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Cardiac phenotype in ATP1A3 -related syndromes

2020; Lippincott Williams & Wilkins; Volume: 95; Issue: 21 Linguagem: Inglês

10.1212/wnl.0000000000010794

1526-632X

Simona Balestrini, Mohamad A. Mikati, Reyes Álvarez‐García‐Rovés, Michael P. Carboni, Arsen Hunanyan, Bassil Kherallah, Melissa McLean, Lyndsey Prange, Elisa De Grandis, Alessandra Gagliardi, Livia Pisciotta, Michela Stagnaro, Edvige Veneselli, Jaume Campistol, Carmen Fons, Leticia Pías‐Peleteiro, Allison Brashear, Charlotte Miller, Raquel Samões, V. Branković, Quasar Saleem Padiath, Ana Potic, Jacek Pilch, Aikaterini Vezyroglou, Ann Bye, Andrew M. Davis, Monique M. Ryan, Christopher Semsarian, Georgina Hollingsworth, Ingrid E. Scheffer, Tiziana Granata, Nardo Nardocci, Francesca Ragona, Alexis Arzimanoglou, Eleni Panagiotakaki, Inês Carrilho, Claudio Zucca, Jan Nový, Karolina Dzieżyc, Marek Parowicz, Maria Mazurkiewicz‐Bełdzińska, Sarah Weckhuysen, Roser Pons, Sergiu Groppa, Daniel S. Sinden, Geoffrey S. Pitt, Andrew Tinker, Michael Ashworth, Zuzanna Michalak, Maria Thom, J. Helen Cross, Rosaria Vavassori, Juan Pablo Kaski, Sanjay M. Sisodiya,

Ion Transport and Channel Regulation

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.