Pathogenic variants in ATP1A3 encoding the neuronal Na/K-ATPase cause a spectrum of neurodevelopmental disorders including alternating hemiplegia of c…

Mutations in the ATP1A3 gene cause movement disorders characterized by dystonia. Akkuratov, Sorrell, and Picton et al. generate an ATP1A3 mutant mouse, and

UCL Discovery is UCL's open access repository, showcasing and providing access to UCL research outputs from all UCL disciplines.

UCL Discovery is UCL's open access repository, showcasing and providing access to UCL research outputs from all UCL disciplines.

UCL Discovery is UCL's open access repository, showcasing and providing access to UCL research outputs from all UCL disciplines.

Background ATP1A3-related disorders are characterized by genetic heterogeneity and phenotypic pleiotropy, posing significant challenges for classification. Although canonical phenotypes have traditi...

Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K…

Short QT syndrome is a heritable arrhythmia disorder linked to sudden cardiac death. We recently identified that individuals with alternating hemiplegia of childhood (AHC), a rare neurodevelopmental disorder, can exhibit shortened corrected QT intervals and elevated risk for ventricular fibrillation. This is especially true for patients with AHC heterozygous for the recurrent ATP1A3-D801N variant, though the underlying cardiac mechanism remains unclear. We hypothesized that the D801N missense impairs Na+/K+-ATPase function, causing Ca2+ overload, shortened action potential duration (APD), and arrhythmias. Using in silico modeling and patient-derived induced pluripotent stem cell cardiomyocytes (iPSC-CMsD801N), we observed shorter APD, elevated intracellular and sarcoplasmic reticulum Ca2+ levels, and delayed afterdepolarizations (DADs) compared with WT. Additionally, increased Ca²+ influx via the Na+/Ca2+ exchanger (NCX1) during depolarization was observed in iPSC-CMsD801N. Simulations and in vitro experiments suggest that reduced ATPase function accelerated inactivation of L-type Ca2+ channels. Pharmacologic inhibition of NCX1 with ORM-10103 normalized APD and reduced DADs. These findings support a Ca2+-mediated mechanism for arrhythmogenesis in ATP1A3-D801N carriers and identify NCX1 as a potential therapeutic target.

Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manife