BETHESDA, Md.—An international team of researchers has foundthat people who carry the gene for a rare genetic problem known as Gaucherdisease have at least five times the normal risk of developing Parkinson'sdisease. The finding suggests that the gene is one cause of the disease, butindicates that other factors must be operating as well, because not allpatients who have Gaucher also develop Parkinson's.
While some clinicians have noticed an apparent link betweenthe two conditions, an international study of nearly 5,700 people, reported inthe New England Journal of Medicine, isthe first to show the magnitude of the risk.
The discovery was made by investigators from the NationalHuman Genome Research Institute (NHGRI) and the National Institute on Aging(NIA), both parts of the National Institutes of Health (NIH), in collaborationwith scientists from 16 research centers across four continents.
"This analysis illustrates how studying a rare but importantdisorder, like Gaucher disease, can provide powerful clues about more commondisorders, such as Parkinson's disease," says NHGRI Scientific Director Dr.Eric Green. "Understanding the genetic basis of rare conditions can thusprovide insights into normal cellular and biological processes, which in turnmay lead to improved diagnostic and therapeutic strategies."
In previous studies, several genes have been linked toParkinson's disease. However, researchers say their work conclusively showsthat mutations in the gene responsible for Gaucher disease are among the mostsignificant risk factors found to date for Parkinson's disease.
Gaucher disease, which afflicts an estimated 5,400Americans, is caused by defects in the gene known as GBA, which serves as theblueprint for the production of an enzyme known as glucocerebrosidase. Theenzyme breaks down a fatty substance called glucocerebroside which, when notdisposed of, can harm the spleen, liver, lungs, bone marrow and, in some cases,the brain. People with two defective genes suffer from the disease, which comesin three distinct types. Lifespan may range from as little as 2 years to asmany as 40 or 50.
Parkinson's disease, a neurological condition that typicallycauses tremors and stiffness in movement, affects about 1 to 2 percent ofpeople over the age of 60. The chance of developing Parkinson's diseaseincreases with age and involves a combination of environmental risk factors andgenetic susceptibility.
In the past, it was thought that people who carry just onealtered GBA gene were unaffected. However, in recent years, research groups atNHGRI and elsewhere have completed small studies suggesting that carriers ofGBA alterations may have an increased risk of developing Parkinson's disease.
People with only one defective gene do not suffer fromsymptoms and are said to be carriers. It is estimated that about one in 100Americans carries the gene. Among certain groups, like Ashkenazi Jews, theincidence rises to one in 15. It was previously thought that the gene washarmless in such people, but the new results show that is not the case.
Dr. Ellen Sidransky of the NHGRI been intrigued by anobserved link between the two disorders. To explore it, she organized aconsortium of 64 researchers at 16 institutions worldwide—virtually everyGaucher researcher in the world. They studied two common GBA variants in 5,691people with Parkinson's disease, including 780 Ashkenazi Jews, and comparedthem to 4,898 disease-free individuals, including 387 Ashkenazi Jews.
"The opportunity was right to amass the data into onepowerful study," says Sidransky, who serves as senior investigator in NHGRI'sMedical Genetics Branch and is the lead author of the study and coordinated theeffort. "Our analyses of the accumulated data provide a convincing associationbetween GBA alterations and Parkinson's disease."
At least one of the two common GBA alterations was found in3.2 percent of Parkinson's patients and 0.6 percent of controls. Among theAshkenazi subjects, 15.3 percent of those with Parkinson's disease carried aGBA alteration compared to 3.4 percent of Ashkenazi controls.
Still, Sidransky points out that Parkinson's disease is afairly common disorder.
"The identification of a relatively common inherited riskfactor for Parkinson disease may lead to targeted therapies, and also may improveour understanding of the pathogenesis of the disorder," she notes, adding thata better understanding of the mechanisms will lead to new therapeutic targets.
However, not everyone with a mutant form of GBA getsParkinson's.
Sidransky says she's fairly certain that not every patientwith this mutation will go on to get Parkinson's disease, "so there are clearlyother environmental or genetic factors that play into the equation."
In addition to screening for the two common alterations,five of the research centers sequenced the entire GBA gene in 1,642non-Ashkenazi patients with Parkinson's disease and 609 non-Ashkenazi controls.Using this more thorough method, they found many additional alterationsassociated with Parkinson's disease, and showed that 7 percent of patientscarried an alteration, indicating that it is important to look beyond the twocommon alterations to gain a true picture of risk in the general population.
Besides significantly increasing the risk of Parkinson'sdisease, GBA alterations also appear to increase the likelihood of earlydisease onset. According to the new study, Parkinson's patients with GBAalterations developed symptoms an average of four years earlier than otherParkinson's patients.
Overall, the researchers found that the association betweenGBA and Parkinson's disease is not confined to any single ethnicity or tospecific GBA mutations, though they did find that some gene alterations areseen more frequently in certain populations. Compared with the general population,in which GBA alterations occur in fewer than one out of 100 people, GBAalterations occur in at least one out of 16 people of Ashkenazi descent.However, many GBA mutation carriers as well as patients with Gaucher diseasenever develop Parkinson's disease, so this appears to be only one of severalrisk factors involved.
It's known that the gene encodes an enzyme. What role GBAplays in Parkinson's disease isn't yet known.
"The ultimate challenge is to establish the mechanismcontributing to this association," Sidransky and colleagues note in theirreport.
Sidransky notes that the next step for the research is toconduct basic studies to elucidate the mechanism for this association.
In addition to increasing the risk of Parkinson's disease,presence of a GBA variant was associated with early onset of the condition,four to five years sooner than ordinarily seen, the study found.
Further research is in progress to understand the fullspectrum GBA alterations, their biological significance and their associationwith both Parkinson's and Gaucher disease. The researchers are also pursuingways to provide more accurate guidance based on the findings for geneticcounseling and for the development of new therapeutic strategies for thesedisorders.
