Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.
AuthorBalestrini, S; Mikati, MA; Álvarez-García-Rovés, R; Carboni, M; Hunanyan, AS; Kherallah, B; McLean, M; Prange, L; De Grandis, E; Gagliardi, A; ...
PublisherOvid Technologies (Wolters Kluwer Health)
University of Melbourne Author/sRyan, Monique; Scheffer, Ingrid; Davis, Andrew; Hollingsworth, Georgina
Medicine and Radiology
Document TypeJournal Article
CitationsBalestrini, S., Mikati, M. A., Álvarez-García-Rovés, R., Carboni, M., Hunanyan, A. S., Kherallah, B., McLean, M., Prange, L., De Grandis, E., Gagliardi, A., Pisciotta, L., Stagnaro, M., Veneselli, E., Campistol, J., Fons, C., Pias-Peleteiro, L., Brashear, A., Miller, C., Samões, R. ,... Sisodiya, S. M. (2020). Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.. Neurology, 95 (21), pp.e2866-e2879. https://doi.org/10.1212/WNL.0000000000010794.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736
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.
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