DIMENSIONS Autumn 2006


by Cheryl Dawes

Researchers have fit another piece into the genetic puzzle of dementia. Mutations in a second gene on chromosome 17—the progranulin gene—have been found to cause frontotemporal dementia (FTD), which, after Alzheimer’s disease (AD), is the second most common form of dementia among people younger than 65 years old.

FTD is actually a broad category of disorders that affect the frontal and temporal lobes of the brain, explains Dr. Thomas Bird, UW ADRC researcher. In 1998, Bird along with UW ADRC researchers Drs. Gerald Schellenberg, Ellen Wijsman, and Parvie Poorkaj Navas identified a mutation in the tau gene on chromosome 17 that caused FTD. (See Dimensions, Autumn 1999.) Since then, other mutations in the tau gene have also been shown to cause FTD.

However, the tau mutations only account for a small fraction of FTD, says Bird. The progranulin gene mutations account for an equal or even greater percentage of familial or inherited FTD.

Like AD, FTD is a progressive neurodegenerative disease that has two forms—familial (caused by genetic mutations) and sporadic (for which there is no clear genetic cause). FTD differs from AD in other ways, explains Bird. For example, 30-50 percent of FTD seems to be inherited, whereas only between 2-5 percent of AD is of the early-onset strictly inherited familial type.

Clinical symptoms are also different. Early symptoms of FTD are usually serious behavioral problems and problems with language, rather than the memory problems that are early symptoms of AD. During the early stages, a person with FTD may exhibit increasingly inappropriate social behavior and a progressive lack of awareness of how his or her behavior affects other people. A person with FTD may have difficulty producing or understanding meaningful language. FTD tends to have an earlier age of onset than AD, usually starting between 45-65 years. AD is uncommon before age 65.

In FTD, brain imaging—CT scans or MRIs—show degeneration in only the frontal and temporal lobes of the brain, the areas responsible for control of behavior, emotion, and language. In contrast, brain imaging shows an overall decrease in brain size in AD.

Pathological examination under a microscope also reveals differences between these two dementias. Examination of brain tissue from a person with FTD may uncover neurofibrillary tangles, which can also be present in AD, but there are none of the amyloid plaques, which are a hallmark of AD.

FTD often has another distinguishing characteristic—a set of physical symptoms that can include either parkinsonism (rigidity or tremor) or motor neuron disease (amyotrophic lateral sclerosis, ALS) or both.

For more than fifteen years, genetic linkage studies in families with FTD indicated that the genetic cause for FTD was located on chromosome 17, explains Bird. However, only some of the families with FTD had mutations in the tau gene, which is located on chromosome 17. Those mutations caused production of abnormal forms of the tau protein, which appeared as neurofibrillary tangles or Pick bodies when examined under a microscope.

Other families with FTD did not have the same abnormal forms of tau, but they did have unusual bits of protein called “ubiquitinated inclusions” in neurons from the frontal and temporal lobes of their brains. Ubiquitinated inclusions also are found in the motor neurons from people with ALS and are one of the microscopic markers of that disease.

By mapping the genes close to the tau gene on chromosome 17, several groups of researchers have now found the second genetic culprit, mutations in the progranulin gene, which by coincidence is also located on chromosome 17. “These mutations diminish the amount of progranulin that the brain produces, cause aggregation of other proteins, and eventually cause neurons to die,” says Bird. “It’s not known why mutations in progranulin cause aggregation of other proteins which then attach to ubiquitin, but this finding links FTD to ALS and opens the door to better understanding of how neurodegenerative diseases develop and to possible new areas of investigation for treatment.”

The UW ADRC is incorporating the latest findings in its continuing studies of families with FTD and UW researchers are actively evaluating families with progranulin mutations.

For more information about these studies, contact Ellen Steinbart at 206-764-2112(toll-free: 1-800-745-4511) or ellenjea@u.washington.edu

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