Genetic Mutation Speeds Onset of Parkinson's Disease

NEW YORK, Sept. 17 -- A genetic mutation known to cause Gaucher disease may also contribute to early onset of Parkinson's disease, particularly in patients with Jewish ancestry, researchers found.
Mutations in the glucocerebrosidase gene were 3.4 times more common in Parkinson's disease cases than in controls and 2.7 times more frequent among patients whose Parkinson's disease set in by age 50 than in those whose disease had a later onset, reported Lorraine N. Clark, Ph.D., of Columbia University here, and colleagues in the Sept. 18 issue of the journal Neurology.
Glucocerebrosidase mutations were also seen more often in Parkinson's disease cases among patients of Jewish ancestry than among cases overall or among participants who were not of Jewish ancestry (16.9% versus 13.7% and 8%).
These findings from the Genetic Epidemiology of Parkinson's Disease study suggest that the gene may impact susceptibility for Parkinson's disease and modify age at onset, the researchers said. .
Gaucher disease, a rare condition that impairs lysosomal lipid storage and can cause parkinsonism, "is one of the most common genetic diseases reported in the Ashkenazi Jewish population," they wrote.
Other research groups had reported that certain glucocerebrosidase mutations were more common among Parkinson's disease patients than healthy controls, but none had sequenced the gene in both populations.
For a more comprehensive look, Dr. Clark's group studied a subset of patients from the larger Genetic Epidemiology of Parkinson's Disease study.
Their analysis included all 178 Parkinson's disease patients and 85 controls with four Jewish grandparents as well as 100 matched Parkinson's disease patients and 94 randomly chosen controls who were not of Jewish ancestry.
Both cases and controls were evaluated for medical history, Unified Parkinson's Disease Rating Scale score, modified Mini-Mental State Examination, family history of Parkinson's disease, and ancestry of each grandparent.
The researchers noted that Ashkenazi origin was not elicited among those with Jewish ancestry, but "approximately 90% of Jews in the United States are Ashkenazi."
Gene sequencing of all exons of the glucocerebrosidase gene turned up nine different mutations in Parkinson's disease cases.
The investigators found that glucocerebrosidase mutations were more common with Parkinson's disease, suggesting a role in susceptibility to the disease, at least among those with Jewish ancestry.
Among the findings, they reported:
Overall, 13.7% of Parkinson's disease patients and 4.5% of controls carried the mutations (odds ratio 3.4, 95% confidence interval 1.5 to 7.4).
Most who tested positive for the mutations had Jewish ancestry (30 of 38 cases and six of eight controls).
16.9% of Jewish Parkinson's disease cases carried the mutations whereas only 7.1% of Jewish controls did (odds ratio 2.7, 95% CI 1.1 to 6.7).
8% of non-Jewish Parkinson's disease cases carried the mutations versus 2.1% of non-Jewish controls, which was not a significant difference (OR 4.0, 95% CI 0.8 to 19.3).
The mutations were more common among Parkinson's disease patients with Jewish grandparents than without Jewish ancestry (OR 2.3, 95% CI 1.02 to 5.30, P=0.045).
Glucocerebrosidase mutations were also tied to earlier age at Parkinson's onset (P<0.01).
Age of onset among mutation carriers was 1.7 years earlier overall even after adjusting for age at evaluation, sex, family history of Parkinson's, and Jewish ancestry (95% CI 0.5 to 3.3, P<0.04).
Among Parkinson's disease patients, those with onset by age 50 were more likely to carry the mutations than those with a later onset both among those with Jewish ancestry (OR 2.4, 95% CI 1.1 to 5.4) and without (OR 5.7, 95% CI 1.1 to 30.0).
This effect appeared to be limited to those with early onset. Age at onset was not significantly earlier with carrier status among those whose Parkinson's disease set in after age 50 (P=0.06).
Parkinson's disease in a first-degree relative did not significantly increase the odds that a participant would carry glucocerebrosidase mutation overall (OR 0.8, 95% CI 0.3 to 2.0) or in those with Jewish ancestry (OR 1.4, 95% CI 0.5 to 4.0).
The lack of aggregation in families suggests other genetic and environmental factors also play a role in determining Parkinson's disease risk, Dr. Clark and colleagues said.
Further studies are needed to determine what role the different mutation variants play in the pathogenesis of Parkinson's disease, they added.
The study was supported by grants from the National Institutes of Health and by the Parkinson's Disease Foundation. The authors reported no conflicts of interest. Primary source: NeurologySource reference: Clark LN, et al "Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease" Neurology 2007;69:1270-1277.