To identify responsible genes and survey the custom-made therapy for West syndrome

背景：ARX是Xp22.13上的同源盒基因，对胎儿大脑中间神经元的发育至关重要。ARX的零突变导致大脑和外生殖器的异常，而错义或多丙氨酸扩增突变导致包括韦斯特综合征在内的非综合征或综合征性智力迟钝。在本研究中，我们对West综合征患者进行了ARX突变筛查，并分析了与ARX突变相关的基因型-表型相关性。方法：对29例隐源性或特发性西部综合征患者（男性21例）经知情同意采集血样。提取基因组DNA，用PCR扩增出ARX基因的5个外显子和侧翼内含子。电泳扩增后的产物直接测序，DHPLC突变筛选结果显示为异双工模式。结果：在一名男孩中发现了一个突变，3333334ins (GCG)_7，该突变可能使第一聚丙氨酸束从16个丙氨酸残基扩展到23个丙氨酸残基。他的母亲是一个杂合携带者，他的弟弟也有相同的突变，从婴儿期就表现出强直性癫痫和肌张力障碍。结论：在来自3个家族的12例患者中已经报道了相同的突变。包括我们的病例在内的所有患者在婴儿期都表现出癫痫发作，严重的智力迟钝和无法行走。11例患者中有8例出现西氏综合征，13例患者中有11例出现肌阵挛性发作。它们比第二次聚丙氨酸扩张的患者更常见。第一次聚丙氨酸扩增比第二次聚丙氨酸扩增具有更严重和特异性的表型。

Background : ARX is a homeobox gene on Xp22.13 and is crucial to the development of interneurons in the fetal brain. Null mutation of ARX causes anomalies of the brain and the external genitalia, while missense or polyalanine expansion mutation causes nonsyndromic or syndromic mental retardation including West syndrome. In this study, we did ARX mutation screening in patients with West syndrome and analyzed the genotype-phenotype correlation associated with ARX mutation.Methods : Blood samples were collected from 29 patients (21 males) with cryptogenic or idiopathic West syndrome with the informed consent. Genomic DNA was extracted and five exons and flanking introns of ARX gene were amplified with PCR. Direct sequencing was performed on the product with expanded size after the electrophoresis and the product showing a heteroduplex pattern on the DHPLC mutation screening.Results : A mutation, 333_334ins(GCG)_7, was found in a boy, which is supposed to expand the first polyalanine tract from 16 to 23 alanine residues. His mother was a heterozygous carrier and his young brother had the same mutation and showed tonic seizures and dystonia from infancy.Conclusions : The same mutation has been already reported in 12 patients from 3 families. All patients including our cases show epileptic attacks in infancy, profound mental retardation, and inability to walk. West syndrome is found in eight of 11 patients and myoclonic seizure in 11 of 13 patients. They are more frequent than those in patients with the second polyalanine expansion. The first polyalanine expansion is associated with more severe and specific phenotype than the second polyalanine expansion.