Evolution and clustering of prodromal parkinsonian features in GBA1 carriers

Abstract

Background Five to 25% of patients with PD carry glucocerebrosidase gene mutations, and 10% to 30% of glucocerebrosidase carriers will develop PD by age 80. Stratification of PD risk in glucocerebrosidase carriers provides an opportunity to target disease‐modifying therapies. Objective Cross‐sectional and longitudinal survey of prodromal PD signs among glucocerebrosidase carriers. Design Prospective assessment of 82 glucocerebrosidase mutation carriers and 35 controls over 4 to 5 years for prodromal clinical PD features. Results At all time points, olfactory (measured using University of Pennsylvania Smell Identification Test) and cognitive (Montreal Cognitive Assessment) function and the International Parkinson and Movement Disorder Society UPDRS parts II and III scores were significantly worse amongst glucocerebrosidase mutation carriers. Progression to microsmia (odds ratio: 8.5; 95% confidence interval: 2.6–28.2; P < 0.05) and mild cognitive impairment (odds ratio: 4.2; 95% confidence interval: 1.1–16.6; P < 0.05) were more rapid compared to controls. Those with worse olfaction also had worse cognition (OR, 1.5; 95% CI: 0.0–2.8; P < 0.05) and depression (OR, 1.3; 95% CI: 0.6–2.8; P < 0.05). No participants reached the MDS prodromal PD diagnostic criteria before PD diagnosis. One participant developed PD. He did not fulfill the International Parkinson and Movement Disorder Society prodromal PD criteria before diagnosis. Conclusion Assessment of individual and clustered PD prodromal features may serve as a useful tool to identify high‐risk subjects for conversion to PD. As a result of the low conversion rate in our glucocerebrosidase mutation carriers to date, prospective validation is needed in larger cohorts to establish the profile of these features in PD convertors. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Glucocerebrosidase: Functions in and Beyond the Lysosome

“…Carriers of GD have a yet unexplained significantly increased (20-fold) risk for developing Parkinson disease (PD) and Lewy body dementia (LBD) [110][111][112]. A recent study in the United Kingdom revealed that 5-25% of patients with PD carry glucocerebrosidase gene mutations, and 10-30% of glucocerebrosidase carriers will develop PD by age 80 [113]. Of note, active GCase activity is also decreased, and corresponding glycosphingolipid substrate levels elevated, in the brain in PD without GBA1 mutations [114,115].…”

Precision medicine in Parkinson’s disease: emerging treatments for genetic Parkinson’s disease

“…The clinical presentation of GD can be divided into systemic, which are present in all forms of GD, and include hepatosplenomegaly, painful skeletal disorders and pancytopenia, and neurological manifestations, which are present in the more severe types of GD, GD-II and GD-III. Both GD patients and healthy heterozygous carriers are at increased risk for PD [10] and longterm follow-up showed worsening in motor and non-motor prodromal PD features [11]. GBA mutations are a common risk for PD and are present in 7-10% of PD patients worldwide.…”

“…As in GBA, different mutations and variants confer different levels of risk for PD. For example, the G2019S mutation, which is common in Whites, confers a higher risk for PD than the common Asian variants, G2385R and R1628P [11,13]. These latter two variants are detected in around 5-10% of Asian PD patients [45].…”

Parkinson’s disease in Gaucher disease patients: what’s changing in the counseling and management of patients and their relatives?

“…From another point of view, GD doctors might be sued for omitted, retarded, incompleted or potentially misleading information on PD risk to those who are potential candidates for future neuroprotective drugs or who already need a symptomatic treatment for early symptoms and signs of PD. Some longitudinal studies on GBA1 variant carriers provide evidence of a progressive worsening of motor and non-motor prodromal PD features [ 24 , 25 ]. The identification of GBA1 variant carriers and the early identification of subjects, either with mono or biallelic GBA1 mutations, who will develop PD is crucial to address patients to future neuroprotective drugs or at least to symptomatic treatments.…”