Mei Davide, Parrini Elena, Marini Carla, Guerrini Renzo
Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, Viale Pieraccini 24, 50139, Florence, Italy.
Mol Diagn Ther. 2017 Aug;21(4):357-373. doi: 10.1007/s40291-017-0257-0.
Next-generation sequencing (NGS) has contributed to the identification of many monogenic epilepsy syndromes and is favouring earlier and more accurate diagnosis in a subset of paediatric patients with epilepsy. The cumulative information emerging from NGS studies is rapidly changing our comprehension of the relations between early-onset severe epilepsy and the associated neurological impairment, progressively delineating specific entities previously gathered under the umbrella definition of epileptic encephalopathies, thereby influencing treatment choices and limiting the most aggressive drug regimens only to those conditions that are likely to actually benefit from them. Although ion channel genes represent the gene family most frequently causally related to epilepsy, other genes have gradually been associated with complex developmental epilepsy conditions, revealing the pathogenic role of mutations affecting diverse molecular pathways that regulate membrane excitability, synaptic plasticity, presynaptic neurotransmitter release, postsynaptic receptors, transporters, cell metabolism, and many formative steps in early brain development. Some of these discoveries are being followed by proof-of-concept laboratory studies that might open new pathways towards personalized treatment choices. No specific treatment is available for most of the monogenic disorders that can now be diagnosed early using NGS, and the main benefits of knowing the specific cause include etiological diagnosis, better prognostication and genetic counselling; however, for a limited number of disorders, timely treatment based on their known molecular pathology is already possible and sometimes decisive. Discovery of a causative gene defect associated with a non-progressive course may reduce the need for further diagnostic investigations in the search for a progressive disorder at the biochemical and imaging level. NGS has also improved the turnaround time for molecular diagnosis and allowed more timely and straightforward treatment choices for specific conditions as well as avoiding needless investigations and inappropriate or unnecessary treatment choices.
下一代测序（NGS）有助于识别许多单基因癫痫综合征，并有利于对一部分小儿癫痫患者进行更早、更准确的诊断。NGS研究中积累的信息正在迅速改变我们对早发性严重癫痫与相关神经功能障碍之间关系的理解，逐步勾勒出以前在癫痫性脑病这一笼统定义下归为一类的特定病症，从而影响治疗选择，并将最激进的药物治疗方案仅限制于那些可能真正从中受益的病症。虽然离子通道基因是与癫痫因果关系最密切的基因家族，但其他基因也逐渐与复杂的发育性癫痫病症相关联，揭示了影响多种分子途径的突变的致病作用，这些分子途径调节膜兴奋性、突触可塑性、突触前神经递质释放、突触后受体、转运体、细胞代谢以及早期脑发育中的许多形成步骤。其中一些发现之后伴随着概念验证实验室研究，这些研究可能会开辟通往个性化治疗选择的新途径。对于目前可以通过NGS早期诊断的大多数单基因疾病，尚无特异性治疗方法，了解具体病因的主要益处包括病因诊断、更好的预后评估和遗传咨询；然而，对于少数疾病，基于已知分子病理学的及时治疗已经可行，有时甚至是决定性的。发现与非进行性病程相关的致病基因缺陷，可能会减少在生化和影像学层面寻找进行性疾病时进一步诊断检查的必要性。NGS还缩短了分子诊断的周转时间，为特定病症提供了更及时、直接的治疗选择，同时避免了不必要的检查和不适当或不必要的治疗选择。
