Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study

S. Balestrini, M.A. Mikati, R. Álvarez-García-Rovés, M. Carboni, A.S. Hunanyan, B. Kherallah, M. McLean, L. Prange, E. De Grandis, A. Gagliardi, L. Pisciotta, M. Stagnaro, E. Veneselli, J. Campistol, C. Fons, L. Pias-Peleteiro, A. Brashear, C. Miller, R. Samões, V. BrankovicQ.S. Padiath, A. Potic, J. Pilch, A. Vezyroglou, A.M.E. Bye, A.M. Davis, M.M. Ryan, C. Semsarian, G. Hollingsworth, I.E. Scheffer, T. Granata, N. Nardocci, F. Ragona, A. Arzimanoglou, E. Panagiotakaki, I. Carrilho, C. Zucca, J. Novy, K. Dzieżyc, M. Parowicz, M. Mazurkiewicz-Bełdzińska, S. Weckhuysen, R. Pons, S. Groppa, D.S. Sinden, G.S. Pitt, A. Tinker, M. Ashworth, Z. Michalak, M. Thom

Research output: Contribution to journalArticlepeer-review


OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: 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 ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: 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. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-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 Atp1a3-related disease. ATP1A3-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.

Original languageEnglish
Pages (from-to)e2866-e2879
Issue number21
Publication statusPublished - 2020


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