Scheffer Ingrid E
Department of Medicine, Florey Institute of Neurosciences and Mental Health, University of Melbourne, Austin Health, Melbourne, Australia.
Neuropediatrics. 2014 Apr;45(2):70-4. doi: 10.1055/s-0034-1371508. Epub 2014 Mar 10.
Epilepsy genetics has undergone a revolution in the past 19 years since the discovery of the first gene for epilepsy. The story of our increasing knowledge and how it impacts on patient care is presented with reference to recent discoveries. Understanding the significance of a genetic variant is challenging both in terms of molecular pathogenicity and in how this finding fits into the rubric of causation. In some cases, it may only be a contributing susceptibility factor; whereas in others, it explains the patient's disease.
A brief overview of the clinicomolecular approaches is discussed in the context of the discovery of epilepsy genes. These include family studies and, more recently, next generation sequencing using multigene panels and whole exome sequencing.
Recent studies illustrating the way in which epilepsy genetics is changing clinical practice are described. A particular focus is DEPDC5, the first gene for nonlesional focal epilepsy likely to be relevant to sporadic patients with focal epilepsies and those from small families, in contrast to rare large families with autosomal dominant focal epilepsies. As DEPDC5 is a negative regulator of the mammalian target of rapamycin (mTOR) pathway, it is likely that some patients with DEPDC5 mutations may have malformations of cortical development akin to the two-hit hypothesis suggested in tuberous sclerosis. The greatest impact of epilepsy genetics at a clinical level is for patients with epileptic encephalopathies as many have de novo mutations-a rapidly expanding list of causative genes is being found.
Epilepsy genetics is changing clinical practice enabling diagnosis in many patients, informing our understanding of comorbidities, prognosis, and genetic counseling. Importantly, a genetic finding may impact on treatment choices. At a biological level, new insights promise to lead to the development of novel therapies and bring together the seemingly disparate genetics of nonlesional epilepsies and epilepsies associated with cortical malformations.
自首个癫痫基因被发现以来，癫痫遗传学在过去19年经历了一场变革。本文结合近期的发现，讲述了我们不断增长的知识及其对患者护理的影响。理解基因变异的意义在分子致病性以及这一发现如何符合病因分类方面都具有挑战性。在某些情况下，它可能只是一个促成易感性的因素；而在其他情况下，它可以解释患者的疾病。
在癫痫基因发现的背景下，讨论了临床分子方法的简要概述。这些方法包括家系研究，以及最近使用多基因panel和全外显子测序的新一代测序技术。
描述了近期说明癫痫遗传学改变临床实践方式的研究。特别关注的是DEPDC5，它是首个与非损伤性局灶性癫痫相关的基因，可能与散发性局灶性癫痫患者以及来自小家庭的患者相关，这与罕见的常染色体显性遗传局灶性癫痫的大家庭情况形成对比。由于DEPDC5是雷帕霉素哺乳动物靶点（mTOR）通路的负调节因子，一些携带DEPDC5突变的患者可能具有类似于结节性硬化症中提出的“二次打击”假说的皮质发育畸形。癫痫遗传学在临床层面上对癫痫性脑病患者影响最大，因为许多患者有新生突变——正在发现一系列迅速扩大的致病基因。
癫痫遗传学正在改变临床实践，使许多患者能够得到诊断，增进我们对合并症、预后和遗传咨询的理解。重要的是，基因发现可能会影响治疗选择。在生物学层面，新的见解有望带来新疗法的开发，并将非损伤性癫痫和与皮质畸形相关的癫痫看似不同的遗传学联系起来。
