AUTHOR=Menozzi Elisa , Schapira Anthony H. V. 

TITLE=Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

JOURNAL=Frontiers in Neurology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.694764

DOI=10.3389/fneur.2021.694764

ISSN=1664-2295

ABSTRACT=Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease. These include pathogenic variants causing Gaucher disease (divided into ‘severe’, ‘mild’, or ‘complex’-resulting from recombinant alleles-based on the phenotypic effects in Gaucher disease) and ‘risk’ variants which are not associated with Gaucher disease but nevertheless confer increased risk of Parkinson disease. As a group, GBA-Parkinson disease patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with non-carriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, ‘complex’ and ‘severe’ variants are associated with a more aggressive and rapidly progressive disease. Conversely, ‘mild’ and ‘risk’ variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous ‘complex’ or ‘severe’ variants carriers. This article reviews genotype-phenotype correlations in GBA-Parkinson disease, focusing on clinical and non-clinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterisation of these patients.