近亲婚配的脊髓小脑共济失调3型家系的临床特征与基因突变分析

Clinical and genetic study of spinocerebellar ataxias 3 within a consanguinity family

目的对1个一级表兄妹婚配的脊髓小脑共济失调3型（SCA3）家系致病基因突变进行研究，分析CAG重复扩展的传递规律及其临床表型。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，对该家系成员的SCA3致病基因CAG三核苷酸重复序列进行检测和精确计数，同时分析该家系患者的临床特征。结果先证者的CAG重复次数为56和72次，2个等位基因的重复次数均在异常范围。先证者父母为表兄妹，其父的致病基因来自于祖父，CAG重复次数为28和66次，具有疾病表型；其母致病基因来自于外祖母，CAG重复次数为33和56次，体检未见明显异常。先证者之子的CAG重复次数为27和85次，临床症状严重，表现为共济失调伴明显的肌张力障碍。结论该一级表兄妹婚配的SCA3家系，CAG重复序列的扩展在父系遗传较母系遗传更为显著。携带56次重复的个体在71岁仍未出现疾病表型，提示56次重复的致病性需要进一步研究。该家系内部临床表型存在明显变异。

Objective To investigate the inheritance principle of the expanded CAG repeat allele and the clinical features of spinocerebellar ataxias 3 （ SCA3 ） in a consanguinity family with first cousin marriage. Methods The CAG repeats of SCA3 gene were amplified by means of polymerase chain reaction. Fragment analysis with laser-induced fluorescence in capillary electrophoresis were performed for the positive samples detected by agarose gel electrophoresis. Furthermore, the clinical features were analyzed carefully. Results Fragment analysis revealed that the proband carried 2 alleles with 56 and 72 CAG repeats separately. The proband＇ s father carried 28 and 66, and the expanded CAG repeat allele inherited from his grandfather. The proband＇ s mother carried 33 and 56, and the expanded CAG repeat allele inherited from his grandmother. The proband＇ s son carried 27 and 85 and presented with dystonia besides ataxia. Conclusions The proband＇ s parents have the common ancestors. Their alleles with expanded CAG repeats probably come from the same allele of their ancestor. The CAG repeat is more unstable in the paternal inheritance than in the maternal inheritance. The 71-year-old asymptomatic family member carry the allele with 56 CAG repeats, which indicates the 56 CAG repeats may be not associated with the disease. The patients within this family have variable clinical features, especially the juvenile-onset case presents with apparent dystonia.