Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, Montal M, Hashikawa T, Shike T, Fujiwara T, Inoue Y, Kaneda M, Yamakawa K
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Neurology. 2009 Sep 29;73(13):1046-53. doi: 10.1212/WNL.0b013e3181b9cebc.
Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.
We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations.
We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation.
The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.
电压门控钠通道α(II)基因SCN2A的突变在多种癫痫中均有报道。虽然在多个轻度癫痫病例中已鉴定出遗传性SCN2A突变，但我们之前在一名散发型难治性儿童局灶性相关性癫痫患者中报道的新生SCN2A-R102X突变仍然是独一无二的。为了验证新生SCN2A突变在难治性癫痫病因中的作用，我们试图寻找更多病例。
我们对116例婴儿严重肌阵挛癫痫、婴儿痉挛症以及其他类型难治性儿童局灶性和全身性癫痫患者的SCN2A进行了突变分析，并对含有已鉴定突变的Na(v)1.2通道进行了全细胞膜片钳记录。
我们又发现了2个新生SCN2A突变。一个突变SCN2A-E1211K在一名散发型婴儿痉挛症患者中被鉴定出来。SCN2A-E1211K产生的通道具有改变的电生理特性，既符合增强的（激活电压依赖性约有18 mV的超极化偏移），也符合减弱的（稳态失活电压依赖性约有22 mV的超极化偏移以及失活后恢复减慢）通道活性。另一个新生突变SCN2A-I1473M在一名散发型新生儿癫痫性脑病患者中被鉴定出来。SCN2A-I1473M导致激活电压依赖性约有14 mV的超极化偏移。
鉴定出的新生突变SCN2A-E1211K、-I1473M和-R102X表明SCN2A是多种难治性儿童癫痫的病因候选基因。患者之间的表型差异可能是由于突变通道不同的电生理特性所致。
