Those with the Gaucher-related mutations also develop PD earlier, as reported in NEJM.

An NIH-led team of researchers have found that those with Gaucher’s disease have more than five times greater risk of developing Parkinson’s disease than the general public. They say that their work conclusively shows that mutations in the gene responsible for Gaucher’s are among the most significant risk factors found to date for Parkinson’s disease.

The findings appear October 22 in the New England Journal of Medicine. The discovery was made by investigators from the National Human Genome Research Institute and the National Institute on Aging in collaboration with scientists from 16 research centers across four continents.

Gaucher’s disease occurs when an individual inherits two 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 the brain. The enzyme functions in the lysosome.

The research team examined the frequency of GBA alterations in 5,691 patients with Parkinson’s disease, including 780 Ashkenazi Jews. Those data was matched against 4,898 unaffected volunteers including 387 Ashkenazi Jews.

At least one of the two 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 to 3.4% of Ashkenazi controls.

In addition to screening for the two common alterations, five research centers sequenced the entire GBA gene in 1,642 non-Ashkenazi Jews with Parkinson’s disease and 609 non-Ashkenazi controls. 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 two common alterations that are associated with Gaucher’s.

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 four years earlier than other Parkinson’s patients, according to the investigators.

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.

Further research is in progress to understand the full spectrum of GBA alterations, their biological significance, and their association with both Parkinson’s and Gaucher’s diseases.

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