摘要： 研究背景  亨廷顿病是一种常染色体显性遗传性神经系统退行性疾病，临床主要表现为舞蹈样动作、进行性认知功能减退及精神症状，神经影像学检查显示尾状核和大脑皮质萎缩。其致病基因IT15 定位于4p16.3，由67 个外显子组成编码亨廷顿蛋白，在其第1 个外显子内存在一段多态胞嘧啶-腺嘌呤-鸟嘌呤（CAG）三核苷酸重复序列，正常范围为6 ~ 35 次、异常36 ~ 250 次。亨廷顿病多于成年期发病，具有外显不完全和延迟外显现象，而青少年型亨廷顿病临床较为少见。本研究针对一例少年期发病的亨廷顿病患者临床表型及其家系IT15 基因CAG 重复动态突变特征进行细致分析。方法   采用聚合酶链反应结合荧光标记毛细管电泳片段分析方法，对115 例临床拟诊为亨廷顿病家系的先证者进行IT15 基因CAG 重复次数分析，经pMD18-T 载体克隆测序验证部分阳性或携带中间重复等位基因的样本。结果   经基因分析共发现109 例患者携带异常扩展的IT15 基因CAG 重复序列，其中一例为少年期发病患者，临床以认知功能障碍和运动功能减退为首发症状，其父母临床表型正常。基因片段分析显示，患者IT15 基因CAG 重复次数为15/68 次；其父母分别为17/37 次和15/17 次。结论   （1）少年期发病的亨廷顿病与成年型临床表型不同，后者临床表现以舞蹈样运动、智能减退和精神异常为主，而少年型患者大多以认知功能障碍发病。（2）IT15 基因扩展CAG 重复序列在代间传递过程中会出现动态突变，引起发病年龄逐代提前，症状加重，即遗传早现。该家系患者之父携带中间等位基因37 次重复，遗传给患者成为68 次重复，在代间传递过程中发生了大幅度扩展，使CAG 三核苷酸重复次数增加了31 次，提示重复序列在父系遗传更不稳定。

关键词: 多态现象, 遗传, 杭廷顿病, 核苷酸类, 重复序列, 核酸, 青少年

Abstract: Background Huntington's disease (HD) is an autosomal dominant hereditary progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dementia, cognitive and affective impairment. There are selective neural cell loss and atrophy in the caudate and putamen. Dr. George Huntington firstly described the disease accurately and insightfully, which led to a widespread recognition of the inherited chorea that now bears his name. Huntington disease gene (IT15) locus on chromosome 4p16.3, and encompasses 67 exons with a trinucleotide repeat (CAG) in the first exon. The CAG repeat length is highly polymorphic in the population and expanded on at least one chromosome of individuals with HD. Clinically, patient with HD are often onset in adulthood. Juvenile-onset HD is relatively rare. Adult-onset HD patients usually have a CAG expansion from 40 to 55 whereas those with juvenile-onset greater than 60 which are often inherited from the father. We investigated the clinical features of a juvenile-onset case with Huntington disease and dynamic mutation of his family. Methods The CAG repeats of IT15 gene were detected using polymerase chain reaction and capillary electrophoresis in 115 individuals with preliminary diagnosis as Huntington disease. The repeat numbers of some samples carried expanded or intermediate alleles were verified by the pMD18-T vector clone sequencing. Results Fragment analysis showed that one juvenile-onset case presenting with cognitive dysfunction and hypokinesis carried 15/68 CAG repeats of IT15. His father carried 17/37 and mother carried 15/17. Conclusion 1) The juvenile-onset case of HD presented with different clinical features compared with adult-onset cases. The typical signs of adult-onset cases include progressive chorea, rigidity and dementia. The most common sign of juvenile-onset Huntington disease is cognitive decline. 2) The dynamic mutation of IT15 gene expansion of the CAG repeats in the intergenerational transmission may lead to anticipation, which is a phenomenon characterized by increasing severity and earlier onset in successive generations. The abnormal allele of the patient inherited from his father and substantially expanded between generations, which indicates the CAG repeats is more unstable in the paternal inheritance.

Key words: Polymorphism, genetic, Huntington disease, Nucleotides, Repetitive sequences, nucleic acid, Adolescent