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Neurology ; 95(21): e2866-e2879, 2020 11 24.
Article in English | MEDLINE | ID: mdl-32913013

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.


Subject(s)
Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Hemiplegia/genetics , Mutation/genetics , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adolescent , Adult , Cerebellar Ataxia/metabolism , Cerebellar Ataxia/therapy , Child , Child, Preschool , Cohort Studies , Female , Foot Deformities, Congenital/metabolism , Foot Deformities, Congenital/therapy , Hearing Loss, Sensorineural/metabolism , Hearing Loss, Sensorineural/therapy , Hemiplegia/diagnosis , Hemiplegia/therapy , Humans , Infant , Male , Middle Aged , Optic Atrophy/metabolism , Optic Atrophy/therapy , Phenotype , Seizures/therapy , Young Adult
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