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Study Conclusively Ties Gaucher Disease Gene to Parkinson's Disease

BETHESDA, Md -- October 21, 2009 -- According to a study published in the October 21 issue of the New England Journal of Medicine, carriers of the rare, genetic condition, Gaucher disease, face a risk of developing Parkinson's disease more than 5 times greater than the general public.

In previous studies, several genes have been linked to Parkinson's disease. However, researchers said their work conclusively shows that mutations in the gene responsible for Gaucher disease are among the most significant risk factors found to date for Parkinson's disease.

Gaucher disease occurs when an individual inherits 2 defective copies of the GBA gene, which codes for an enzyme called glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside, which, when not properly disposed of, can harm the spleen, liver, lungs, bone marrow and, in some cases, the brain.

In the past, it was thought that people who carry just 1 altered GBA gene were unaffected. However, in recent years, research groups at National Human Genome Research Institute (NHGRI), Bethesda, Maryland, and elsewhere have completed small studies suggesting that carriers of GBA alterations may have an increased risk of developing Parkinson's disease.

"The opportunity was right to amass the data into one powerful study," said senior investigator Ellen Sidransky, MD, NHGRI's Medical Genetics Branch. "Our analyses of the accumulated data provide a convincing association between GBA alterations and Parkinson's disease."

The research team examined the frequency of GBA alterations in 5,691 patients with Parkinson's disease, including 780 Ashkenazi Jews, a population in which a particular type of Gaucher disease is more prevalent. Those data were matched against 4,898 controls, which included 387 Ashkenazi Jews.

At least 1 of the 2 common GBA alterations was found in 3.2% of Parkinson's patients and 0.6% of controls. Among the Ashkenazi subjects, 15.3% of those with Parkinson's disease carried a GBA alteration compared with 3.4% of Ashkenazi controls.

In addition to screening for the 2 common alterations, 5 of the research centres sequenced the entire GBA gene in 1,642 non-Ashkenazi patients with Parkinson's disease and 609 non-Ashkenazi controls. Using this more thorough method, they found many additional alterations associated with Parkinson's disease, and showed that 7% of patients carried an alteration, indicating that it is important to look beyond the 2 common alterations to gain a true picture of risk in the general population.

Besides significantly increasing the risk of Parkinson's disease, GBA alterations also appear to increase the likelihood of early disease onset. Parkinson's patients with GBA alterations developed symptoms an average of 4 years earlier than other Parkinson's patients.

Overall, the researchers found that the association between GBA and Parkinson's disease is not confined to any single ethnicity or to specific GBA mutations, though they did find that some gene alterations are seen more frequently in certain populations. Compared with the general population, in which GBA alterations occur in fewer than 1 out of 100 people, GBA alterations occur in at least 1 out of 16 people of Ashkenazi descent.

However, many GBA mutation carriers as well as patients with Gaucher disease never develop Parkinson's disease, so this appears to be only 2 of several risk factors involved.

SOURCE: National Institutes of Health

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