Mishra Vikas, Karumuri Bharat K, Gautier Nicole M, Liu Rui, Hutson Timothy N, Vanhoof-Villalba Stephanie L, Vlachos Ioannis, Iasemidis Leonidas, Glasscock Edward
Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
Biomedical Engineering, Louisiana Tech University, Ruston, LA 71272, USA.
Hum Mol Genet. 2017 Jun 1;26(11):2091-2103. doi: 10.1093/hmg/ddx104.
People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.
癫痫患者因癫痫性猝死（SUDEP）导致过早死亡的概率大幅增加。由于复杂的遗传病因、对潜在病理生理学的不完全理解以及缺乏预后生物标志物，确定哪些患者最易发生SUDEP受到阻碍。在此，我们评估了杂合型Scn2a基因缺失（Scn2a+/-）在SUDEP的Kcna1基因敲除小鼠（Kcna1-/-）模型中作为一种保护性遗传修饰因子的作用，同时寻找脑电图（EEG）和心电图（ECG）记录中所蕴含的SUDEP风险生物标志物。人类癫痫基因Kcna1编码电压门控性Kv1.1钾通道，其作用是抑制神经元兴奋性，而Scn2a编码对动作电位起始和传导很重要的电压门控性Nav1.2钠通道。具有部分Nav1.2通道基因消融的SUDEP易感Kcna1-/-小鼠（即Scn2a+/-; Kcna1-/-）存活率提高了两倍。分别对EEG和ECG记录进行的经典分析显示，与Kcna1-/-小鼠相比，Scn2a+/-; Kcna1-/-小鼠的癫痫发作持续时间显著缩短，而心脏异常无实质性改变。对EEG和ECG进行的新分析显示，与野生型相比，Kcna1-/-小鼠的EEG-ECG关联性显著降低，而在Scn2a+/-; Kcna1-/-小鼠中部分恢复。EEG-ECG关联性程度也与各基因型小鼠的存活率成正比。这些结果表明，Scn2a基因缺失可作为SUDEP的保护性遗传修饰因子，并提示脑-心关联指标可作为SUDEP易感性的潜在指标。
