<i>ATP1A3</i>-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.

Abstract

Background Pathogenic variation in the <i>ATP1A3</i>-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic basis for this risk remains unknown. The objective was to determine the role of <i>ATP1A3</i> genetic variants on cardiac outcomes as determined by QT and corrected QT (QTc) measurements. Methods and Results We analyzed 12-lead ECG recordings from 62 patients (male subjects=31, female subjects=31) referred for AHC evaluation. Patients were grouped according to AHC presentation (typical versus atypical), <i>ATP1A3</i> variant status (positive versus negative), and <i>ATP1A3</i> variant (D801N versus other variants). Manual remeasurements of QT intervals and QTc calculations were performed by 2 pediatric electrophysiologists. QTc measurements were significantly shorter in patients with positive <i>ATP1A3</i> variant status (<i>P</i><0.001) than in patients with genotype-negative status, and significantly shorter in patients with the ATP1A3-D801N variant than patients with other variants (<i>P</i><0.001). The mean QTc for ATP1A3-D801N was 344.9 milliseconds, which varied little with age, and remained <370 milliseconds throughout adulthood. <i>ATP1A3</i> genotype status was significantly associated with shortened QTc by multivariant regression analysis. Two patients with the ATP1A3-D801N variant experienced ventricular fibrillation, resulting in death in 1 patient. Rare variants in <i>ATP1A3</i> were identified in a large cohort of genotype-negative patients referred for arrhythmia and sudden unexplained death. Conclusions Patients with AHC who carry the ATP1A3-D801N variant have significantly shorter QTc intervals and an increased likelihood of experiencing bradycardia associated with life-threatening arrhythmias. <i>ATP1A3</i> variants may represent an independent cause of sudden unexplained death. Patients with AHC should be evaluated to identify risk of sudden death.