Maljevic Snezana, Reid Christopher A, Petrou Steven
The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
University of Melbourne, Melbourne, Australia.
J Neurochem. 2017 Oct;143(1):30-48. doi: 10.1111/jnc.14134. Epub 2017 Sep 5.
Epileptic encephalopathies are severe disorders emerging in the first days to years of life that commonly include refractory seizures, various types of movement disorders, and different levels of developmental delay. In recent years, many de novo occurring variants have been identified in individuals with these devastating disorders. To unravel disease mechanisms, the functional impact of detected variants associated with epileptic encephalopathies is investigated in a range of cellular and animal models. This review addresses efforts to advance and use such models to identify specific molecular and cellular targets for the development of novel therapies. We focus on ion channels as the best-studied group of epilepsy genes. Given the clinical and genetic heterogeneity of epileptic encephalopathy disorders, experimental models that can reflect this complexity are critical for the development of disease mechanisms-based targeted therapy. The convergence of technological advances in gene sequencing, stem cell biology, genome editing, and high throughput functional screening together with massive unmet clinical needs provides unprecedented opportunities and imperatives for precision medicine in epileptic encephalopathies.
癫痫性脑病是在生命最初几天至几年内出现的严重疾病，通常包括难治性癫痫发作、各种类型的运动障碍以及不同程度的发育迟缓。近年来，在患有这些毁灭性疾病的个体中发现了许多新生变异。为了阐明疾病机制，在一系列细胞和动物模型中研究了与癫痫性脑病相关的检测变异的功能影响。本综述阐述了推进和使用此类模型以识别新型疗法开发的特定分子和细胞靶点的努力。我们将重点放在离子通道上，因为它是研究最深入的癫痫相关基因群体。鉴于癫痫性脑病疾病的临床和遗传异质性，能够反映这种复杂性的实验模型对于基于疾病机制的靶向治疗的发展至关重要。基因测序、干细胞生物学、基因组编辑和高通量功能筛选等技术进步与大量未满足的临床需求相结合，为癫痫性脑病的精准医学提供了前所未有的机遇和迫切需求。
