Severe GBA1 variants drive the GBA-PD clinical phenotype: implications for counselling and clinical trials
Published December 11, 2024
Output Details
Preprint March 11, 2025
Published December 11, 2024
Description
**Background** Variants 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.
**Objectives** Comparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients.
**Methods** Patients 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.
**Results** Three hundred fifteen PD patients were recruited: 186 iPD, 39 severe GBA-PD, 24 mild GBA-PD, 56 risk GBA-PD, and 10 patients carrying variants of unknown significance. Groups were matched for sex, disease duration and medications. Mild and severe GBA-PD were younger and developed PD earlier. Severe GBA-PD had worse depression, cognitive impairment and hyposmia, and a trend for higher rates of motor complications.
**Conclusions** Only severe variant GBA-PD have a distinctive, more severe clinical profile.
Identifier (DOI)
10.1038/s41531-025-01063-3
