The multistep hypothesis of ALS revisited The role of genetic mutations
The multistep hypothesis of ALS revisited The role of genetic mutations
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DOI：
10.1212/wnl.0000000000005996
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发表时间：
2018-08-14
期刊：
影响因子：
9.9
通讯作者：
Al-Chalabi, Ammar
中科院分区：
文献类型：
--
作者：
Chio, Adriano;Mazzini, Letizia;Al-Chalabi, Ammar
肌萎缩侧索硬化症(ALS)的发病率与ALS是一个多步骤过程的假设是一致的。我们测试了这样的假设，即携带一个大效应突变可能解释了突变效应的>；=1步，因此在ALS开始之前剩下的步骤更少。方法我们从意大利的ALS人群登记(2007-2015)生成发病数据，82%的发病病例进行了C9orf72、SOD1、TARDBP和FUS基因的基因分析。作为确认，我们使用了爱尔兰共和国诊断的ALS病例的数据(2006-2014)。结果在1077例基因检测病例中，74例(6.9%)携带C9orf72突变，20例(1.9%)携带SOD1突变，15例(1.4%)携带TARDBP突变，3例(0.3%)携带FUS突变。在整个种群中，原木发病率与原木年龄呈线性关系(r(2)=0.98)，斜率估计为4.65(4.37~4.95)，符合6步过程。对C9orf72突变患者的分析证实了线性关系(r(2)=0.94)，斜率估计为2.22(1.74-2.29)，表明这是一个3步过程。爱尔兰肌萎缩侧索硬化症登记处的数据证实了这一估计。斜率的估计与SOD1的2步过程和TARDBP的4步过程是一致的。结论在有基因突变的ALS患者中，与无突变的患者相比，步骤数减少了，这支持了ALS是一个多步骤过程的观点，是解剖ALS发病过程的重要进展。
ObjectiveAmyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for >= 1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins.MethodsWe generated incidence data from an ALS population register in Italy (2007-2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006-2014). We regressed the log of age-specific incidence against the log of age with leastsquares regression for the subpopulation carrying disease-associated variation in each separate gene.ResultsOf the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r(2) = 0.98) with a slope estimate of 4.65 (4.37-4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r(2) = 0.94) with a slope estimate of 2.22 (1.74-2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP.ConclusionThe identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS.