A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease—Identifying Those at the Greatest Risk

Abstract

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy

“…ABX is currently studied (also IIRs) as a PC therapy for patients with GBA1-related and idiopathic PD [ 22 ], and in GBA1-related dementia [ 25 ]; it will soon be studied for the prevention of GBA1-related PD in individuals with advanced prodromal features [ 26 , 27 ]. Given the high prevalence of PD among patients with GD, the administration of oral ABX might have added value.…”

Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy

“…L444P variant carriers exhibited the highest percentage of abnormal clinical tests assessing various domains of PD compared to N370S variant carriers [ 57 ]. However, there are some contradictory results on the presence of this pathogenic variant in early or late forms of PD [ 47 , 58 , 59 ]. Our data showed not only an elevated mRNA concentration but also a positive correlation of this factor with age.…”

Has Parkinson Disease Gone to the Dogs?

“…5 We have demonstrated the feasibility of screening subjects that are carriers of a GBA1 mutation for a battery of prodromal features of PD combined with more specific testing such as transcranial ultrasonography. 4,6 Unfortunately, these features are not specific and many individuals with "classical" prodromal symptoms will not develop PD.One of us (U.B.) is currently training dogs to sniff PD, and so far, the dogs have correctly identified both a patient with PD and an asymptomatic carrier of GBA1 mutation with advanced prodromal features as PD positive and a carrier of GBA1 mutation without prodromal features as negative.…”

“…5 We have demonstrated the feasibility of screening subjects that are carriers of a GBA1 mutation for a battery of prodromal features of PD combined with more specific testing such as transcranial ultrasonography. 4,6 Unfortunately, these features are not specific and many individuals with "classical" prodromal symptoms will not develop PD.…”