Association Between Glucocerebrosidase Mutations and Parkinson's Disease in Ireland.

Diana A Olszewska,Russell L Mclaughlin,Orla Hardiman,Alexandra I Soto-Beasley,Allan Mccarthy,Tim Lynch,Brian Magennis,Ronald L Walton,Owen A Ross

doi:10.3389/fneur.2020.00527

Abstract

Multiple studies implicate heterozygous GBA mutations as a major genetic risk factor for Parkinson's disease (PD); however, the frequency of mutations has never been examined in PD patients from the Irish population. We prospectively recruited 314 unrelated Irish PD patients (UK Brain Bank Criteria) and 96 Irish healthy controls (without any signs or family history of parkinsonism) attending. The Dublin Neurological Institute (DNI). Complete exon GBA Sanger sequencing analysis with flanking intronic regions was performed. The GBA carrier frequency was 8.3% in PD and 3.1% in controls. We identified a number of potentially pathogenic mutations including a p.G195E substitution and a p.G377C variant, previously described in a case study of Gaucher's disease in Ireland. On genotype–phenotype assessment hallucinations, dyskinesia, and dystonia were more prevalent in GBA-PD. The genetic etiology of PD in Ireland differs from the continental Europe as seen with the lower LRRK2 and higher than in most European countries GBA mutation frequency. Determining genetic risk factors in different ethnicities will be critical for future personalized therapeutic approach.

Highlights

Glucocerebrosidase gene (GBA) encodes B-glucocerebrosidase enzyme hydrolyzing glucocerebroside to glucose and ceramide
GBA-related Parkinson’s disease (PD) was thought to reflect the clinical phenotype of idiopathic PD [3]; current evidence suggests unique motor, non-motor [autonomic symptoms, younger age at onset (2.6–0.9 year earlier age at onset)] [4], increased prevalence of rapid eye movement (REM) sleep behavior disorder (RBD) and daytime sleepiness [5] features and cognitive impairment [5,6,7]
We examined 314 patients for genes associated with autosomal dominant PD

Summary

INTRODUCTION

Glucocerebrosidase gene (GBA) encodes B-glucocerebrosidase enzyme hydrolyzing glucocerebroside to glucose and ceramide. Until recently, believed to be a benign polymorphism, p.E326K is an established risk factor (large meta-analyses) causing rapid motor progression of PD (β = 3.42; 95% CI, 0.66–6.17; p = 0.02) [12, 13], cognitive decline, and the development of RBD among those who did not have the disorder at baseline [5, 6, 11]. There is an emerging trend in the literature to classify p.T369M as a risk variant (with the reported effect size similar to that of p.E326K, baseline RBD, associated cognitive decline, and higher hazard ratio of reaching H&Y3) [4, 6, 14, 15]. We and others reported that genetics of PD in the Irish population differs from that in the continental Europe, e.g., LRRK2 mutations are rare [17]. The prevalence of GBA in PD and genotypephenotype correlation has never been studied in Ireland, and we hypothesized that to LRRK2, it may differ from that in other populations

Participants

RESULTS

23 RecNcil missing 2 PDD

DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT