BACKGROUND Postural instability is a disease milestone signaling advanced disease. OBJECTIVES To estimate the onset of postural instability in monogenic parkinsonisms. METHODS We systematically reviewed studies (PubMed 1996-2017) in SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, FBXO7, VPS35, DNAJC6, or SYNJ1-related monogenic parkinsonisms, with documented postural instability. Genes with ≥ 15 patients were included in an individual-patient meta-analysis and compared with a retrospectively collected sporadic Parkinson's disease cohort from our center. The primary outcome measure was the progression-free survival from postural instability using Kaplan-Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR). RESULTS Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, whereas a total of 871 subjects (270 from sporadic cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis. Postural instability was reported in 80% of DJ-1, 40% of PRKN, 39% of PINK1, 34% of ATP13A2, 31% of LRRK2, and 29% of SNCA patients. Progression-free survival from postural instability at 10 years after disease onset was longest in ATP13A2 (97%) and shortest in SNCA (50%). Halfway between these two extremes were PRKN (88%), PINK1 (87%), and LRRK2 (81%), similar to sporadic Parkinson's disease (72%). Higher risk of postural instability was observed in SNCA (HR = 3.2, p = 0.007) and DJ-1 (HR = 3.96, p = 0.001) compared to sporadic Parkinson's disease. Young age at onset in PINK1 and female sex in LRRK2 were associated with a decreased risk of postural instability. CONCLUSIONS Monogenic parkinsonisms exhibit differential timelines to postural instability, informing prognostic counseling and interpretation of future genotype-specific treatment trials.

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单基因帕金森综合征何时出现姿势不稳？个体患者荟萃分析。

背景姿势不稳定性是疾病进展的里程碑信号。目的 估计单基因帕金森综合征中姿势不稳定的发作。方法 我们系统地回顾了 SNCA、PRKN、PINK1、DJ-1、LRRK2、ATP13A2、FBXO7、VPS35、DNAJC6 或 SYNJ1 相关的单基因帕金森症的研究（PubMed 1996-2017），并记录了姿势不稳定。≥ 15 名患者的基因被纳入个体患者荟萃分析，并与从我们中心回顾性收集的散发性帕金森病队列进行比较。主要结局指标是使用 Kaplan-Meier 生存曲线计算的姿势不稳导致的无进展生存。Cox 比例风险分析使用风险比 (HR) 进行总结。结果 在 2085 项符合条件的研究中，124 项符合系统评价的全部标准（636 名患者），而共有 871 名受试者（270 名来自散发性队列，601 名单基因帕金森病）被纳入个体患者荟萃分析。80% 的 DJ-1、40% 的 PRKN、39% 的 PINK1、34% 的 ATP13A2、31% 的 LRRK2 和 29% 的 SNCA 患者报告了姿势不稳定。疾病发作后 10 年姿势不稳导致的无进展生存期在 ATP13A2 中最长（97%），在 SNCA 中最短（50%）。介于这两个极端之间的是 PRKN (88%)、PINK1 (87%) 和 LRRK2 (81%)，类似于散发性帕金森病 (72%)。与散发性帕金森病相比，在 SNCA (HR = 3.2, p = 0.007) 和 DJ-1 (HR = 3.96, p = 0.001) 中观察到姿势不稳定的风险更高。PINK1 的年轻发病年龄和 LRRK2 的女性与姿势不稳定的风险降低有关。