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New Genetic Clues to Dementia
This week, two research groups report they have uncovered genetic mutations
that underlie two different forms of dementia. One group discovered genetic mutations
that cause a large proportion of inherited familial frontotemporal dementia (FTD),
a rare brain disorder that usually affects people between 40 and 64 with symptoms
including personality changes and inappropriate social behavior. Another group
identified alterations in a gene that may contribute to dementia with Lewy bodies
(DLB), the second most common form of dementia among the elderly after Alzheimer's
disease.
FTD encompasses a set of rare brain disorders. People with FTD may exhibit uninhibited
and socially inappropriate behavior, changes in personality and, in late stages,
loss of memory, motor skills and speech. There is no treatment.
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| The light purple sphere near the center of the image
is a Lewy body. Image courtesy of Kondi Wong, Armed Forces Institute of
Pathology. |
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Geneticist Dr. Michael Hutton of the Mayo Clinic College of Medicine in Jacksonville,
Florida, led an international scientific team funded in part by NIH's National
Institute on Aging (NIA) to discover the new gene for FTD. In the July 16, 2006
online edition of Nature, they describe the role of the progranulin, or PGRN, gene,
which makes a growth factor protein that stimulates cell division and motility
during embryonic development, wound repair and inflammation
The scientists say it's unclear what role progranulin plays in the normal brain,
but in the FTD families, the PGRN mutations appear to cut short the assembly
process for the protein in brain nerve cells (neurons), and the lack of progranulin
eventually causes neurons to die. Understanding how this mutation helps bring
about neuronal death might help scientists better understand the different pathways
that cause dementia.
"This new finding is an important advance in our understanding of frontotemporal
dementia," says NIA director Richard J. Hodes.
In the other study, reported in the journal Neurology, researchers
found that alterations in the gene that codes for an enzyme called glucocerebrosidase
(GBA) may contribute to the development of DLB. Mutations in this gene had previously
been identified as the cause of Gaucher disease, a rare, inherited metabolic
disorder.
DLB is named for Lewy bodies, the abnormal clumps of protein that develop
inside nerve cells in both DLB and Parkinson's disease. 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. At least 5% of people age 85 and
older are thought to have DLB, and the condition accounts for about one-fifth
of all cases of dementia. There currently is no good treatment.
A research group led by Dr. Ellen Sidransky of NIH's National Human Genome Research
Institute 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 eight of the 35 patients
with DLB. That rate (23%) is nearly 40 times higher than the frequency of GBA
mutations in the general population. In contrast, only one of 28 patients with "classic" Parkinson's
disease had a GBA alteration, while no mutations were found among 12 patients
with multiple system atrophy, another condition that can bring dementia.
"Our findings are particularly significant because this is among the first examples
of a genetic change associated with dementia with Lewy bodies," Dr. Sidransky
said.
These results offer intriguing new avenues for exploring the basic mechanisms
at the cellular level that lead to dementia.
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