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Genotype-phenotype relations for the Parkinson's disease genes SNCA, LRRK2, VPS35: MDSGene systematic review
Joanne Trinh1, Florentine M J Zeldenrust2, Jana Huang2
1Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Abstract:
This comprehensive MDSGene review is devoted to the three autosomal-dominant PD forms: PARK-SNCA, PARK-LRRK2, and PARK-VPS35. It follows MDSGene's standardized data extraction protocol, screened a total of 2,972 citations, and is based on fully curated phenotypic and genotypic data on 937 patients with dominantly inherited PD attributed to 44 different mutations in SNCA, LRRK2, or VPS35. All of these data are also available in an easily searchable online database (www.mdsgene.org), which additionally provides descriptive summary statistics on phenotypic and genetic data. Despite the high degree of missingness of phenotypic features and unsystematic reporting of genotype data in the original literature, the present review recapitulates many of the previously described findings including later onset of disease (median age at onset: ∼49 years) compared to recessive forms of PD of an overall excellent treatment response. Our systematic review validates previous reports showing that SNCA mutation carriers have a younger age at onset compared to LRRK2 and VPS35 (P < 0.001). SNCA mutation carriers often have additional psychiatric symptoms, and although not exclusive to only LRRK2 or VPS35 mutation carriers, LRRK2 mutation carriers have a typical form of PD, and, lastly, VPS35 mutation carriers have good response to l-dopa. © 2018 International Parkinson and Movement Disorder Society.
Insights
This review examines three dominant forms of Parkinson disease (PD), focusing on SNCA, LRRK2, and VPS35 mutations. It confirms SNCA mutations lead to earlier onset and psychiatric symptoms compared to LRRK2 and VPS35.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Parkinson disease (PD) has genetic forms, including autosomal-dominant types.
- Understanding genotype-phenotype correlations is crucial for PD management.
- MDSGene provides a platform for curated genetic and phenotypic data.
Purpose of the Study:
- To review and synthesize data on three major autosomal-dominant Parkinson disease forms: SNCA, LRRK2, and VPS35.
- To analyze phenotypic and genotypic data from 937 patients with 44 distinct mutations.
- To provide an accessible, searchable database of this information.
Main Methods:
- Systematic literature review following MDSGene's protocol.
- Screening of 2,972 citations for relevant data.
- Curation of phenotypic and genotypic data from 937 patients.
Main Results:
- Confirmed later disease onset (median ~49 years) for dominant PD compared to recessive forms.
- SNCA mutation carriers exhibit earlier onset than LRRK2 and VPS35 carriers (P < 0.001).
- Identified distinct clinical features: psychiatric symptoms in SNCA, typical PD in LRRK2, and good l-dopa response in VPS35.
Conclusions:
- Autosomal-dominant PD forms linked to SNCA, LRRK2, and VPS35 have specific clinical and genetic profiles.
- The MDSGene database offers a valuable resource for researchers studying these PD subtypes.
- Further research is needed to address data gaps in phenotypic and genotypic reporting.