Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72
Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72
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DOI：
10.1093/brain/awr366
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发表时间：
2012-03-01
期刊：
影响因子：
14.5
通讯作者：
Sabatelli, Mario
中科院分区：
文献类型：
--
作者：
Chio, Adriano;Borghero, Giuseppe;Sabatelli, Mario
最近有报道称，位于染色体9 p21上的基因C9 ORF 72的第一内含子中的大六核苷酸（GGGGCC）重复扩增与40%的欧洲血统家族性肌萎缩侧索硬化症病例有关。目前的文章的目的是描述肌萎缩侧索硬化症的表型进行扩展，通过提供一个详细的临床描述的受影响的情况下，从代表性的多代kinetics，并通过分析发病年龄，性别比例和生存在一个大的队列的家族性肌萎缩侧索硬化症患者。我们收集了141例索引意大利家族性肌萎缩侧索硬化症病例（21例撒丁岛血统）和41例德国索引家族性肌萎缩侧索硬化症病例的DNA和分析表型数据。在45例（37.5%）来自意大利大陆的患者、12例（57.1%）撒丁岛血统的患者和9例（22.0%）41例德国指数家族性肌萎缩侧索硬化症病例中检测到致病性重复扩增。27个家系（49.1%）为母系传播，28个家系（50.9%）为父系传播（P =无显著性）。平均而言，儿童比父母早7.0年患病[儿童：55.8岁（标准差7.9），父母：62.8岁（标准差10.9）; P = 0.003]。父母的表型影响儿童表现出的临床症状类型：在13例受影响的父母患有肌萎缩侧索硬化-额颞叶痴呆或额颞叶痴呆的病例中，受影响的儿童在9例病例中也患有肌萎缩侧索硬化-额颞叶痴呆。与携带其他肌萎缩侧索硬化症相关基因突变的患者相比，C9 ORF 72扩增的患者通常有延髓发作（42.2%，非C9 ORF 72扩增病例为25.0%，P = 0.03）和认知障碍（46.7%，非C9 ORF 72扩增病例为9.1%，P = 0.0001）。携带C9 ORF 72重复扩增的病例从症状发作开始的中位生存期比携带TARDBP突变的患者（5.0年; 95%置信区间：3.6-7.2）低3.2年，比携带FUS突变的患者（1.9年; 95%置信区间：1.7-2.1）长。我们的结论是，C9 ORF 72六核苷酸重复扩增是最常见的突变在我们的大型队列的家族性肌萎缩侧索硬化症患者的意大利，撒丁岛和德国血统。在意大利，家族性肌萎缩侧索硬化症中，C9 ORF 72突变与SOD 1、TARDBP和FUS突变一起约占60%。与其他基因突变或未知突变的患者相比，C9 ORF 72六核苷酸重复扩增的患者存在一些表型差异，即高发病率的延髓发病和额颞叶痴呆的合并症。他们的家系典型地显示了高频率的纯额颞叶痴呆病例，拓宽了家族性肌萎缩侧索硬化症的概念。
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.