Sisodiya Sanjay M, Ragge Nicola K, Cavalleri Gianpiero L, Hever Ann, Lorenz Birgit, Schneider Adele, Williamson Kathleen A, Stevens John M, Free Samantha L, Thompson Pamela J, van Heyningen Veronica, Fitzpatrick David R
Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, and National Society for Epilepsy, Bucks SL90RJ, London, UK.
Epilepsia. 2006 Mar;47(3):534-42. doi: 10.1111/j.1528-1167.2006.00464.x.
Seizures are noted in a significant proportion of cases of de novo, heterozygous, loss-of-function mutations in SOX2, ascertained because of severe bilateral eye malformations. We wished to determine the underlying cerebral phenotype in SOX2 mutation and to test the candidacy of SOX2 as a gene contributing to human epilepsies.
We examined high-resolution MRI scans in four patients with SOX2 mutations, two of whom had seizures. We determined the Sox2 expression pattern in developing murine brain. We searched for SOX2 mutation in 24 patients with typical hippocampal sclerosis and for common variations in SOX2 in 655 patients without eye disease but with epilepsy, including 91 patients with febrile seizures, 93 with hippocampal sclerosis, and 258 with temporal lobe epilepsy.
Striking hippocampal and parahippocampal malformations were seen in all cases, with a history of febrile seizures or epilepsy in two of four cases. The Sox2 expression pattern in developing mouse brain supports the pattern of malformations observed. Mutation screening in patients with epilepsy did not reveal any abnormalities in SOX2. No associations were found between any clinical epilepsy phenotype and common variation in SOX2.
SOX2 haploinsufficiency causes mesial temporal malformation in humans, making SOX2 dysfunction a candidate mechanism for mesial temporal abnormalities associated with chronic epilepsy. However, although mutation of SOX2 in humans causes hippocampal malformation, SOX2 mutation or variation is unlikely to contribute commonly to mesial temporal lobe epilepsy or its structural (hippocampal sclerosis) or historic (febrile seizures) associations in humans.
在因严重双侧眼部畸形而确诊的新发、杂合、功能丧失性SOX2突变病例中，有相当比例的患者出现癫痫发作。我们希望确定SOX2突变的潜在脑表型，并测试SOX2作为导致人类癫痫的基因的可能性。
我们检查了4例SOX2突变患者的高分辨率MRI扫描，其中2例有癫痫发作。我们确定了发育中小鼠大脑中Sox2的表达模式。我们在24例典型海马硬化患者中寻找SOX2突变，并在655例无眼部疾病但患有癫痫的患者中寻找SOX2的常见变异，其中包括91例热性惊厥患者、93例海马硬化患者和258例颞叶癫痫患者。
所有病例均可见明显的海马和海马旁畸形，4例中有2例有热性惊厥或癫痫病史。发育中小鼠大脑中Sox2的表达模式支持观察到的畸形模式。癫痫患者的突变筛查未发现SOX2有任何异常。未发现任何临床癫痫表型与SOX2的常见变异之间存在关联。
SOX2单倍体不足导致人类内侧颞叶畸形，使SOX2功能障碍成为与慢性癫痫相关的内侧颞叶异常的候选机制。然而，尽管人类SOX2突变会导致海马畸形，但SOX2突变或变异不太可能普遍导致人类内侧颞叶癫痫或其结构（海马硬化）或病史（热性惊厥）关联。
