Objective: To evaluate prodromal features of Parkinson disease in a cohort of “at-risk”  Gaucher patients and GBA1 carriers .

Background: Variants in GBA1 mutations are the most common genetic risk factor for Parkinson disease (PD), yet most patients with Gaucher disease (GD) and GBA1 carriers (GC) never develop PD, highlighting the need for predictive clinical parameters to identify patients who might benefit from early PD therapeutic intervention. We followed a cohort of 127 patients for up to 16 years including 60 individuals with GD and 36 GCs, most with a family history of PD as well as 31 with PD who were GBA1 heterozygotes or homozygotes (GBA-PD) to better establish their PD course. Our cohort included 10 discordant sibling pairs with GD where only one developed PD.

Method: Multiple assessments were performed at each patient visit, including neurological evaluations, self-reported scales of depression, sleepiness, fatigue, anxiety, as well as longitudinal neuroimaging measurement of nigral echogenicity using transcranial sonography (TCS), olfactory testing using the UPSIT, and periodic neuropsychiatric evaluation of cognition.

Results: Evaluations of olfaction showed severe olfactory dysfunction in those with PD, but the GD and GC individuals  without clinical signs of PD had normal olfactory function or mild deficits that were stable over time. Comparing TCS nigral echogenic area to dopamine synthesis using neuroimaging, we saw a strong inverse relationship between area of echogenicity and decreased dopamine uptake in subjects with PD, but neither modality identified a predictive pattern in patients without PD. To date, only one “at risk” participant and none of the GD only siblings have developed PD. Autopsies of ten participants (6 with GD+PD and 4 GD alone) revealed Lewy body pathology only in those with established parkinsonian features.

Conclusion: This dearth of “converters” has limited our ability to draw meaningful conclusions, as no clear trend has been identified in at-risk participants with regards to memory, depression, anxiety, nigral echogenicity, fatigue, or daytime sleepiness. Continued clinical follow up of this well-characterized cohort is essential, as the greatest risk factor for developing PD is advancing age.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/16-years-of-evaluations-for-prodromal-parkinson-features-in-an-at-risk-cohort-with-gaucher-disease/