Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.
Curr Neurol Neurosci Rep. 2020 Aug 13;20(10):46. doi: 10.1007/s11910-020-01059-x.
Seizures can arise in neocortical, thalamocortical, limbic or brainstem networks. Here, we review recent genetic mechanisms implicated in focal and genetic generalized epilepsies (GGEs).
Pathogenic variation in GAP activity toward RAGs 1 (GATOR1) complex genes (i.e., DEPDC5, NPRL2 and NPRL3) mainly result in focal epilepsies. They are associated with high rates of sudden unexpected death in epilepsy and malformations of cortical development (MCD), where "two-hits" in GATOR1-related pathways are also found in MCDs. Large-scale sequencing studies continue to reveal new genetic risk (germline or somatic) variants, and new genes relevant to epileptic encephalopathies (EEs). Genes previously associated with EEs, including GABA receptor genes, are now known to play a role in both common focal and GGEs in individuals without intellectual disabilities. These findings suggest that there may be a common pathophysiological mechanism in GGEs and focal epilepsies. Finally, polygenic risk scores, based on common genetic variation, offer promise in helping to differentiate between GGEs and common forms of focal epilepsies. Genetic abnormalities are a significant cause of common sporadic epilepsies, epilepsies associated with inflammatory markers, and focal epilepsies with or without MCD. Future studies using genome sequencing may provide more answers to the remaining unresolved epilepsy cases.
癫痫发作可起源于皮质、丘脑皮质、边缘或脑干网络。在此，我们综述了最近与局灶性和遗传性全面性癫痫（GGE）相关的遗传机制。
RAGs 1（GATOR1）复合物基因（即 DEPDC5、NPRL2 和 NPRL3）中 GAP 活性的致病性变异主要导致局灶性癫痫。它们与癫痫猝死和皮质发育畸形（MCD）的高发生率相关，在 MCD 中也发现了 GATOR1 相关途径的“两次打击”。大规模测序研究继续揭示新的遗传风险（种系或体细胞）变异和与癫痫性脑病（EE）相关的新基因。以前与 EE 相关的基因，包括 GABA 受体基因，现在已知在没有智力障碍的个体中也与常见局灶性和 GGE 有关。这些发现表明 GGE 和局灶性癫痫可能存在共同的病理生理机制。最后，基于常见遗传变异的多基因风险评分有望帮助区分 GGE 和常见局灶性癫痫。遗传异常是常见散发性癫痫、与炎症标志物相关的癫痫和伴或不伴 MCD 的局灶性癫痫的重要原因。使用基因组测序的未来研究可能会为剩余的未解决的癫痫病例提供更多答案。
