When does postural instability appear in monogenic parkinsonisms? An individual-patient meta-analysis

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.