Familial Focal Epilepsy with Focal Cortical Dysplasia Due to DEPDC5 Mutations
Familial Focal Epilepsy with Focal Cortical Dysplasia Due to DEPDC5 Mutations
复制标题
DOI：
10.1002/ana.24368
复制
发表时间：
2015-04-01
影响因子：
11.2
通讯作者：
Picard, Fabienne
中科院分区：
文献类型：
--
作者：
Baulac, Stephanie;Ishida, Saeko;Picard, Fabienne
目的编码 mTORC1 信号通路阻遏蛋白的 DEPDC5（含 DEP 结构域的蛋白 5）基因最近已成为家族性局灶性癫痫中的主要突变基因。我们的目的是进一步扩展 DEPDC5 在局灶性皮质发育不良 (FCD) 中的作用。方法招募了来自 4 个家族的 7 名患有 DEPDC5 突变且患有 FCD 相关局灶性癫痫的患者，并在临床、神经影像和组织病理学水平上进行了研究。从基因组血液和脑DNA中对DEPDC5基因进行测序。结果所有患者均患有耐药性局灶性癫痫，其中5例接受了手术，1例进行了脑活检。尽管磁共振成像 (MRI) 仅在 4 例病例中具有典型特征，但电临床表型与 FCD II 一致。组织病理学证实 2 名患者（包括 1 名 MRI 阴性病例）为 FCD IIa，另外 2 名患者显示为 FCD I，最后 2 名患者的组织病理学结果仍不确定。 3 名患者术后无癫痫发作，1 名患者病情有所改善。血液 DNA 测序显示所有 4 个家族均存在 DEPDC5 突变；在一位无症状的父亲身上发现了 1 个突变是嵌合体。除了种系突变外，在 1 名患者中还发现了脑体细胞 DEPDC5 突变。解释种系、种系嵌合体和脑体细胞 DEPDC5 突变可能导致与 FCD 相关的癫痫，从而加强了 mTORC1 通路与 FCD 之间的联系。与其他 mTORopathies 类似，2 次突变模型可能导致皮质病变。我们的研究还表明，即使 MRI 表现不明显，癫痫手术也是治疗耐药 DEPDC5 阳性局灶性癫痫的一种有价值的替代方案。安·尼罗尔 2015；77:675-683
ObjectiveThe DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has recently emerged as a major gene mutated in familial focal epilepsies. We aimed to further extend the role of DEPDC5 to focal cortical dysplasias (FCDs).MethodsSeven patients from 4 families with DEPDC5 mutations and focal epilepsy associated with FCD were recruited and investigated at the clinical, neuroimaging, and histopathological levels. The DEPDC5 gene was sequenced from genomic blood and brain DNA.ResultsAll patients had drug-resistant focal epilepsy, 5 of them underwent surgery, and 1 had a brain biopsy. Electroclinical phenotypes were compatible with FCD II, although magnetic resonance imaging (MRI) was typical in only 4 cases. Histopathology confirmed FCD IIa in 2 patients (including 1 MRI-negative case) and showed FCD I in 2 other patients, and remained inconclusive in the last 2 patients. Three patients were seizure-free postsurgically, and 1 had a worthwhile improvement. Sequencing of blood DNA revealed truncating DEPDC5 mutations in all 4 families; 1 mutation was found to be mosaic in an asymptomatic father. A brain somatic DEPDC5 mutation was identified in 1 patient in addition to the germline mutation.InterpretationGermline, germline mosaic, and brain somatic DEPDC5 mutations may cause epilepsy associated with FCD, reinforcing the link between mTORC1 pathway and FCDs. Similarly to other mTORopathies, a 2-hit mutational model could be responsible for cortical lesions. Our study also indicates that epilepsy surgery is a valuable alternative in the treatment of drug-resistant DEPDC5-positive focal epilepsies, even if the MRI is unremarkable. Ann Neurol 2015;77:675-683