Progressive central cardiorespiratory rate downregulation and intensifying epilepsy lead to sudden unexpected death in epilepsy in mouse model of the most common human ATP1A3 mutation.

OBJECTIVE: This study was undertaken to test the following hypotheses in the Atp1a3Mashl/+ mouse (which carries the most common human ATP1A3 (the major subunit of the neuronal Na+/K+-adenosine triphosphatase [ATPase]) mutation, D801N): sudden unexpected death in epilepsy (SUDEP) occurs during seizures and is due to terminal apneas in some and due to lethal cardiac arrhythmias in others; and Atp1a3Mashl/+ mice have central cardiorespiratory dysregulation and abnormal respiratory drive. METHODS: Comparison was made of littermate wild-type and Atp1a3Mashl/+ groups using (1) simultaneous in vivo video-telemetry recordings of electroencephalogram, electrocardiogram, and breathing; (2) whole-body plethysmography; and (3) hypoglossal nerve recordings. RESULTS: In Atp1a3Mashl/+ mice, (1) SUDEP consistently occurred during seizures that were more severe than preterminal seizures; (2) seizure clustering occurred in periods preceding SUDEP; (3) slowing of breathing rate (BR) and heart rate was observed preictally before preterminal and terminal seizures; and (4) the sequence during terminal seizures was as follows: bradypnea with bradycardia/cardiac arrhythmias, then terminal apnea, followed by terminal cardiac arrhythmias. Compared to wild-type, mutants showed (1) abnormal resting BR variability but no difference in cardiac PR, QRS, QTc, or RR intervals; (2) abnormal hypoglossal nerve firing in response to hypoxia; and (3) abnormal whole-body plethysmography, consisting of baseline predisposition to apnea and abnormal responses to respiratory challenge. SIGNIFICANCE: Atp1a3Mashl/+, an alternating hemiplegia of childhood (AHC) model, is also a revealing SUDEP model of Na+/K+-ATPase mutation resulting in abnormal central respiratory drive and in progressive cardiorespiratory dysregulation concurrent with worsening epilepsy. SUDEP results from seizure-triggered bradypnea/bradycardia followed by terminal apnea, then terminal cardiac arrhythmias. Because many epilepsy/SUDEP models of other etiologies manifest secondary ATPase deficiency, future studies in those models may benefit from considering possible contributions of ATPase dysfunction to SUDEP in those models too.

Duke Scholars

Author Debolina Biswas  

Author Mai ElMallah Pediatrics, Pulmonary and Sleep Medicine

Author Mohamad Abdul Mikati Pediatrics, Neurology

Author Andrew Paul Landstrom Pediatrics, Cardiology