{Reference Type}: Journal Article
{Title}: Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.
{Author}: 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;
{Journal}: Neurology
{Volume}: 95
{Issue}: 21
{Year}: 11 2020 24
{Factor}: 11.8
{DOI}: 10.1212/WNL.0000000000010794
{Abstract}: 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.