Objective: The objective of this study is to investigate the natural history of genetic subtypes of Parkinson’s disease (PD) and characterize the genetic architecture of PD in a local Colorado population.

Background: Monogenic variants account for 10-15% of PD, with several of these variants having known associations with specific clinical features ^(1-5). There is a need to characterize genotype-phenotype associations to improve prognostication and potentially guide treatment decisions. In order to advance our knowledge of gene specific natural history in PD, longitudinal data of clinical assessments across the genetic spectrum of PD are needed.

Method: We created a genetic PD registry to include all people with PD who received genetic testing from CLIA certified laboratories as part of their clinical care at the University of Colorado. This population received a retrospective chart review and will be followed with standardized clinical measures as part of the clinic workflow at follow up visits. The clinical measures followed will include cognitive, sleep, mood, quality of life, autonomic features, impulsivity, and motor assessments. Demographic information and distributions of variables from the registry were described.

Results: To date, we have identified 430 individuals with PD and genetic testing who populate the registry. Of those, pathogenic or likely pathogenic variants were found in 11.9% (n=51), VUS were found in 15.4% (n=66), and negative testing occurred in the remainder. Of those with any variant, 41.3% had a family history of PD. Of pathogenic and likely pathogenic variants, 24.6% were in LRRK2 (n=19, 9 male, 10 female), while 19.7% were in GBA, (n=11, 7 male, 4 female). The most common pathogenic variant in LRRK2 was G2019S (n=11, 57.9%), while in GBA N409S (n=5, 45.5%) and L444P (n=4, 36.4%) variants were more evenly distributed. In those who had a Montreal Cognitive Assessment (MoCA) the average time from diagnosis to first MoCa was 3.4 years in LRRK2 PD (n=10) and 6.3 years in GBA PD (n=3).

Conclusion: Results from this project provide a unique snapshot of genotype-phenotype data from a large university hospital PD population. Ongoing collection of standardized clinical measures will be analyzed with current genetic data to better understand the gene specific natural history of PD.

References: 1. Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm (Vienna). 2017 Aug;124(8):901-905
2. Verstraeten A, Theuns J, Van Broeckhoven C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. (2015) 31:140–9
3. Parkinson’s Disease Foundation. Statistics on Parkinson’s. Available at: https://www.parkinson.org/Understanding-Parkinsons/Statistics. Accessed March 21 2022.
4. Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. Lancet Neurol. (2020)
5. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021 Jun 12;397(10291):2284-2303.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-subtypes-of-parkinsons-disease-in-a-colorado-clinic/