Cardiac phenotype in <i>ATP1A3</i>-related syndromes: A multicenter cohort study.

Abstract

To define the risks and consequences of cardiac abnormalities in <i>ATP1A3</i>-related syndromes. Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with <i>ATP1A3</i> genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an <i>Atp1a3</i> knock-in mouse (Mashl^+/-) to determine the sequence of events in seizure-related cardiac death. Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. We found increased prevalence of ECG dynamic abnormalities in all <i>ATP1A3</i>-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine <i>Atp1a3</i>-related disease. <i>ATP1A3</i>-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.