摘要： 研究背景 脊髓小脑共济失调2 型（SCA2）为常染色体显性遗传性疾病，是由致病基因ATXN2 编码区胞嘧啶-腺嘌呤-鸟嘌呤（CAG）三核苷酸重复序列扩展突变引起，目前较公认的正常重复范围为13 ~ 31 次，异常重复范围> 34 次。主要表现包括小脑共济失调、眼肌麻痹、慢眼动、腱反射减弱，可伴有动作性震颤、智力减退和周围性感觉神经病等；头部MRI显示脑干、小脑明显萎缩（典型的橄榄脑桥小脑萎缩改变）。本研究针对5 例经基因检测明确诊断的SCA2 家系先证者进行临床和影像学特点，以及表型与基因型相关性分析。方法 对708 例常染色体显性遗传性SCA 家系的先证者和119 例临床拟诊SCA 的散发患者进行常规基因学检测，分析SCA1 ~ 3、6、7、17 型和齿状核红核苍白球路易体萎缩致病基因CAG 序列重复动态突变。采用聚合酶链反应扩增重复序列、琼脂糖凝胶电泳检测扩增产物，对于出现2 个电泳条带的样品通过荧光标记毛细管电泳片段分析方法进行重复序列计数。结合基因学检测结果，对患者临床表型和神经影像学特征进行分析。结果 其中45 例患者携带SCA2 基因CAG 重复扩展突变，临床表现为小脑共济失调、眼肌麻痹、慢眼动、腱反射减弱或消失，部分患者可伴有动作性震颤，MRI 均显示脑干、小脑明显萎缩。其中5 例典型病例的临床表型均与其基因型相符。结论 基因学检测可为SCA2 的明确诊断提供依据，临床和神经影像学特征有助于诊断与鉴别诊断。对于携带中间重复等位基因个体的诊断，需结合临床和影像学特点以及家系上下代动态突变进行分析。

关键词: 脊髓小脑共济失调, 三核苷酸重复, 核苷酸类, 磁共振成像

Abstract: Background  Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant genetic disease characterized by cerebellar ataxia, ophthalmoplegia, slow saccade, hyporeflexia, action tremor, cognitive decline and peripheral neuropathy. The brain MRI shows obvious atrophy of cerebellum and brainstem, indicating typical change of olivopontocerebellar atrophy. SCA2 is caused by an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat in the encoding region of ATXN2. The normal CAG repeats range from 13 to 31, and ataxic phenotype occurs when the repeats are more than 34. This study focused on the clinical and imaging features of 5 SCA2 families confirmed by genetic testing. The correlation between phenotype and genotype was analyzed. Methods  The pathological CAG triplet repeat expansions of SCA1-3, 6, 7, 17 and dentatorubral-pallidoluysian atrophy (DRPLA) genes were analyzed in the probands of 708 autosomal dominant SCA families and 119 sporadic SCA cases. The CAG repeat of ATXN2 gene was amplified by polymerase chain reaction (PCR) and agarose gel electrophoresis. Fragment analysis based on CEQ8000 sequencer were applied to analyze expanded alleles. Results Expanded CAG repeats of ATXN2 gene were detected in 45 probands of SCA2 families. Most of the patients manifested with the typical clinical features of SCA2 such as cerebellar ataxia, ophthalmoplegia, slow saccade and hyporeflexia. Some of them also associated with action tremor. The brain MRI showed obvious atrophy of cerebellum and brainstem. The correlation between clinical features and CAG repeat of ATXN2 gene was studied carefully in 5 families. Conclusion Genetic analysis provides the basis for the diagnosis of SCA2. Clinical and neuroimaging features are very helpful in the diagnosis and differential diagnosis of this disease. For the identification of cases carrying intermediate allele, it is important to combine clinical, imaging features with dynamic mutation analysis in the affected cases within the family.

Key words: Spinocerebellar ataxias, Trinucleotide repeats, Nucleotides, Magnetic resonance imaging