背景:这项研究旨在验证以下假设:系统性白细胞基因表达具有区分低发作频率和高发作频率难治性颞叶癫痫(TLE)的预后价值。
方法:对一系列难治性颞叶癫痫患者进行研究。基于平均每月2.0次癫痫发作的基线发作频率,低发作频率与高发作频率定义为≤2次发作/月和>2次发作/月,分别。分析系统性白细胞基因表达对TLE发作频率的预后价值。分析了所有差异表达的基因,使用Ingenuity®途径分析(IPA®)和Reactome,确定白细胞基因表达和生物学通路对癫痫发作频率具有预后价值。
结果:有10名男性和6名女性,平均年龄为39.4岁(范围:16至62岁,平均值标准误差:3.6年)。癫痫发作频率较高的有5名患者,低发作频率的有11名患者,分别。基于双重变化的阈值(p<0.001,FC>2.0,FDR<0.05)以及来自Reactome和Ingenuity®途径分析(IPA®)的至少两个途径内的表达,鉴定了13种差异表达的白细胞基因,与高发作频率组相比,这些基因在低发作频率组中都过表达。包括NCF2,HMOX1,RHOB,FCGR2A,PRKCD,RAC2,TLR1,CHP1,TNFRSF1A,IFNGR1,LYN,MYD88和CASP1。类似的分析确定了四个差异表达基因,当与低发作频率组相比时,它们都在高表达。包括AK1、F2R、GNB5和TYMS。
结论:通过参与神经炎症典型途径的特定白细胞基因的上调和下调来预测TLE的低发作频率和高发作频率,氧化应激和脂质过氧化,GABA(γ-氨基丁酸)抑制,以及AMPA和NMDA受体信号传导。此外,高发作频率-TLE与低发作频率-TLE在预后上的区别在于与GABA抑制和NMDA受体信号传导有关的特异性白细胞基因表达差异增加。根据白细胞基因表达,高发作频率和低发作频率患者似乎代表了两种机制上不同的颞叶癫痫形式。
BACKGROUND: This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE).
METHODS: A consecutive series of patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as ≤ 2 seizures/month and > 2 seizures/month, respectively. Systemic leukocyte gene expression was analyzed for prognostic value for TLE seizure frequency. All differentially expressed genes were analyzed, with Ingenuity® Pathway Analysis (IPA®) and Reactome, to identify leukocyte gene expression and biological pathways with prognostic value for seizure frequency.
RESULTS: There were ten males and six females with a mean age of 39.4 years (range: 16 to 62 years, standard error of mean: 3.6 years). There were five patients in the high and eleven patients in the low seizure frequency cohorts, respectively. Based on a threshold of twofold change (p < 0.001, FC > 2.0, FDR < 0.05) and expression within at least two pathways from both Reactome and Ingenuity® Pathway Analysis (IPA®), 13 differentially expressed leukocyte genes were identified which were all over-expressed in the low when compared to the high seizure frequency groups, including NCF2, HMOX1, RHOB, FCGR2A, PRKCD, RAC2, TLR1, CHP1, TNFRSF1A, IFNGR1, LYN, MYD88, and CASP1. Similar analysis identified four differentially expressed genes which were all over-expressed in the high when compared to the low seizure frequency groups, including AK1, F2R, GNB5, and TYMS.
CONCLUSIONS: Low and high seizure frequency TLE are predicted by the respective upregulation and downregulation of specific leukocyte genes involved in canonical pathways of neuroinflammation, oxidative stress and lipid peroxidation, GABA (γ-aminobutyric acid) inhibition, and AMPA and NMDA receptor signaling. Furthermore, high seizure frequency-TLE is distinguished prognostically from low seizure frequency-TLE by differentially increased specific leukocyte gene expression involved in GABA inhibition and NMDA receptor signaling. High and low seizure frequency patients appear to represent two mechanistically different forms of temporal lobe epilepsy based on leukocyte gene expression.