Author(s):
Balestrini, Simona ; Mikati, Mohamad A. ; Álvarez-García-Rovés, Reyes ; Carboni, Michael ; Hunanyan, Arsen S. ; Kherallah, Bassil ; McLean, Melissa ; Prange, Lyndsey ; De Grandis, Elisa ; Gagliardi, Alessandra ; Pisciotta, Livia ; Stagnaro, Michela ; Veneselli, Edvige ; Campistol, Jaume ; Fons, Carmen ; Pias-Peleteiro, Leticia ; Brashear, Allison ; Miller, Charlotte ; Samões, Raquel ; Brankovic, Vesna ; Padiath, Quasar S. ; Potic, Ana ; Pilch, Jacek ; Vezyroglou, Aikaterini ; Bye, Ann M.E. ; Davis, Andrew M. ; Ryan, Monique M. ; Semsarian, Christopher ; Hollingsworth, Georgina ; Scheffer, Ingrid E. ; Granata, Tiziana ; Nardocci, Nardo ; Ragona, Francesca ; Arzimanoglou, Alexis ; Panagiotakaki, Eleni ; Carrilho, Inês ; Zucca, Claudio ; Novy, Jan ; Dzieżyc, Karolina ; Parowicz, Marek ; Mazurkiewicz-Bełdzińska, Maria ; Weckhuysen, Sarah ; Pons, Roser ; Groppa, Sergiu ; Sinden, Daniel S. ; Pitt, Geoffrey S. ; Tinker, Andrew ; Ashworth, Michael ; Michalak, Zuzanna ; Thom, Maria ; Cross, J. Helen ; Vavassori, Rosaria ; Kaski, Juan P. ; Sisodiya, Sanjay M.
Date: 2020
Persistent ID: http://hdl.handle.net/10400.16/2686
Origin: Repositório Científico da Unidade Local de Saúde de Santo António (ULSSA)
Description
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.
