Abstract
ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients 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.ResultsNinety-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.ConclusionsWe 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.
Highlights
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
Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease
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
Summary
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. Patients Patients were recruited from 19 participating centers in 13 different countries: Duke University Medical Center, Durham, NC (n = 21); Istituto Giannina Gaslini, University of Genoa, Italy (n = 17); Hospital Sant Joan de De’u Barcelona, Spain (n = 13); Wake Forest School of Medicine, WinstonSalem, NC (n = 11); The National Hospital for Neurology and Neurosurgery, UK (n = 8); Department of Pediatric Neurology, Medical University of Silesia, Katowice, Poland (n = 6); University Clinic for Child Neurology and Psychiatry, Belgrade, Serbia (n = 5); Great Ormond Street Hospital for Children, UK (n = 5); Royal Children’s Hospital, Melbourne, Australia (n = 4); C. Patients meeting the clinical diagnostic criteria for typical AHC or other ATP1A3-associated syndromes and who underwent genetic analysis of ATP1A3, with or without identified mutations in ATP1A3, were included. Eleven patients were excluded due to genetic testing being unavailable or not performed (n = 3), poor-quality/uninterpretable cardiac data (n = 6), or pathogenic mutation in genes not associated with AHC being identified (n = 2) (figure 1). De novo mutation status was evaluated by Sanger sequencing when parental DNA was available; when unavailable, pathogenicity was declared if the same mutation was previously reported as de novo in another patient with an ATP1A3-related condition
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