1 NIHR University College London Hospitals Biomedical Research Centre, Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
Brain. 2013 Oct;136(Pt 10):3140-50. doi: 10.1093/brain/awt233. Epub 2013 Sep 6.
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
癫痫包括多种综合征，其中最常见的是伴海马硬化的内侧颞叶癫痫。伴海马硬化的内侧颞叶癫痫的发作通常对药物有抗性，并且常伴有重要的合并症，这需要我们更好地理解和治疗。伴海马硬化的内侧颞叶癫痫的病因尚不清楚，但与儿童热性惊厥有关。几种伴有热性惊厥的罕见癫痫是由 SCN1A 基因突变引起的，该基因编码大脑表达的钠通道亚基，许多抗癫痫药物都以其为靶点。我们对 1018 名伴海马硬化的内侧颞叶癫痫患者和 7552 名对照者进行了全基因组关联研究，并在包含 959 名伴海马硬化的内侧颞叶癫痫患者和 3591 名对照者的独立样本中进行了验证。为了剖析与热性惊厥史相关的变异，我们测试了伴有（总病例数为 757 例）和不伴有（总病例数为 803 例）热性惊厥史的伴海马硬化的内侧颞叶癫痫患者。荟萃分析显示，与伴海马硬化的内侧颞叶癫痫伴热性惊厥相关的基因簇在 2q24.3 染色体上具有全基因组显著相关性[rs7587026，位于 SCN1A 基因内含子中，P = 3.36×10(-9)，优势比（A）= 1.42，95%置信区间：1.26-1.59]。在 172 名热性惊厥患者（前瞻性随访至 13 岁时未发生癫痫）和 6456 名对照者的队列中，未发现 rs7587026 与热性惊厥相关。这些发现表明 SCN1A 参与了一种常见的癫痫综合征，为理解伴海马硬化的内侧颞叶癫痫伴热性惊厥提供了新的方向，并为研究某些热性惊厥儿童的预后因素和可能的癫痫预防开辟了途径。
