%0 Journal Article
%T Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.
%A Balestrini S
%A Mikati MA
%A Álvarez-García-Rovés R
%A Carboni M
%A Hunanyan AS
%A Kherallah B
%A McLean M
%A Prange L
%A De Grandis E
%A Gagliardi A
%A Pisciotta L
%A Stagnaro M
%A Veneselli E
%A Campistol J
%A Fons C
%A Pias-Peleteiro L
%A Brashear A
%A Miller C
%A Samões R
%A Brankovic V
%A Padiath QS
%A Potic A
%A Pilch J
%A Vezyroglou A
%A Bye AME
%A Davis AM
%A Ryan MM
%A Semsarian C
%A Hollingsworth G
%A Scheffer IE
%A Granata T
%A Nardocci N
%A Ragona F
%A Arzimanoglou A
%A Panagiotakaki E
%A Carrilho I
%A Zucca C
%A Novy J
%A Dzieżyc K
%A Parowicz M
%A Mazurkiewicz-Bełdzińska M
%A Weckhuysen S
%A Pons R
%A Groppa S
%A Sinden DS
%A Pitt GS
%A Tinker A
%A Ashworth M
%A Michalak Z
%A Thom M
%A Cross JH
%A Vavassori R
%A Kaski JP
%A Sisodiya SM
%J Neurology
%V 95
%N 21
%D 11 2020 24
%M 32913013
%F 11.8
%R 10.1212/WNL.0000000000010794
%X To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.<BR>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.<BR>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.<BR>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.