View ORCID Profile Simona Balestrini, Mohamad A Mikati, Reyes Alvarez Garcia-Roves,  View ORCID Profile Michael Carboni, Arsen S Hunanyan, Bassil Kherallah, Melissa McLean, Lyndsey Prange, Elisa De Grandis, Alessandra Gagliardi,  View ORCID Profile Livia Pisciotta, Michela Stagnaro, Edvige Veneselli, Jaume Campistol, Carmen Fons, Leticia Pias-Peleteiro,  View ORCID Profile Allison Brashear, Charlotte Miller, Raquel Samoes, Vesna Brankovic, Quasar S Padiath, Ana Potic,  View ORCID Profile Jacek Pilch, Katharina Vezyroglou,  View ORCID Profile Ann M E Bye,  View ORCID Profile Andrew M Davis,  View ORCID Profile Monique M Ryan, Christopher Semsarian, Georgina Hollingsworth, Ingrid E Scheffer, Tiziana Granata, Nardo Nardocci, Francesca Ragona,  View ORCID Profile Alexis Arzimanoglou, Eleni Panagiotakaki, Ines Carrilho, Claudio Zucca, Jan Novy, Karolina Dzieżyc, Marek Parowicz,  View ORCID Profile Maria Mazurkiewicz-Bełdzińska,  View ORCID Profile Sarah Weckhuysen, Roser Pons, Sergiu Groppa, Daniel S Sinden, Geoffrey S Pitt, Andrew Tinker, Michael Ashworth, Zuzanna Michalak,  View ORCID Profile Maria Thom, J Helen Cross, Rosaria Vavassori,  View ORCID Profile Juan P Kaski, Sanjay M SisodiyaFirst published September 10, 2020, DOI:


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 had at least one 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. 98 AHC, nine RDP, and three CAPOS patients (63 females, mean age 17 years) were included. Resting EKG abnormalities were found in 52/87 (60%) AHC, 2/3 (67%) CAPOS, and 6/9 (67%) RDP patients. Serial EKGs showed dynamic changes in 10/18 AHC patients. The first Holter EKG was abnormal in 24/65 (37%) AHC and RDP cases, with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3/98 (∼3%) AHC patients. In the mouse model, resting EKGs showed intra-cardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions. We found an increased prevalence of EKG 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 as well as neurological diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from the insertion of a pacemaker or implantable cardioverter-defibrillator.

The Article is available for Open Access on the NEUROLOGY Website at this link
Read the pdf version of the Editorial Comment

   ECG2 ATP1A3 Study Authors    

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