ARTICLE IN BRIEF
Heterozygous mutations in the gene for Gaucher disease may serve as a biomarker for Lewy Body disease, two new studies suggest.
CHICAGO—Two studies presented at the AAN meeting here strengthened and clarified the association between heterozygous mutations in the gene for Gaucher disease and the risk of developing Lewy Body disease.
One study, the first ever involving a Japanese population, found that 7.7 percent of patients clinically diagnosed with Parkinson disease (PD) had a single copy of a mutation for glucocerebrosidase, or GBA (two copies of which cause Gaucher disease). By comparison, only 0.4 percent of controls had the mutation, meaning that carriers were estimated to have 22 times the risk of being diagnosed with PD compared to non-carriers.
The other study, involving 76 subjects from the New York Brain Bank at Columbia University, for whom the GBA gene was sequenced, revealed that carriers of the mutation were significantly more likely than non-carriers to have a clinical diagnosis of PD or Lewy Body dementia (LBD) that was confirmed pathologically, and significantly less likely than non-carriers to meet diagnostic criteria for Alzheimer disease.
Together, the studies prompted some of the researchers to suggest that GBA mutations might become useful as a diagnostic marker, and might even provide a target for therapy.
“With a GBA mutation we believe we may be able to better detect those who will meet pathological criteria for LBD compared to Lewy Body variant of AD,” said Karen Marder, MD, professor and chief of the division of Aging and Dementia in the department of neurology at Columbia University and co-author of the pathology study. Moreover, she added, “It raises the issue of etiology. Is the GBA gene going to give us some clues as to how to treat Parkinson disease? Perhaps.”
The presenter of the Japanese study said the large size of his sample, involving over a thousand people, should help move GBA from the realm of scientific curiosity to one of clinical utility.
“Although several studies have suggested an association of GBA and PD, most of them analyzed only specific variants, and sample sizes were also small, making the medical implications of GBA variants associated with Parkinson disease inconclusive,” said Jun Mitsui, MD, a neurologist at the University of Tokyo.
“Our study has established GBA as a robust and relatively prevalent genetic risk factor for sporadic Parkinson disease. Further studies on the biological implications of mutant GBA in the pathophysiology of PD are expected to open new avenues for developing therapeutic measures for PD.”
But the NIH researcher who first identified the link between Gaucher and PD remained cautious about interpreting the results.
“It is fulfilling to find that insights we've earned for a rare disease may end up being important for studying and treating a relatively common disorder,” said Ellen Sidransky, MD, chief of the Section on Molecular Neurogenetics in the Medical Genetics Branch of the National Human Genome Research Institute. “But having the GBA mutation is only a risk factor for developing Parkinson disease; it's not predictive. Our studies of patients with Gaucher disease and Gaucher carriers show that the vast majority of people with the mutation never develop PD. The last thing I'd want to do is cause patients and families with Gaucher disease to panic that they're going to get PD. At the same time we are very impressed with how frequent this mutation is seen in PD and LBD patients worldwide. Learning how the two disorders are related will teach us a lot about the pathophysiology, genetics, and treatment of both diseases.”
The costly enzyme replacement therapy used to treat Gaucher disease would likely prove ineffective for carriers of the mutation who have PD, because it doesn't cross the blood-brain-barrier, Dr. Sidransky said. But, she added, “I do believe we may be able to come up with therapies specific for patients with PD who have mutations in this gene. First, though, we need to understand the mechanism.”
Rather than looking only for the particular mutations in the GBA gene that had been reported previously, Dr. Mitsui and colleagues began their study by re-sequencing the entire GBA gene in 61 PD patients and 47 controls to identify mutations peculiar to that population. They found that six of the PD patients had pathogenic mutations in one of four different sites on the gene, whereas none of the 47 control subjects had any of those mutations.
They then looked for those same sequence variations in a second tier of subjects, involving 483 PD patients and 497 controls. Combining results from both tiers, 42 of 544 PD patients had a mutation, compared with only two of 544 controls, for an odds ratio of 22.7 (95 percent confidence interval, 5.5 to 94.2). PD patients carrying mutant GBA were significantly younger than those who lacked them. Dr. Mitsui's group also identified six multiplex families where PD patients concordantly carried the GBA mutations.
The first author of the New York pathology study commended Dr. Mitsui's group for using its two-tiered approach to identifying those mutations most common to the sample population.
“Previous studies genotyped specific mutations in the gene, and they reported low rates of the mutation in Asian populations,” said Lorraine N. Clark, PhD, assistant professor of clinical pathology at the Taub Institute of Alzheimer's Disease and Aging Research in the Center for Human Genetics at Columbia University College of Physicians and Surgeons. “The rate found here is much higher, I think because they've done a more comprehensive analysis of the gene. By doing this two-tiered study, it really strengthens their findings.”
The study by the Columbia University investigators involved 76 subjects from the New York Brain Bank, all with LB pathology. Among the 64 subjects for whom clinical data were available, 17 had been diagnosed with AD, 27 with PD, 11 with Lewy Body dementia, two with essential tremor, three with other parkinsonism, two with other dementia, and two with diagnoses unknown.
On pathological exam, all had Lewy Bodies: 31 had Lewy Body variant of Alzheimer disease, 30 had diffuse Lewy Body disease, 12 had PD, and three had incidental Lewy bodies.
Sequencing of the GBA mutation revealed that 18 of the 76 subjects, or 23.6 percent, had at least one mutation. Carriers of a GBA mutation were significantly less likely to meet AD diagnosis criteria than were non-carriers, after adjusting for age at death and gender (OR=0.24, 95 percent CI: 0.06-0.87, p=0.030).
Of the 64 subjects with clinical data, the GBA mutation was significantly associated with LBD pathological diagnosis, even after adjusting for age at death, gender, and LBD clinical diagnosis (OR=7.9, 95 percent CI: 1.9-31.7, p=0.004). Of the 38 subjects clinically diagnosed with PD or DLB, 14 of 16 (87.5 percent) GBA carriers compared to 12 of 22 (54.5 percent) GBA non-carriers were diagnosed pathologically with PD or LBD (p=0.026). The remaining two out of 16 GBA carriers and ten of 22 non-carriers who had been clinically diagnosed with PD or diffuse LBD were pathologically diagnosed as LB variant of Alzheimer disease.
“In the future, it may be possible to identify a much purer diagnosis of Lewy Body disorders if the patient has a GBA mutation,” Dr. Marder said. “But we're still far from saying people should get genetic testing for this.”
Greater understanding of the relationship between the mutation and PD is expected to come from a study involving at least 5,000 cases worldwide being led by Dr. Sidransky. •