Hypokalemic periodic paralysis: novel perspectives from genetic mutations to clinical management.

Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant neuromuscular disorder characterized by episodic flaccid weakness with hypokalemia. It is primarily caused by mutations in the CACNA1S gene, encoding the voltage-gated calcium channel Cav1.1, and the SCN4A gene, encoding the voltage-gated sodium channel Nav1.4. A unified pathophysiological mechanism proposes that these mutations neutralize positively charged residues in the S4 voltage-sensor segments, generating "gating pore currents" (ω currents). These currents destabilize the resting membrane potential, trigger paradoxical depolarization, and lead to reversible loss of muscle excitability. Genotype-phenotype correlations are evident: CACNA1S mutations typically cause earlier onset and high male penetrance, whereas SCN4A mutations exhibit greater phenotypic heterogeneity and a propensity for interictal weakness. Genetic testing is the gold standard for diagnosis, and a targeted next-generation sequencing (NGS) panel is recommended as the first-tier diagnostic approach. Management focuses on trigger avoidance, acute potassium replacement, and long-term prophylaxis with carbonic anhydrase inhibitors or potassium-sparing diuretics; pregnant patients require a multidisciplinary care model. This review provides a systematic overview of the clinical diagnosis, pathogenesis, genotype-phenotype correlations, and individualized treatment of HypoPP, aiming to serve as a practical reference for its clinical management.