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Researchers find chromosomal anomaly in carriers of fragile X gene

Male carriers found to have abnormally shortened telomeres, a sign of premature aging

Learn more about fragile X research at the UC Davis M.I.N.D. Institute

UC Davis M.I.N.D. InstituteThe M.I.N.D. Institute established the Fragile X Research and Treatment Center directed by Randi Hagerman, M.D., in 2001. In 2003, the National Institutes of Child Health and Development (NICHD) provided funding for the center in collaboration with the University of Washington in Seattle.

Our Fragile X Research and Treatment Center includes research funded by NICHD and research funded by NINDS and private donors.

Our clinical evaluations and treatments of patients with fragile X is an important component of our center and our clinical experience guides our research. Our center involves the expertise of professionals in molecular biology, including Drs. Paul Hagerman and Flora Tassone, and the close interaction of clinicians and molecular biologists had lead to important advances in our understanding of fragile X and treatment.

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Grandson with grandfather
This current study may lead to better understanding and possible future treatments for FXTAS.

UC Davis M.I.N.D. Institute researchers have found that, when compared to men their own age, male carriers of fragile X syndrome have chromosomes shortened at the tips. These tips, called telomeres, naturally get shorter over time. The finding may help to explain why these carriers sometimes develop fragile X-associated tremor/ataxia syndrome (FXTAS) that causes tremor and balance problems in addition to Alzheimer's like symptoms later in life.

"If we can understand the mechanism that leads to shorter telomeres, we can understand more about the role it plays in bringing on premature aging in male carriers of the premutation of the fragile X gene and the aging process, in general," said Randi Hagerman, medical director and endowed chair of fragile X research at the M.I.N.D. Institute.

The study was published in the American Journal of Medical Genetics Part A.

Hagerman and her colleagues at the M.I.N.D. Institute first described FXTAS (pronounced FAX-tass) in 2004. It occurs in male carriers of the FMR1 gene found on the X chromosome. This gene change can mutate as it is passed on to subsequent generations, causing fragile X syndrome and the learning disabilities, mental retardation and autism associated with it. It can also cause the development of FXTAS in as many as 30 percent of the carriers and usually showing symptoms around age 50.

In the current study, researchers looked at the chromosomes of ten male carriers of the FMR1 gene. Five men had FXTAS with dementia, two had FXTAS without dementia and three had the premutation only. In all carriers, the men had shorter telomeres than their age-matched controls.

"If we can understand the mechanism that leads to shorter telomeres, we can understand more about the role it plays in bringing on premature aging in male Dr. Randi Hagermancarriers of the premutation of the fragile X gene and the aging process, in general."
—Randi Hagerman, M.I.N.D. Institute medical director and endowed chair of fragile X research

Telomeres are protective segments of repetitive DNA found at the tips of chromosomes. They protect a cell's chromosomes from fusing with each other or rearranging during normal cell division. Telomeres are consumed during this process and later are replenished by an enzyme. Over time, however, the replenishing breaks down and telomere get shorter.

First author of the current study, Edmund Jenkins, and his New York colleagues have a long history of studying the correlation between telomere length and the onset of neurodegenerative disease.

"Just as in the general population, people with Down syndrome who get Alzheimer's disease have shorter telomeres," he said. Hagerman and her colleagues at the M.I.N.D. Institute approached Jenkins about looking at the chromosomes of male carriers of the Fragile X gene.

Jenkins, Hagerman and their colleagues plan to follow up the current study with others aimed at understanding the role of telomere length in the development of FXTAS "What we hope to do is test younger carriers to see if there is a cutoff in the age where they show the telomere shortening," Jenkins said. "We also want to do a long-term study to see if those with shortening go on to develop FXTAS and dementia."

American Journal of Medical Genetics
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journal article
 

According to Hagerman, the current study may lead to better understanding and possible future treatments for FXTAS. "There should be further research to understand the molecular mechanisms underlying these chromosomal changes if we are to improve diagnosis, treatment and quality of life for the carriers of this gene," she said.

The M.I.N.D. Institute is a unique, collaborative center devoted to finding improved treatments, causes and eventually cures for autism fragile X syndrome, Tourette syndrome, learning disabilities and other neurodevelopmental disorders. The community can help speed that process by enrolling their children in research studies. For more information about M.I.N.D. Institute research studies currently enrolling participants, visit http://www.ucdmc.ucdavis.edu/mindinstitute.

For more information about autism, visit the National Institute of Mental Health Web site at at http://www.nimh.nih.gov/healthinformation/autismmenu.cfm.