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

Journal Article (Journal Article;Multicenter Study)

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.

Full Text

Duke Authors

Cited Authors

  • Balestrini, S; Mikati, MA; Álvarez-García-Rovés, R; Carboni, M; Hunanyan, AS; Kherallah, B; McLean, M; Prange, L; De Grandis, E; Gagliardi, A; Pisciotta, L; Stagnaro, M; Veneselli, E; Campistol, J; Fons, C; Pias-Peleteiro, L; Brashear, A; Miller, C; Samões, R; Brankovic, V; Padiath, QS; Potic, A; Pilch, J; Vezyroglou, A; Bye, AME; Davis, AM; Ryan, MM; Semsarian, C; Hollingsworth, G; Scheffer, IE; Granata, T; Nardocci, N; Ragona, F; Arzimanoglou, A; Panagiotakaki, E; Carrilho, I; Zucca, C; Novy, J; Dzieżyc, K; Parowicz, M; Mazurkiewicz-Bełdzińska, M; Weckhuysen, S; Pons, R; Groppa, S; Sinden, DS; Pitt, GS; Tinker, A; Ashworth, M; Michalak, Z; Thom, M; Cross, JH; Vavassori, R; Kaski, JP; Sisodiya, SM

Published Date

  • November 24, 2020

Published In

Volume / Issue

  • 95 / 21

Start / End Page

  • e2866 - e2879

PubMed ID

  • 32913013

Pubmed Central ID

  • PMC7734736

Electronic International Standard Serial Number (EISSN)

  • 1526-632X

Digital Object Identifier (DOI)

  • 10.1212/WNL.0000000000010794


  • eng

Conference Location

  • United States