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

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2020-11

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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.

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Humans, Foot Deformities, Congenital, Hearing Loss, Sensorineural, Seizures, Optic Atrophy, Cerebellar Ataxia, Hemiplegia, Reflex, Abnormal, Cohort Studies, Phenotype, Mutation, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Sodium-Potassium-Exchanging ATPase, Young Adult

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https://hdl.handle.net/10161/24313

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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