Objective: To provide a comprehensive and systematic review of genotype-phenotype associations of GBA variants for Parkinson’s disease (PD).

Background: Biallelic pathogenic variants in the glucocerebrosidase gene (GBA) cause Gaucher disease (GD). More than 300 pathogenic GBA variants have been linked to GD and about 130 GBA variants have been reported in conjunction with PD. The most common variant in individuals of Ashkenazi Jewish (AJ) ancestry that is associated both with GD and PD, is N370S, while it is L444P in non-AJ patients. However, the relationship of less frequent variants, or variants not causing GD but seemingly increasing the risk for PD currently remains elusive.

Method: This systematic review followed MDSGene’s standardized data extraction protocol. Titles, abstracts and articles published in English were screened in PubMed. Articles with clinically affected mutation carriers were included; demographic, clinical and genetic data were abstracted.

Results: In total, 3053 publications were screened and 770 articles from 1965 to mid-2019 identified for data abstraction. Out of 15,022 currently included individuals from 630 publications, 10,815 (72%) had isolated GD, 3810 (25.3%) isolated PD, 129 (0.9%) GD and PD, 255 (1.7%) other disorders (atypical parkinsonism, ataxia, dystonia) and 13 (0.1%) GD and another disease. The most common variant was N370S (n=9670; 64%), followed by L444P (n=2199; 15%). For 8013 individuals (53%) only group level data (disease status and genetic variant) were available. From the 2675 individuals with gender information (82% missing data), 50.5% were male. Median age at examination was 27 years, with a median disease onset across all subforms of GD at 4 years and of PD at 53 years.
Among 4066 patients with parkinsonism, in 415 (10.2%) specific signs and symptoms were partially reported: 54 (13%) had rigidity, 53 (13%) tremor, 146 (35%) responded to levodopa, and 138 (33%) had cognitive decline.

Conclusion: These preliminary results from a comprehensive overview of the published phenotypic and genotypic data onGBA gene confirm an earlier age of PD onset and a relatively high prevalence of cognitive decline. The most commonly reported variants are N370S and L444P, in line with previous reports.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genotype-phenotype-relations-for-gba-as-a-parkinsons-disease-risk-factor-gene-mdsgene-systematic-review/