Discovery of Novel Molecular Abnormalities Underlying Non-Lesional Focal Epilepsy

描述（由申请人提供）：本提案的目标是探索分子异常的作用-体细胞突变，微生物核酸的存在，或两者兼而有之-潜在的非病变局灶性癫痫（NLFE）。癫痫影响着世界上近1%的人口，其中三分之一的患者对目前可用的抗惊厥药物没有反应。对于这些患者来说，癫痫控制的最大希望来自于癫痫手术，切除癫痫病灶，当病灶可以被识别时。在MRI上明确显示病因病变的患者中，60-80%的患者术后无癫痫发作。在没有可识别的MRI病变的明确局灶性癫痫患者中，手术治愈率较低，约为30-50%。我们认为NLFE的问题是一个解决方案——异常可能在MRI上不可见，但在分子水平上以两种形式之一或两种形式存在：1)体细胞突变，在仅限于大脑的细胞中；2)微生物的存在，例如病毒核

DESCRIPTION (provided by applicant): The goal of this proposal is to explore the role of molecular abnormalities-somatic mutation, the presence of microbial nucleic acids, or both--underlying non-lesion focal epilepsy (NLFE). Epilepsy affects nearly 1% of the world's population and 1/3 of patients do not respond to currently available anticonvulsant medications. For these patients the best hope for seizure control comes from epilepsy surgery with resection of the seizure focus, when a focus can be identified. In patients for whom a causative lesion is clearly demonstrable on MRI, 60-80% of patients are seizure-free after surgery. In patients with clear focal epilepsy with no identifiable MRI lesion, surgical cure is less common, ranging from 30-50%. We propose that the problem of NLFE is one of resolution-that the abnormalities may not be visible on MRI but are present at the molecular level, in one or both of two forms: 1) somatic mutation, in cells restricted to brain and 2) the presence of microbial, e.g. viral nucleic acids, which may cause molecular abnormalities and influence epilepsy onset. There is some evidence to suggest that somatic mutation plays a role in epilepsies resulting from developmental structural lesions such as hemimegalencephaly, but somatic mutation has not yet been shown to occur in non-lesion epilepsies. The role of viral infection in epilepsy and developmental molecular lesions of the cortex has been suggested based on the detection of HHV6 in brain tissue from temporal lobe epilepsy patients with mesial temporal sclerosis and with the recent discovery of human papilloma virus in areas of focal cortical dysplasia, a developmental malformation strongly associated with epilepsy. The broader role of viruses in NLFE has not been demonstrated, nor the role of other pathogens. We will investigate whether somatic mutations and microbial nucleic acids are present in the seizure foci of individuals with epilepsy who undergo surgery, using next generation sequencing approaches to identify these molecular abnormalities in resected brain tissue. We will accomplish this using a systems biology approach, integrating state-of-the-art cortical intraoperative recordings to identify the seizure focus, co-registered with clinical, histopathology, and molecular sequence data. We will thereby create a repository of NLFE brain tissue with detailed phenotypic data which will be the first of its kind. Proving that seizures can arise from somatic mutations or infection without altering brain macrostructure would shift the paradigm for understanding epileptogenesis, and could lead to identification of novel biomarkers and treatments.