Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
Brain. 2022 Aug 27;145(8):2671-2676. doi: 10.1093/brain/awac167.
Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis.
中间 CAG（多聚 Q）扩展在基因 ataxin-2（ATXN2）中现在被认为是肌萎缩侧索硬化症的一个风险因素。风险增加的阈值尚未确定，报告范围从 27 到 31 次重复。我们调查了 9268 份来自肌萎缩侧索硬化症、肌萎缩侧索硬化症伴额颞叶痴呆、单纯额颞叶痴呆、路易体痴呆和年龄匹配对照者的 DNA 样本中 ATXN2 多聚 Q 扩展的存在情况。这项分析证实了 ATXN2 中间多聚 Q 扩展≥31 是肌萎缩侧索硬化症的一个风险因素，其比值比为 6.31。扩展对于肌萎缩侧索硬化症伴额颞叶痴呆的风险更高（比值比 27.59），对于单纯额颞叶痴呆的风险略低（比值比 3.14）。对于路易体痴呆没有增加的风险。在 1362 名具有完整临床数据的肌萎缩侧索硬化症患者的亚组中，我们无法证实以前关于扩展患者肌萎缩侧索硬化症发病较早或生存时间较短的报告。这些新数据证实 ATXN2 中的≥31 个多聚 Q 重复增加了肌萎缩侧索硬化症的风险，并且首次显示出对于肌萎缩侧索硬化症伴额颞叶痴呆的风险更高。扩展患者的肌萎缩侧索硬化症表型不更具侵袭性，这对正在进行的肌萎缩侧索硬化症基因沉默试验具有影响。
