Hunanyan Arsen S, Verma Amitesh, Bidzimou Minu-Tshyeto, Biswas Debolina D, Da Cruz Emily, Srour Meredith K, Marek Joshua, Hume Cordelia, Elmallah Mai K, Landstrom Andrew P, Mikati Mohamad A
Division of Pediatric Neurology and Developmental Medicine, Department of Pediatrics, Duke University, Durham, North Carolina, USA.
Division of Pediatric Cardiology, Department of Pediatrics, Duke University, Durham, North Carolina, USA.
Epilepsia. 2025 Mar;66(3):899-913. doi: 10.1111/epi.18236. Epub 2025 Jan 11.
This study was undertaken to test the following hypotheses in the Atp1a3 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 Atp1a3 mice have central cardiorespiratory dysregulation and abnormal respiratory drive.
Comparison was made of littermate wild-type and Atp1a3 groups using (1) simultaneous in vivo video-telemetry recordings of electroencephalogram, electrocardiogram, and breathing; (2) whole-body plethysmography; and (3) hypoglossal nerve recordings.
In Atp1a3 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.
Atp1a3, 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.
本研究旨在验证Atp1a3小鼠（携带最常见的人类ATP1A3突变，即神经元钠/钾 - 三磷酸腺苷酶[ATP酶]的主要亚基D801N）中的以下假设：癫痫性猝死（SUDEP）发生在癫痫发作期间，部分是由于终末期呼吸暂停，部分是由于致命性心律失常；并且Atp1a3小鼠存在中枢性心肺调节异常和呼吸驱动异常。
对同窝野生型和Atp1a3组进行比较，采用（1）同步体内视频遥测记录脑电图、心电图和呼吸；（2）全身体积描记法；以及（3）舌下神经记录。
在Atp1a3小鼠中，（1）SUDEP始终发生在比终末期前发作更严重的癫痫发作期间；（2）在SUDEP之前的时期出现癫痫发作聚集；（3）在终末期前和终末期癫痫发作前观察到发作前期呼吸频率（BR）和心率减慢；（4）终末期癫痫发作期间的顺序如下：呼吸过缓伴心动过缓/心律失常，然后是终末期呼吸暂停，接着是终末期心律失常。与野生型相比，突变体表现出（1）静息BR变异性异常，但心脏PR、QRS、QTc或RR间期无差异；（2）对缺氧的舌下神经放电异常；以及（3）全身体积描记法异常，包括基线时的呼吸暂停倾向和对呼吸刺激的异常反应。
Atp1a3是一种儿童交替性偏瘫（AHC）模型，也是一种揭示性SUDEP模型，其钠/钾 - ATP酶突变导致中枢呼吸驱动异常以及随着癫痫恶化并发进行性心肺调节异常。SUDEP由癫痫发作引发的呼吸过缓/心动过缓，随后是终末期呼吸暂停，然后是终末期心律失常导致。由于许多其他病因的癫痫/SUDEP模型表现出继发性ATP酶缺乏，未来在这些模型中的研究可能也会受益于考虑ATP酶功能障碍对这些模型中SUDEP的可能贡献。
