ATP1A3 Variants, Variably Penetrant Short QT Intervals, and Lethal Ventricular Arrhythmias

Importance: Alternating hemiplegia of childhood (AHC) is a disorder that can result from pathogenic variants in ATP1A3-encoded sodium-potassium adenosine triphosphatase alpha 3 (ATP1A3). While AHC is primarily a neurologic disease, some individuals experience sudden unexplained death (SUD) potentially associated with cardiac arrhythmias. Objective: To determine the impact of ATP1A3 variants on cardiac electrophysiology and whether lethal ventricular arrhythmias are associated with SUD in patients with AHC. Design, Setting, and Participants: In this international, multicenter case-control study from 12 centers across 10 countries, patients with AHC were grouped by ATP1A3 variant status (positive vs negative) and into subgroups with the most common AHC variants (D801N, E815K, G947R, and other). A healthy control cohort was established for comparison. Blinded, manual measurements of QT intervals and corrected QT interval (QTc) were performed independently by 2 pediatric cardiac electrophysiologists. Induced pluripotent stem cell cardiomyocytes were derived from patients with AHC who were positive for the D801N variant of ATP1A3 (iPSC-CM^D801N cells). Data analysis was performed from April to June 2022. Exposure: Presence of ATP1A3 variant. Main Outcomes and Measures: The primary outcome was QTc. Outcomes, including survival, were abstracted and variants were mapped on cryogenic electron microscopy structure maps. iPSC-CM^D801N cells were used to validate ventricular repolarization and arrhythmic susceptibility in vitro. Results: Among the 222 individuals included (148 with AHC and 74 control), the mean (SD) age at diagnostic electrocardiography was 11.0 (9.4) years and 119 (54%) were female. The cohort with AHC consisted of 148 largely unrelated probands (mean [SD] age at diagnostic electrocardiography, 11.5 [10.5] years). Of these, 123 individuals were ATP1A3 genotype positive, including 35 (28%) with the D801N variant, 21 (17%) with the E815K variant, 8 (7%) with the G947R variant, and 8 (7%) with a loss-of-function variant. Probands with the D801N variant had shorter mean (SD) QTcs (381.8 [36.6] milliseconds; 24 [69%] with QTc <370 milliseconds) compared with those who had the E815K variant (393.6 [43.1] milliseconds; P =.001; 4 [19%] with QTC <370 milliseconds), the G947R variant (388.4 [26.5] milliseconds; P =.02; 1 [13%] with QTc <370 milliseconds), a loss-of-function variant (403.0 [33.5] milliseconds; P <.001; 1 [13%] with QTc <370 milliseconds), all other variants (387.8 [37.1] milliseconds; P <.001; 44 [86%] with QTc <370 milliseconds), and healthy controls (415.4 [21.0] milliseconds; P <.001; 0 with QTc <370 milliseconds). Three D801N-positive individuals had a major cardiac event, compared with 0 major cardiac events in all other individuals (P =.02). The D801N variant and 4 rare variants (D805N, P323S, S772R, and C333F) found in individuals with the shortest QTcs localized to the potassium-binding domain of ATP1A3. IPSC-CM^D801N lines demonstrated shortened action potential duration, higher mean diastolic potential, and delayed afterdepolarizations compared with controls. Conclusions and Relevance: Nearly 70% of individuals with D801N variants of ATP1A3 had short QTcs (<370 milliseconds), with an association between ventricular arrhythmias and cardiac arrest. This may underlie the SUD etiology in AHC.