|Researchers Uncover Genetic Clues to a Common Form of Age-Related
Bethesda, Maryland — 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 recently published online 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.
“This work shows how genetic and genomic research involving rare diseases can
help unravel the mysteries of more common disorders,” said NHGRI Scientific Director
Eric Green, M.D., Ph.D., “Knowledge gained from studying rare diseases not only
provides insights into specific medical conditions, it also deepens our understanding
of normal cell processes and human biology in general.”
DLB 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 DLB, and the condition accounts for about one-fifth of all cases of dementia.
People affected by DLB often show symptoms of Alzheimer’s and Parkinson’s disease,
but most experts now consider DLB to be a distinct disorder. As is the case for
Alzheimer’s disease, there currently is no good treatment for DLB.
A research group led by Ellen Sidransky, M.D., a senior investigator in NHGRI’s
Division of Intramural Research, sequenced DNA from autopsy samples that had
been carefully examined and classified by neuropathologists at the University
of Pennsylvania. Dr. Sidransky’s group found mutations in the GBA gene in 23
percent of patients with DLB. 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 Dr. Sidransky, who is also acting chief of NHGRI’s
Medical Genetics Branch.
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, Dr. 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 DLB 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
“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, M.D., the first author of
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 DLB, Parkinson’s disease and multiple
Researchers found GBA mutations in the brain tissue of eight of the 35 cases
of DLB. 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
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.
To download microphotographs of brain cells containing Lewy bodies, go to http://www.genome.gov/pressDisplay.cfm?photoID=10004 and http://www.genome.gov/pressDisplay.cfm?photoID=10005.
The NHGRI Division of Intramural Research develops and implements technology
to understand, diagnose and treat genomic and genetic diseases. Additional information
about NHGRI can be found at www.genome.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.