Cardiac phenotype in <i>ATP1A3</i>-related syndromes: A multicenter cohort study.

Abstract

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1212/wnl.0000000000010794

Publication Info

Balestrini, Simona, Mohamad A Mikati, Reyes Álvarez-García-Rovés, Michael Carboni, Arsen S Hunanyan, Bassil Kherallah, Melissa McLean, Lyndsey Prange, et al. (2020). Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study. Neurology, 95(21). pp. e2866–e2879. 10.1212/wnl.0000000000010794 Retrieved from https://hdl.handle.net/10161/24313.

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Scholars@Duke

Mikati

Mohamad Abdul Mikati

Wilburt C. Davison Distinguished Professor

Mohamad A.  Mikati M.D., is the Wilburt C. Davison Professor of Pediatrics, Professor of Neurobiology, and Chief of the Division of Pediatric Neurology. Dr. Mikati’s clinical research has centered on characterization and therapy of pediatric epilepsy and neurology syndromes, describing several new pediatric neurological entities with two carrying his name (POSSUM syndromes # 3708 and 4468), developing novel therapeutic strategies for epilepsy and related disorders particularly Alternating Hemiplegia of Childhood, and applying cutting edge genetic and Magnetic Resonance Imaging techniques to drug resistant pediatric epilepsy.  In the laboratory he has elucidated mechanisms of seizure related neuronal injury, particularly those related to the ceramide pathway, and demonstrated neuroprotective effects of several agents including erythropoietin. Most recently he has concentrated his laboratory research on the pathophysiology of ATP1A3 dysfunction in the brain as model for epilepsy and of Alternating Hemiplegia of Childhood. He has more than 290 peer reviewed publications, 400 abstracts 41 chapters one book and two booklets. He also has more than 10,497 citations in the literature with an h-index of 58 and an i-10index of 190. Dr. Mikati has written chapters on epilepsy and related disorders in the major textbooks of Pediatrics and Pediatric Neurology including Swaiman’s Pediatric Neurology and Nelson’s Pediatrics. Before joining Duke in 2008 he had completed his M.D. and Pediatric training at the American University of Beirut, his Neurology at the Massachusetts General Hospital, his Neurophysiology at Boston Children’s Hospital and had been on the Faculty at Harvard as Director of Research in the Epilepsy Program at Boston Children’s Hospital and then as Professor and Chairman, Department of Pediatrics, Founder and Director of the Adult and Pediatric Epilepsy Program at the American University of Beirut. Dr. Mikati has had several international leadership roles including being President of the Union of the Middle Eastern and Mediterranean Pediatric Societies, on the Standing Committee of the International Pediatric Association (IPA), Chair of the Strategic Advisory Group on Early Childhood Development of the IPA, Officer of the International Child Neurology Association, Consultant to UNICEF, WHO, and the American Board of Pediatrics. He was selected to organize and chair the American Epilepsy Society's Merritt-Putnam Symposium and was one of only two Pediatric Neurologists, initially chosen worldwide, on the WHO advisory committee for the International Classification of Disease. He has received several national and international honors including, among others, Merritt Putnam American Epilepsy Society Fellowship Award, Harvard Community Health Plan Peer recognition Award, Debs Research Award, Hamdan Award for contributions to Medicine, Hans Zellweger Award for contributions to Pediatric Neurology, Patient Choice Award and the Michael Frank Award for research and lifetime contributions to the field of Pediatric Neurology.

Carboni

Michael Paul Carboni

Associate Professor of Pediatrics

Transplant cardiology
Heart failure and cardiomyopathy in children
Arrhythmias in children and congenital heart disease
Inherited arrhythmias/channelopathies (e.g., Long QT syndrome, Brugada Syndrome) 
Rhythm device management & implantation in children and congenital heart disease

Pitt

Geoffrey Stuart Pitt

Adjunct Professor in the Department of Medicine

Our research focuses on how intracellular Ca2+, the ultimate signal of membrane excitability, regulates membrane excitability and the consequent function of excitable cells. We have discovered and described multiple mechanisms that control Ca2+ influx through voltage-gated Ca2+ channels and feedback mechanisms by which internal calcium regulates other channels that influence Ca2+ channel function. The work has entailed structure-function analyses of ion channels and their regulatory subunits and studies of mutations that lead to inherited channelopathies such as cardiac arrhythmias and epilepsy.


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