Severe GBA1 variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials

BackgroundVariants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype- phenotype correlations exist but with conflicting data, particularly in the cognitive domain. ObjectivesComparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients. MethodsPatients underwent a comprehensive assessment of motor and non-motor functions. Two-group (GBA- PD vs iPD) and multiple-group comparisons (iPD, risk, mild, and severe variant GBA-PD) were performed. ResultsThree hundred eleven PD patients were recruited: 183 iPD, 39 severe GBA-PD, 24 mild GBA-PD, 55 risk GBA-PD, and 10 patients carrying variants of unknown significance. Groups were matched for sex, education, disease duration and medications. Mild and severe GBA-PD were younger and developed PD earlier. Severe GBA-PD had worse depression, cognitive impairment, hyposmia, and motor complications. ConclusionsOnly severe variant GBA-PD have a distinctive, more severe clinical profile.