Gaucher's Disease Mutation a Strong Risk Factor for Parkinson's

Susan Jeffrey

October 23, 2009

October 23, 2009 (UPDATED October 26, 2009) — It has been a long road, but researchers have finally confirmed that mutations in the gene encoding for glucocerebrosidase (GBA), the enzyme that is deficient in Gaucher's disease, are commonly found in patients with Parkinson's disease.

"No matter what population we look at and what ethnicity, there seems to be this odds ratio of about 5 to 6, suggesting that mutations in this gene are 1 of the most — if not the most — prevalent risk factors known for Parkinson's disease," lead author Ellen Sidransky, MD, from the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Maryland, told Medscape Neurology.

In addition, PD patients who carry a GBA mutation appear to present earlier with the disease, are more likely to have affected relatives, and are more likely to have atypical clinical manifestations.

The findings are the fruit of an international collaboration of 62 authors from 16 centers across the globe. Their report was published in the October 22 issue of the New England Journal of Medicine.

"A Great Serendipitous Story"

Making the link between these diseases "unfolded as a great serendipitous story," Dr. Sidransky said. She is a medical geneticist whose primary research interest is in Gaucher's disease, a rare and inherited genetic disorder caused by a mutation in the GBA gene coding for the enzyme GBA that cleaves glucose off a lipid called glucocerebrocide. Without the enzyme, lipid accumulates primarily within the lysosome of cells in the liver, spleen, bone marrow, and sometimes brain, she explains.

"What has been interesting to me about Gaucher's disease is that clinical manifestations vary incredibly from babies that die from this in utero, to asymptomatic octogenarians with a whole spectrum of associated manifestations in between," she said. It is among the most common inherited disorders in Ashkenazi Jews and is the most common of the lysosomal storage disorders, of which there are up to 40, she added.

Several years ago, her group had a patient with both Gaucher's and Parkinson's disease. "We initially thought it could be a coincidence — after all, PD is a common disorder — but we found in the literature, and in talking to other people, that every group had a few (such patients), and a few years later, we published that as a case-series of 18 patients with both Gaucher's disease and Parkinson's."

Subsequently, Dr. Sidransky heard from a former student, Dr. Kathy Newell, who was then chief neuropathology fellow at the Massachusetts General Hospital in Boston. "She was doing an autopsy and the patient had Parkinson's, but in the chart history she saw that the patient also had Gaucher's," she said. "She Googled it, and realized that I was working on that and asked if I was interested in studying the brain sample."

Dr. Sidransky quickly accepted and asked whether other samples from Parkinson's patients around the same age could also be sent for comparative purposes. When the researchers measured GBA, they found that the sample from the Gaucher's patient was deficient in the enzyme, as expected, but also that levels in the other 2 samples were lower than would have been anticipated. When the researchers extracted DNA, they found there were also mutations in the GBA gene in the Parkinson's patients.

"I got very excited and called her back, and asked for as many Parkinson's brain samples as she could give me," Dr. Sidransky recalls. From various brain banks around the country, the researchers collected more samples, and within 6 months they had almost 60 samples, 8 of which had mutations in the gene.

"When we tried to publish that, there was great reluctance in the community — they all thought it could be a coincidence, or that maybe brain bank donors were biased toward Jewish donors because in the Jewish population there are more carriers," she said. "We went back and found brain samples from non-Parkinson patients in the same brain banks and didn't find any mutations there, but it still didn't convince people."

However, other groups worldwide had begun looking at the connection and were reporting increased frequencies of GBA mutations in Parkinson's patients. Still, the studies were all viewed as limited in some way in their power or control groups.

"So about 2 years ago we put together a conference at the [National Institutes of Health,] and we invited everybody we knew working on the subject together," she said — groups from 16 centers in the Americas, Europe, Israel, and Asia. The result is the new paper. "For me, it was a great journey because it started from a rare disorder, and the research now has implications for a very common, complex disorder," Dr. Sidransky said.

Early Onset

In this report, genotypic and phenotypic information on 5691 patients with PD, including 780 Ashkenazi Jews, and 4898 control subjects, of whom 387 were Ashkenazi Jews, from the 16 centers were analyzed. All centers could detect 2 GBA mutations, L444P and N370S, the authors report.

Among Ashkenazi Jewish subjects, 1 of these mutations was found in 15% of patients and 3% of control participants; among non-Ashkenazi Jewish participants, the mutations were present in 3% of patients and less than 1% of control participants. However, 5 of the research centers sequenced the entire GBA gene in 1882 non-Ashkenazi patients with PD and found that 7% had some mutation in the GBA gene, "showing that limited mutation screening can miss half the mutant alleles," the authors write.

Overall, the odds ratio for any GBA mutation in patients vs control participants was 5.43 across the centers.

Compared with patients who did not carry a GBA mutation, those with a mutation presented earlier with PD, at a mean age of 54.9 years vs 58.8 years (P < .001), and 18% of those without mutations reported a first- or second-degree relative with PD vs 24% of those with a mutation (P = .006).

Although, in general, symptom profiles for the 2 groups were similar, GBA mutations were associated with a significantly lower frequency of asymmetric onset, bradykinesia, resting tremor, and rigidity, the authors note.

The mechanism linking these conditions is "the million dollar question," Dr. Sidransky said. Gaucher's disease is an enzyme deficiency and a lysosomal storage disorder that provides a variety of different avenues to explore, she said. "I think when we learn that link it's going to teach us a lot about Parkinson's disease, and probably about Gaucher's disease, too."

Susceptibility Factor?

Asked for some perspective on these findings, Kapil D. Sethi, MD, director of the Movement Disorders Program at the Medical College of Georgia in Augusta, and a member of the editorial advisory board for Medscape Neurology, said the new study confirms the results of smaller prior studies suggesting an increased risk of PD for those with GBA mutations. Although the mutations are more prevalent in Ashkenazi Jewish populations, the relationship was also seen among non–Ashkenazi Jewish individuals.

"Importantly, if a full sequence analysis of the GBA gene was carried out, the prevalence rates were found to be much higher," Dr. Sethi noted. "This makes GBA gene mutations the most common genetic predisposition for PD in all populations.

There was also a trend seen for earlier disease onset and a positive family history related to GBA mutations, he noted. However, he cautioned, "since the data collection across centers was not uniform, one cannot make any definite conclusions about clinical features associated with these mutations. GBA mutations are likely a susceptibility factor for PD, and further research is needed to understand the mechanisms for susceptibility."

"This analysis illustrates how studying a rare but important disorder, like Gaucher disease, can provide powerful clues about more common disorders, such as Parkinson's disease," National Human Genome Research Institute Scientific Director Eric Green, MD, PhD, said in a statement from the National Institutes of Health. "Understanding the genetic basis of rare conditions can thus provide insights into normal cellular and biological processes, which in turn may lead to improved diagnostic and therapeutic strategies."

The study was supported in part by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Center for Research Resources, all at the National Institutes of Health; the Parkinson's Disease Foundation; a Merit Review Award from the Department of Veterans Affairs, Seattle; the German National Genome Network, German Ministry for Education and Research; the French Parkinson's Disease Genetics Study Group; the Duke-National University of Singapore Graduate Medical School; the National Medical Research Council; the Biomedical Research Council; the Singapore Millennium Foundation; SingHealth, Singapore General Hospital; the National Neuroscience Institute; the Tel Aviv Sourasky Medical Center Grant of Excellence; the Wolfson and Kahn Foundations; the Portuguese Fundaçāo para a Ciência e a Technologia; the National Science Council, Executive Yuan, Taiwan; and the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Dr. Sidransky has disclosed no relevant financial relationships. Disclosures for coauthors appear in the paper.

N Engl J Med. 2009;361:1651–1661. Abstract

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