations, molecular mechanisms, and disease pathogenesis. Particular emphasis is placed on the molecular consequences of ATP1A3 dysfunction, including impaired Na⁺/K⁺-ATPase activity, disrupted neuronal excitability, altered ion homeostasis, and downstream cellular responses. We further review current symptomatic management and emerging disease-modifying therapeutic strategies, including antisense oligonucleotide therapy, viral vector-mediated gene delivery, genome editing technologies, and other precision medicine approaches. Current challenges and future research priorities are also discussed. By integrating recent clinical and experimental evidence, this review provides an updated perspective on ATP1A3-related disorders and aims to facilitate improved disease recognition, mechanistic understanding, and the development of targeted therapeutic strategies.