一个遗传性多巴反应性肌张力障碍家系的临床特点及GCH-Ⅰ基因突变分析  

The clinical features and identification of a novel GCH-1 gene mutation in a Chinese family with dopa-responsive dystonia.

作　　者：薛原[1] 陈先文[1] 高宗良[1] 严孙宏[1] 

机构地区：[1]安徽医科大学第一附属医院神经内科,合肥230022

出　　处：《中国神经精神疾病杂志》2011年第4期193-196,共4页Chinese Journal of Nervous and Mental Diseases

基　　金：安徽省科技厅科技项目(编号:10021303036)

摘　　要：目的探讨一遗传性多巴反应性肌张力障碍(dopa-responsive dystonia,DRD)家系临床特点和相关基因突变。方法收集一个多巴反应性肌张力障碍家系全部家庭成员临床资料并随访,采集家系成员静脉血,常规提取基因组DNA,利用PCR技术扩增三磷酸鸟苷环化水解酶Ⅰ(guanosine triphosphate cyclohydrolase 1,GCH-Ⅰ)基因全部6个外显子,进行DNA直接测序并分析。结果该家系患病成员临床主要表现为肌张力障碍和帕金森综合征,但症状严重程度个体差异大,所以患者对多巴丝肼治疗均有较好反应,1例患者长期大剂量不规律使用左旋多巴后出现异动症。基因测序显示4例患病成员GCH-Ⅰ第四外显子102号碱基由胸腺嘧啶替换为腺嘌呤(T→A),并导致176位丝氨酸(Ser)转变为精氨酸(Arg)Arg176 Ser,该突变类型尚未见文献报道。其余家系成员未发现GCH-Ⅰ基因突变。结论多巴反应性肌张力障碍临床表现在同一家系不同个体之间可有较大差异,部分患者长期大量不规律使用左旋多巴亦可导致异动症产生。GCH-Ⅰ基因第四外显子102号碱基(T→A)突变是DRD患病的分子遗传学原因之一。Objective To study the clinical features of dopa-responsive dystonia（DRD） and guanosine triphosphate cyclohydrolase 1（GCH-1） gene mutation in a Chinese family.Methods This family had been followed up for three years after confirmation of diagnosis.Blood samples were collected from the family members and their genome DNA was extracted by standard technique.PCR and DNA sequencer were used to amplify all of 6 exons of GCH-1 gene,and sequence PCR products,respectively.Results The clinical features were mainly dystonia and parkinsonism.But the symptom severity varied among affected individuals.All affected family members had quite good response to levedopa treatment except one patient developed severe dyskinesia after a long-term high-dose treatment,which was rarely reported before.DNA sequencing showed a novel point mutation with transition of T to A at the 102 base of exon 4 of GCH-1 gene,resulting in a substitution of arginine by serine at point of 176 in the GCH-1 protein in the 4 affected members.Conclusions The symptom severity of DRD may vary significantly among individuals even in the same family.In rare cases,patient can developed severe dyskinesia after long-term improper high-dose levedopa therapy.Mutation wit T →A at point 102 of exon 4 in GCH-1 gene should be considered as a novel pathogenic mutation for dopa-responsive dystonia.

关 键 词：多巴反应性肌张力障碍 临床表现 GCH-Ⅰ基因 突变 

分 类 号：R746[医药卫生—神经病学与精神病学]