Objective: To investigate clinical, neuropsychological, biomarker, and imaging differences between siblings carrying the same GBA1 variant but discordant for Parkinson’s disease (PD).

Background: Variants in the GBA1 gene are among the most common genetic risk factors for Parkinson’s disease (PD) but show incomplete penetrance. The mechanisms underlying why some carriers develop PD while others remain unaffected remain poorly understood. Studying siblings carrying the same mutation but discordant for PD provides a unique model to investigate factors associated with disease expression.

Method: We analyzed sibling pairs carrying the same GBA1 variant but discordant for PD. For each pair we compared GCase activity and total α-syn levels measured in PBMCs using ELISA. Prodromal markers included olfaction (UPSIT), RBD symptoms (RBDSQ), and autonomic dysfunction (SCOPA-AUT). Neuropsychological data and, when available, neuroimaging (DAT-SPECT, 18F-FDG PET) were also analyzed. Within-pair differences (PD − carrier) were assessed using the Wilcoxon signed-rank test for continuous variables and the chi-square test for categorical variables.

Results: Ten sibling pairs carrying GBA1 variants were included. Individuals with PD showed significantly reduced UPSIT scores (p = 0.0039) and higher RBDSQ scores (p = 0.039), with a trend toward greater autonomic dysfunction compared with unaffected siblings. Neuropsychological differences were mild, with occasional lower visuospatial performance in PD. α-Synuclein levels were significantly higher in PD individuals than in unaffected siblings (p = 0.0078), with consistent direction across all pairs. In contrast, GCase activity did not differ significantly and showed heterogeneous intra-pair patterns. Integrated analyses of clinical, biochemical, and imaging data suggested that PD subjects exhibited a biological and prodromal profile consistent with active synucleinopathy.

Conclusion: Among carriers of the same GBA1 variants, PD manifestation appears primarily associated with biological and prodromal markers of synucleinopathy, particularly increased α-synuclein levels and impaired olfaction. Reduced GCase activity may reflect a shared genetic vulnerability rather than distinguishing affected from unaffected carriers. These findings suggest that activation of α-synuclein–related pathogenic processes may represent a key determinant of clinical penetrance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/discordant-siblings-reveal-determinants-of-clinical-penetrance-in-gba-associated-parkinsons-disease/