Glucocerebrosidase Mutations in Dementia with Lewy Bodies
By Claire Henchcliffe, MD, Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College. Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmithKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidepoint Global.
Synopsis: This multicenter study compared genotype data to establish that mutations in the glucocerebrosidase (GBA1) gene are a risk factor for developing dementia with Lewy bodies.
Source:Nalls MA, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol 2013;70:727-735.
Mutations in the glucocerebrosidase gene (gba1) have long been established to cause Gaucher’s disease. However, multiple studies have now demonstrated that GBA1 mutations are a significant risk factor for Parkinson’s disease (PD) and are associated with a higher incidence of cognitive changes and earlier disease onset. The primary objective of this study was to establish whether mutations in the GBA1 gene are a risk factor for developing dementia with Lewy bodies (DLB). This international, multicenter analysis was undertaken to further evaluate the relationship between GBA1 mutations and risk of DLB, and to compare with Parkinson’s disease dementia (PDD). Eleven centers with previous experience in GBA1 genotyping contributed data for the study, which were analyzed at the National Institutes of Health. Included subjects met McKeith criteria for DLB or the Movement Disorders Task Force criteria for PDD. Cases examined comprised 721 with DLB, 151 with PDD, and 1962 controls. Ascertainment of mutations varied by site. Full sequencing of all GBA1 exons was performed in 80.6% DLB samples, 66.2% PDD samples, and 30.8% control samples. Remaining samples underwent screening for either 5-10 mutations (13% DLB, 33.1% PDD, 18.9% controls) or up to four mutations (6.4% DLB, 0.7% PDD, 50.3% controls). Of the subjects included, 34.5% and 36% were women (DLB and PDD, respectively), whereas 52.8% of the controls were women. Control subjects’ mean age at examination was less than that for DLB and PDD (DLB: 75 years, PDD: 76 years, controls: 65 years). Subjects self-reported European descent in 98-100% cases, and less than 1% of patients were of Ashkenazi Jewish or Asian descent. Data aggregated from all sites revealed that DLB subjects were approximately eight times more likely than controls to carry a GBA1 mutation (odds ratio [OR], 8.28). Subjects considered to have PDD were found to have a slightly lower association (OR, 6.48). Logistic regression models adjusted for site found an OR of 8.66 for DLB and 3.82 for PDD. Further analysis revealed a significant association between earlier ages of disease onset in subjects with GBA1 mutations, and cases with GBA1 mutation developed symptoms approximately 5 years earlier than those without (P < 0.001).
PD associated with GBA1 mutations is likely associated with a higher incidence of dementia, and findings from this study extend this concept to DLB. Combined genotyping results in this multicenter study find that risk for DLB is approximately eight times higher in subjects with GBA1 mutations compared with controls. This finding is important in understanding genetics of the "alpha-synucleinopathies," and once again underscores the overlap between PD and DLB. It also highlights the advantage of a collaborative approach. There are several fundamental weaknesses of this study, however. Most importantly, there was considerable variation in the methods used for mutation analysis. Efforts were made to adjust for this in the statistical analysis, but this makes interpretation of the results far more difficult. Also, some sites did not include control cases, and some cases relied on clinical diagnosis while pathology was available for others. Examination of results by site in fact reveals considerable variation, although all demonstrated a positive association. As noted above, there are differences in age and gender between the DLB/PDD and control groups. Finally, it would be interesting to see how these findings compare to other ethnic groups. At this time, genetic testing is not routinely recommended in patients presenting with parkinsonism, but as we move toward this potential, this and similar studies will be critically important. Moreover, a better understanding of genetic mechanisms underlying the development of parkinsonism may provide novel therapeutic targets, and the finding of GBA1 association with PD, PDD, and DLB newly establishes the importance of lysosomal function in these challenging disorders.