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

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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.

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Acknowledgements

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Neurology, Gardner Family Center for Parkinson’s Disease and Movement Disorders, University 6 of Cincinnati, Cincinnati, OH, USA

    Luca Marsili, Joaquin A. Vizcarra, Andrea Sturchio, Elizabeth G. Keeling, Dhiren Patel, Murli Mishra, Ashar Farooqi & Alberto J. Espay

  2. Department of Neurology, Emory University, Atlanta, GA, USA

    Joaquin A. Vizcarra

  3. Division of Biostatistics and Epidemiology, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Alok K. Dwivedi

  4. St. George’s University School of Medicine, St. George, Grenada

    Murli Mishra

  5. Wexner Medical Center Department of Neurology, Ohio State University, Columbus, Ohio, USA

    Aristide Merola

  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

    Alfonso Fasano

  7. Krembil Brain Institute, Toronto, ON, Canada

    Alfonso Fasano

  8. CenteR for Advancing Neurotechnological Innovation To Application (CRANIA), Toronto, ON, Canada

    Alfonso Fasano

  9. Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Ignacio F. Mata

  10. Consultorio Y Laboratorio de Neurogenética, Centro Universitario de Neurología José María Ramos Mejía, Buenos Aires, Argentina

    Marcelo A. Kauffman

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  1. Luca Marsili
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Contributions

(1) Research project: A. conception, B. organization, C. execution; (2) statistical analysis: A. design, B. execution, C. review and critique; (3) manuscript: A. writing of the first draft, B. review and critique. LM, JAV, AS: 1A, 1B, 1C, 2A, 2B, 3A. AD: 2A, 2B, 2C. EGK, DP, MM, AF: 1C, 3B. AM, AF, IFM, MAK: 3B. AJE: 1A, 1B, 1C, 3B. All the co-authors listed above gave their final approval for this manuscript version.

Corresponding author

Correspondence to Alberto J. Espay.

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Conflicts of interest

Dr. Marsili reports no disclosure. Dr. Vizcarra reports no disclosure. Dr. Sturchio reports no disclosure. Dr. Dwivedi reports no disclosure. Ms. Keeling reports no disclosure. Dr. Patel reports no disclosure. Dr. Mishra reports no disclosure. Dr. Farooqi reports no disclosure. Dr. Merola is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring, and Cynapsus Therapeutics. He has received grant support from Lundbeck. Dr. Fasano has received grant support from the University of Toronto, the McLaughlin Centre and the Michael J. Fox Foundation; he received speaking honoraria from UCB pharma, Medtronic, Boston Scientific, Abbvie, Novartis, Chiesi pharmaceutical, Ipsen, TEVA, the American Academy of Neurology, and the Movement Disorders Society; he receives publishing royalties from Springer; he is in an advisory board for Abbvie and Ipsen and provided consultancies for Sunovion, UCB pharma, Medtronic, Boston Scientific, and Abbvie. Dr. Kauffman is an employee of the CONICET. He has received grant support from Ministry of Science and Technology of Argentina and Ministry of Health of Buenos Aires. Dr. Mata receives funding support from the Department of Veterans Affairs, National Institute of Health, Parkinson’s Foundation and American Parkinson Disease Association. Dr. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, InTrance, Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from USWorldMeds, Acadia, and Sunovion.

Ethical approval

The study has been approved by the local ethics committee and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Marsili, L., Vizcarra, J.A., Sturchio, A. et al. When does postural instability appear in monogenic parkinsonisms? An individual-patient meta-analysis. J Neurol 268, 3203–3211 (2021). https://doi.org/10.1007/s00415-020-09892-3

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