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 (approximate to 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
(approximate to 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