Researchers have found that genetic alterations originally identified in people suffering from a rare disease may also be an important risk factor for the second most common form of dementia among the elderly.

In a study published in the journal Neurology, a group from the National Human Genome Research Institute ( NHGRI ), part of the National Institutes of Health ( NIH ), and the University of Pennsylvania School of Medicine in Philadelphia reported that alterations in the gene that codes for an enzyme called glucocerebrosidase ( GBA ) may contribute to the development of a relatively common neurodegenerative disease known as dementia with Lewy bodies, or DLB.

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in both DLB and Parkinson's disease. Mutations in the GBA gene had previously been identified as the cause of Gaucher disease, a rare, inherited metabolic disorder.

Dementia with Lewy bodies is the second most common form of age-related dementia, exceeded only by Alzheimer's disease. At least 5 percent of people age 85 and older are thought to have dementia with Lewy bodies, and the condition accounts for about one-fifth of all cases of dementia. People affected by dementia with Lewy bodies often show symptoms of Alzheimer's and Parkinson's disease, but most experts now consider dementia with Lewy bodies to be a distinct disorder. As is the case for Alzheimer's disease, there currently is no good treatment for dementia with Lewy bodies.

A research group led by Ellen Sidransky, at NHGRI, sequenced DNA from autopsy samples that had been carefully examined and classified by neuropathologists at the University of Pennsylvania. Sidransky's group found mutations in the GBA gene in 23 percent of patients with dementia with Lewy bodies. That rate is nearly 40 times higher than the frequency of GBA mutations in the general population.

" Our findings are particularly significant because this is among the first examples of a genetic change associated with dementia with Lewy bodies. This discovery will serve to advance our understanding of the mechanisms underlying this devastating disease," said Sidransky.

Until recently, most research on GBA focused on Gaucher disease, a rare, inherited metabolic disorder in which harmful quantities of a fatty substance, called glucocerebroside, accumulate in the spleen, liver, lungs, bone marrow and, in some cases, the brain. All people with Gaucher disease have a deficiency of the GBA enzyme, which is involved in the breakdown and recycling of glucocerebroside.

Over the past few years, Sidransky's lab and other research groups have uncovered data suggesting that GBA alterations may also be a risk factor for the development of symptoms that resemble those seen in Parkinson's disease. The latest findings add dementia with Lewy bodies to the list of disorders in which the GBA gene may play a role. People with Gaucher disease have two mutated copies of the GBA gene, while the DLB patients with GBA alterations have one mutated copy and one normal copy.

" This serves as an example of how a genetic alteration may lead to a key enzyme taking on a totally different role from its primary function, contributing to a common, complex disorder," said Ozlem Goker-Alpan, the first author of the study.

Specifically, the NHGRI-led group examined the GBA gene in autopsy specimens from 75 patients who had been diagnosed with a class of neurodegenerative disorders known as synucleinopathies, which are characterized by abnormal aggregates of a protein called alpha-synuclein within brain and other neural cells. The three synucleinopathies examined in the study were dementia with Lewy bodies, Parkinson's disease and multiple system atrophy.

Researchers found GBA mutations in the brain tissue of eight of the 35 cases of dementia with Lewy bodies. Only one of 28 patients with "classic" Parkinson's disease had a GBA alteration, while no mutations were found among the 12 patients with multiple system atrophy.

The results may offer intriguing new avenues for exploring the basic causes of a complex disease at the cellular level. However, the researchers emphasized that more work and larger groups of samples are needed to confirm these associations and determine exactly how GBA alterations may contribute to the accumulation of alpha-synuclein in neuronal cells.

Source: National Institutes of Health, 2006


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