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UC Davis Health System

UC Davis researcher awarded grant to define psychiatric issues of fragile X carriers

Photo of Dr. Hessl Hessl's study will involve men ages 18 to 45 from around the country who have the fragile X premutation and their brothers without the premutation.

UC Davis M.I.N.D. Institute researcher David Hessl has received a five-year $1.5 million grant from the National Institute of Mental Health  to study men who are carriers of the gene that causes fragile X syndrome, a common cause of mental impairment. Hessl's study will identify whether or not psychiatric problems affect carriers of the gene mutation.

“Based on clinical assessments, we suspect that carriers are more likely to develop specific social, emotional and cognitive problems, even autism and mental retardation,” said David Hessl, a psychologist, principal investigator on the grant and specialist in the genetic, brain and behavioral issues affecting people with fragile X syndrome. “Our goal is to more conclusively define with a well-controlled study, if carriers are affected and how they are affected, and what brain changes occur that could contribute to those problems.”

Genetic mutation

Fragile X syndrome is caused by a genetic mutation on the X chromosome that can lead to a variety of developmental, physical and behavioral impairments that are usually apparent early in life. It is the most common cause of inherited mental retardation and the leading known single-gene cause of autism. Carriers of the FMR1 gene, who do not have the full mutation that leads to fragile X syndrome but do have the premutation, are at risk later in life of a neurodegenerative disorder called fragile X associated/tremor ataxia syndrome. Also called FXTAS (pronounced “fax-TASS”), the disorder causes debilitating tremors, balance problems and dementia. Hessl's study will help define whether or not the premutation could also lead to psychiatric problems in mid-life, which is the first step to identifying treatments that can reduce or eliminating symptoms altogether.

“These younger guys are a long way off from developing FXTAS, but it is important to learn all we can while they are younger, which I think could eventually lead us to better ways to identify who is at highest risk and how to intervene early, especially if memory or emotional problems precede the classic FXTAS disease,” he said.

"These younger guys are a long way off from developing FXTAS, but it is important to learn all we can while they are younger, which I think could eventually lead us to better ways to identify who is at highest risk and how to intervene early, especially if memory or emotional problems precede the classic FXTAS disease."
— David Hessl

Study participants

Hessl's study will involve men ages 18 to 45 from around the country who have the fragile X premutation and their brothers without the premutation. Men will also be recruited from the local region to serve as normal controls. The participants will undergo neuropsychological testing, a genetic evaluation and an MRI.

“This comprehensive approach allows us for the first time to examine links among the FMR1 gene, brain function, cognition and behavior in this group of men,” Hessl said.

He is collaborating on the study with Susan Rivera, a UC Davis specialist in the neuroanatomy and brain function of fragile X syndrome, who will lead the brain imaging portion of the study. The team will be investigating both the structure of the brain as well as activity of specific brain regions involved in memory and emotion. According to Hessl, their results could have far-reaching implications. The fragile X premutation is fairly common, occurring in approximately one in 250 women and one in 800 men.

Fragile X syndrome results from a trinucleotide repeat expansion in a stretch of DNA, or the repeat of the same three nucleotides — cytocine and two guanines (CGG). Typically, people have about five to 45 of these CGG repeats. Fragile X syndrome results when the three nucleotides repeat more than 200 times. The fragile X premutation, which is the focus of Hessl's study, occurs when the repeat occurs somewhere in the middle — 55 to 200 times.

In children with fragile X syndrome, there is a reduction or absence of the fragile X mental retardation 1 (FMR1) protein, ultimately causing the cognitive and behavioral impairments that are characteristic of the syndrome. Scientists already know that a person with the FMR1 premutation risks transmitting the gene to their children and, when passed from mother to child, the gene can expand and cause the disorder.

The UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute is a collaborative center for research into the causes, preventions and treatments of neurodevelopmental disorders. The Fragile X Research and Treatment Center, funded by the National Institute of Child Health and Human Development, is based at the institute.

For more information or to enroll in Hessl's study, visit www.mindinstitute.org.