Importance The c9orf72 repeat expansion (c9 or c9orf72^RE) confers a survival disadvantage in amyotrophic lateral sclerosis (ALS); its effect on prognosis in frontotemporal dementia (FTD) remains uncertain. Data on prognostic factors in c9orf72^RE disorders could inform patient care, genetic counseling, and trial design.

Objective To examine prognostic factors in c9ALS, c9FTD, c9ALS-FTD, and atypical phenotypes.

Data Sources The MEDLINE, Embase, Amed, ProQuest, PsychINFO, CINAHL, and LILACS databases were searched between January 2011 and January 2019. Keywords used were c9orf72 and chromosome 9 open reading frame 72. Reference lists, citations of eligible studies, and review articles were also searched by hand.

Study Selection Studies reporting disease duration for patients with a confirmed c9orf72^RE and a neurological and/or psychiatric disorder were included. A second author independently reviewed studies classified as irrelevant by the first author. Analysis began in January 2019.

Data Extraction and Synthesis Data were extracted by 1 author; a further author independently extracted 10% of data. Data were synthesized in univariate and multivariable Cox regression and are displayed as hazard ratios (HR) and 95% confidence intervals.

Main Outcomes and Measures Survival after symptom onset.

Results Overall, 206 studies reporting on 1060 patients were included from 2878 publications identified (c9ALS: n = 455; c9FTD: n = 296; c9ALS-FTD: n = 198; atypical phenotypes: n = 111); 197 duplicate cases were excluded. The median (95% CI) survival (in years) differed significantly between patients with c9ALS (2.8 [2.67-3.00]), c9FTD (9.0 [8.09-9.91]), and c9ALS-FTD (3.0 [2.73-3.27]); survival in atypical phenotypes varied substantially. Older age at onset was associated with shorter survival in c9ALS (HR, 1.03; 95% CI, 1.02-1.04; P < .001), c9FTD (HR, 1.04; 95% CI, 1.02-1.06; P < .001), and c9ALS-FTD (HR, 1.02; 95% CI, 1.004-1.04; P = .016). Bulbar onset was associated with shorter survival in c9ALS (HR, 1.64; 95% CI, 1.27-2.08; P < .001). Age at onset and bulbar onset ALS remained significant in multivariable regression including variables indicating potential diagnostic ascertainment bias, selection bias, and reporting bias. Family history, sex, study continent, FTD subtype, or the presence of additional pathogenic sequence variants were not significantly associated with survival. Clinical phenotypes in patients with neuropathologically confirmed frontotemporal lobar degeneration–TDP-43, motor neuron disease–TDP-43 and frontotemporal lobar degeneration–motor neuron disease–TDP-43 were heterogenous and impacted on survival.

Conclusions and Relevance Several factors associated with survival in c9orf72^RE disorders were identified. The inherent limitations of our methodological approach must be considered; nonetheless, the reported prognostic factors were not significantly associated with the bias indicators examined.

重要性 的c9orf72重复扩张（C9或c9orf72 ^RE）赋予在肌萎缩侧索硬化症生存缺点（ALS）; 其对额颞叶痴呆（FTD）预后的影响尚不确定。有关c9orf72 ^RE疾病预后因素的数据可为患者护理，遗传咨询和试验设计提供信息。

目的 探讨c9ALS，c9FTD，c9ALS-FTD和非典型表型的预后因素。

数据来源 在2011年1月至2019年1月之间搜索MEDLINE，Embase，Amed，ProQuest，PsychINFO，CINAHL和LILACS数据库。使用的关键词为c9orf72和9号染色体开放阅读框72。还手动搜索参考文献列表，合格研究的引文和评论文章。

研究选择包括 报告确诊c9orf72 ^RE和神经系统疾病和/或精神疾病的患者的疾病持续时间的研究。第二位作者独立审查了第一位作者归类为不相关的研究。分析于2019年1月开始。

数据提取和综合 数据由1位作者提取；另一位作者独立提取了10％的数据。数据以单变量和多变量Cox回归进行合成，并以危险比（HR）和95％置信区间显示。

主要结果和措施 症状发作后的生存率。

结果 总体而言，从2878份已确定的出版物中纳入了206项针对1060例患者的研究报告（c9ALS：n = 455； c9FTD：n = 296； c9ALS-FTD：n = 198；非典型表型：n = 111）；以及 排除了197个重复案例。c9ALS（2.8 [2.67-3.00]），c9FTD（9.0 [8.09-9.91]）和c9ALS-FTD（3.0 [2.73-3.27]）患者之间的中位（95％CI）生存期（以年为单位）存在显着差异。非典型表型的存活率差异很大。发病年龄大与c9ALS（HR，1.03； 95％CI，1.02-1.04；P  <.001），c9FTD（HR，1.04； 95％CI，1.02-1.06；P  <.001），和c9ALS-FTD（HR，1.02； 95％CI，1.004-1.04；P  = .016 ）。球茎发作与c9ALS生存期较短相关（HR，1.64; 95％CI，1.27-2.08; P <.001）。在多变量回归中，发病年龄和延髓发病ALS仍然很显着，包括表明潜在的诊断确定性偏倚，选择偏倚和报告偏倚的变量。家族史，性别，研究大陆，FTD亚型或其他病原体序列变异的存在与生存率无显着相关性。经神经病理学证实的额颞叶变性-TDP-43，运动神经元疾病-TDP-43和额颞叶变性-运动神经元疾病-TDP-43的患者的临床表型是异质的，并影响生存。

结论与相关性 鉴定了与c9orf72 ^RE疾病生存相关的几个因素。必须考虑我们方法论方法的固有局限性；尽管如此，报告的预后因素与所检查的偏倚指标没有显着相关。