离子通道变异与癫痫病

Relationship between ion channelopathies and epilepsy

离子通道是神经系统和其它可兴奋组织(肌肉和腺体)产生兴奋和行使功能活动的核心基本物质之一。因编码离子通道基因的突变所导致的各类先天性疾病被称之为通道病因学。临床上常见的先天性癫痫综合征多属于通道病。先天性癫痫占癫痫人群的40%,常见的有以下几种:由N型乙酰胆碱受体CHRNA4或CHRNB亚基突变所致的常染色体显性夜间额叶癫痫;因电压门控钾通道KCNQ2和KCNQ3缺陷所致的良性家族性新生儿惊厥;因电压门控钠通道SCN1B,SCN1A和SCN2A亚基以及GABA受体GABRG2亚基突变诱发的高热抽搐全身型癫痫叠加综合征;由电压门控氯通道(ClC2突变)和GABAA受体或亚基突变所致的几种特发性全身性癫痫;此外,近来还发现了与电压门控钾通道KCNA1有关的另一种与1型共济失调伴发的局限性癫痫。研究分析先天性癫痫家系基因遗传谱及其突变通道的电生理特性,有利于更深入地认识和了解先天性癫痫的通道突变发病机制,制定新的抗癫痫策略,开发针对性抗癫痫新药。本文将对先天性癫痫的通道病因学研究进展作一简要梳理。

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, the mutations in ion channels encoding a variety of inherited diseases are defined as channelopathies. Clinically, most idiopathic epilepsies are caused by mutation of ion channels: mutations in the CHRNA4 or CHRNB subunits of the neuronal nicotinic acetylcholine receptor result in familial nocturnal frontal lobe epilepsy while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been demonstrated to produce benign familial neonatal convulsions; the voltage-gated sodium channel subunits SCN1B, SCN1A and SCN2A as well as the GABRG2 subunit of the GABAA receptor are involved in the pathology of generalized epilepsy with febrile seizures plus. In addition, mutations in ClC2 of voltage-gated chlorine channel and GABRA1, GABRG2 of GABAA receptor lead to idiopathic generalized epilepsies. Recently it is found that partial epilepsy with episodic ataxia type 1 is associated with mutations in another voltage-gated potassium channel (KCNA1). As an interesting model, these rare disorders can be used to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies and anti-epilepsy drugs can be developed.