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

背景：ARX是Xp22.13上的同源框基因，对胎儿大脑中间神经元的发育起着至关重要的作用。ARX零突变会导致大脑和外生殖器的异常，而错义或聚丙氨酸扩张性突变会导致包括West综合征在内的非综合征性或综合征性智力低下。在本研究中，我们对West综合征患者进行ARX突变筛查，并分析与ARX突变相关的基因-表型相关性。方法：对29例隐匿性或特发性West综合征患者在知情同意的情况下采集血液样本。提取基因组DNA，用聚合酶链式反应扩增ARX基因的5个外显子和侧翼内含子。结果：在1例男童中发现了333_334ins(GCG)_7突变，其第一个丙氨酸残基从16个扩增到23个氨基酸残基。他的母亲是杂合子携带者，他的弟弟也有相同的突变，并从婴儿时期就表现出强直性癫痫和肌张力障碍。结论：已经报道了来自3个家系的12例患者的相同突变。包括我们的病例在内的所有患者都表现出婴儿期癫痫发作、严重的精神发育迟滞和不能行走。11例患者中有8例出现West综合征，13例患者中有11例出现肌阵挛发作。它们比第二次聚丙氨酸扩张的患者更常见。与第二次聚丙氨酸扩张相比，第一次聚丙氨酸扩张与更严重和特定的表型有关。

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.