Luca Marsili1, Joaquin A Vizcarra1,2, Andrea Sturchio1, Alok K Dwivedi3, Elizabeth G Keeling1, Dhiren Patel1, Murli Mishra1,4, Ashar Farooqi1, Aristide Merola5, Alfonso Fasano6,7,8, Ignacio F Mata9, Marcelo A Kauffman10, Alberto J Espay11. 1. Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University 6 of Cincinnati, Cincinnati, OH, USA. 2. Department of Neurology, Emory University, Atlanta, GA, USA. 3. Division of Biostatistics and Epidemiology, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA. 4. St. George's University School of Medicine, St. George, Grenada. 5. Wexner Medical Center Department of Neurology, Ohio State University, Columbus, Ohio, USA. 6. Division of Neurology, Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, University of Toronto, Toronto, ON, Canada. 7. Krembil Brain Institute, Toronto, ON, Canada. 8. CenteR for Advancing Neurotechnological Innovation To Application (CRANIA), Toronto, ON, Canada. 9. Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. 10. Consultorio Y Laboratorio de Neurogenética, Centro Universitario de Neurología José María Ramos Mejía, Buenos Aires, Argentina. 11. Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University 6 of Cincinnati, Cincinnati, OH, USA. alberto.espay@uc.edu.
Abstract
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.
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 SNCApatients. 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.
Authors: Emilio Fernández-Espejo; Ana L Gavito; Juan Suárez; Eduardo Tolosa; Dolores Vilas; Iban Aldecoa; Joan Berenguer; Antonio Córdoba-Fernández; Fátima Damas-Hermoso; Fernando Rodríguez de Fonseca Journal: Clin Park Relat Disord Date: 2022-08-28