Subscribe to eTOC

Glucocerebrosidase Mutations Implicated in Sporadic Parkinson Disease



No caption available.

Parkinson disease (PD) patients with glucocerebrosidase gene variants had an earlier age at onset for the disease than those who didn't have the gene mutations.

Mutations in the glucocerebrosidase (GBA) gene are best known for causing the lysosomal storage disorder, Gaucher disease. But research in the past five years has made it clear the gene also plays an important role in some cases of sporadic Parkinson disease (PD).

A new report in the Jan. 27 Neurology now shows it also figures in familial PD, not only increasing the risk but also lowering the age at onset. In combination with previous work, the study highlights just how important GBA is in assessing the risk of PD. But even as the gene takes center stage, experts believe it is still “way too early” to contemplate genetic testing for mutations among people most at risk.

Despite the involvement of a heritable mutation, previous studies of GBA in PD had not examined familial cases closely, according to William C. Nichols, PhD, the lead scientist of the new study and a genetics researcher at the Cincinnati Children's Hospital Medical Center in Ohio.

As part of a large collaborative group investigating the genetics of PD, Dr. Nichols and colleagues looked for GBA mutations in over 1,300 individuals from 566 families that had at least two members affected with PD. The location of the GBA gene on chromosome 1 is well characterized, and so, rather than sequencing the gene in every individual in every family — a forbidding task — they instead determined which families were most likely carrying GBA variants based on an increase in allele sharing in four markers around the GBA locus.

Of the 566 families, 96 appeared likely to be carrying GBA variants, and so the team completely sequenced the GBA gene in one member of each of those families, along with 359 neurologically normal controls. In the PD patients, they identified nine sequence variants in all, including four new variants, and several common mutations previously linked to both Gaucher disease and PD. The new variants appeared to be causative for PD, since in each case, the same variant was present in multiple PD patients within the same family, and three of the four variants were excluded from the control population (the fourth could not be tested).

In Gaucher disease, GBA mutations are autosomal recessive, and it is expected that some proportion of any population will be carriers; 5.3 percent of controls in the current study carried GBA mutations that had been previously associated with Gaucher disease and had been implicated in PD as well. In contrast, 12.6 percent of PD patients carried those mutations, indicating that GBA mutations more than doubled the risk of PD.


Not every PD patient carried a GBA mutation, of course. But when those who didn't were compared to those who did, the authors found that the presence of a GBA mutation lowered the age of onset by approximately six years, from an average age of 63 for those without to 57 for those with a mutation. No other clinical characteristics were affected by the gene.

Previous studies had suggested that GBA-related PD cases are most common in Ashkenazi Jewish people, who have a high frequency of mutation carriers. One study found GBA mutations in 17 percent of Jewish PD cases, but only 8 percent of non-Jewish cases. Dr. Nichols believes that less than 10 percent of his entire population was Jewish. Nonetheless, he said his results indicate that GBA may be an even more common cause of PD than previously thought among people from all backgrounds.

Ellen Sidransky, MD, a senior investigator at the NIH National Human Genome Research Institute, called Dr. Nichols's study “an important confirmation” of the role of GBA in the genetics of PD. Dr. Sidransky published the initial finding of GBA mutations in PD patients.

As the role of GBA in PD risk begins to be clarified, two central questions emerge. The first concerns pathogenesis — how does a mutation in glucocerebrosidase increase the risk for PD? “I don't think anyone knows the answer to that,” Dr. Nichols said, but he noted that since most carriers don't develop PD, there must be multiple risk factors involved in addition to GBA. He thinks it is possible that GBA can only heighten PD risk in the presence of some other, still unidentified, gene or environmental exposure.


DR. WILLIAM C. NICHOLS: “Its way too early to think about using this for diagnostics or counseling. Unless there is something you can do with the information, I dont think the test should be offered.”

Dr. Sidransky concurred. Although parkinsonian signs were seen in some of the earliest Gaucher patients, “even most people with Gaucher disease don't get Parkinson disease,” despite have two mutated GBA genes, she pointed out in an interview with Neurology Today. “This gene seems to be one of the most important ones for PD, but we don't know why.” Normally, glucocerebrosidase catabolizes lipids by cleaving sugars off them, but whether a loss of this function plays a role, or instead whether the mutated protein gains some other toxic function, is entirely unknown.


The second question raised by GBA's growing importance, and especially by the current study's demonstration for a prominent role in familial PD, is whether genetic testing should be offered to those at risk. The answer from both Dr. Nichols and Dr. Sidransky was an unequivocal “no.”

“It's way too early to think about using this for diagnostics or counseling,” Dr. Nichols said. “Unless there is something you can do with the information, I don't think the test should be offered.”

“We are still trying to dissect the genetics of Parkinson disease, and what additional genes may contribute,” he said. “At some point, we hope to have a gene panel to type patients for one of these variants. But we also have to worry about penetrance.” Because most people with a single GBA mutation never develop PD, a positive test result would not be diagnostically informative until more is learned about the conditions under which it increases risk.

Dr. Sidransky has even seen two siblings with the same mutation, one of whom has PD, while the other doesn't, highlighting how much is still unknown about additional risk factors. In addition, she said, knowing one's GBA status can't yet lead to better treatment. “I feel that genetic testing should be in the research setting, because we have no interventions,” she said. “None of the Gaucher medications have any impact on Parkinson disease.”

Patients in Dr. Nichols's study consented to have no access to their own test results. Tatiana Foroud, PhD, professor of medical and molecular genetics at Indiana University Medical Center in Indianapolis, who leads the genetic collaborative within which Dr. Nichols's study was performed, said that “while genetic testing is currently available clinically, we believe in many cases such testing is premature until we are able to provide accurate estimates of the penetrance of particular mutations and the disease-associated risk of particular disease-associated variants.”

Nonetheless, she said, some patients do ask about testing, and they are referred to commercial labs that offer testing and counseling for multiple PD genes. “We have found this to be the best way to allow subjects to make an informed decision about molecular testing and ensure that this information is provided to them with appropriate counseling.”


• Nichols WC, Pankratz N, Foroud T, et al., for the Parkinson Study Group—PROGENI Investigators. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 2009; 72: 310–316.