Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study

Neurology. 2020 Nov 24;95(21):e2866-e2879. doi: 10.1212/WNL.0000000000010794. Epub 2020 Sep 10.


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • ATP1A3 protein, human
  • Sodium-Potassium-Exchanging ATPase

Supplementary concepts

  • Alternating hemiplegia of childhood
  • CAPOS syndrome