the tough case of fragile X
by Anton Zuiker

hen twelve-year-old Sam May visits Chapel Hill each year, he becomes the center of a genetics dream team. Deep inside each of his X chromosomes is a mutation — a mutation responsible for the delay in Sam's cognitive growth. But Sam clearly understands that the Carolina researchers awaiting his visits are learning valuable lessons from him.

"He loves going there," says his mother, Kathy May. "And when he's done, he asks, 'Has the research helped?'"

.: Don Bailey. Photo by Steve Exum; click to enlarge. :.

Sam has grown up with the researchers at the Frank Porter Graham Child Development Institute (FPG). For ten years he's participated in their studies of fragile X syndrome (FXS), the most common inherited cause of mental retardation. These studies have distinguished the institute, where scientists, physicians, and educators study young children and their families, researching factors that put children at risk for developmental problems.

While other university research centers investigate the basic genetics underlying fragile X, the FPG's Carolina Fragile X Project focuses on child development and how families learn to cope with FXS.

"They're very family-focused," says May, cofounder of the FRAXA Research Foundation, a national advocacy group. Her family's work with FPG has been a positive experience, she says. "I think that they learn a lot from us and from Sam's teachers, and they bring that back into the project."

he institute's researchers are busier than ever, and they are about to embark on a series of new studies that may have implications for other genetic disorders. In a special competition of FXS research centers held by the National Institutes of Health, FPG earned the highest score and a grant for more than $5 million over five years to study parental adaptation to FXS.

"This takes our focus away from the kids alone and looks at the challenges that families face," says Don Bailey, senior scientist and director of FPG. The new grant funds three studies: on how families adapt to the learning needs of their children, to the challenging behaviors of their children, and to the knowledge of their genetic status.

A single gene

n the 1940s, English researcher Julia Bell and Irishman James Purdon Martin noticed that mental retardation can run in families. One condition they identified became known as Martin-Bell syndrome.

Eventually, scientists came to understand that this syndrome had a genetic base. Under a microscope, they noticed that the X chromosomes of Martin-Bell kids looked as if their ends were pinched — some genetic mutation was causing this "fragile" X. This became the new name of the syndrome.

When Bailey first learned about fragile X in the 1980s, the single genetic mutation that causes FXS had yet to be discovered. That came in the early 1990s with the mapping of the human genome and the identification of FMR-1. This gene, on the X chromosome, tells cells to produce a protein that scientists believe is essential for normal brain functioning. One in every 4,000 newborns inherits a mutation in this gene.

Normal FMR-1 genes include a sequence of DNA code, CGG (cytosine-guanine-guanine), repeated 5 to 50 times. This sequence gives instructions to produce the FMRP protein, which helps the brain to develop and function. If that code is repeated 50 to 200 times, the individual is a "premutation carrier" of fragile X syndrome. These individuals are not usually affected, but their children can inherit the full mutation, with more than 200 code repeats. The full mutation inhibits production of the FMRP and leads to mental retardation, behavioral abnormalities, and some physical characteristics such as large ears and a prominent forehead.

While the cause of fragile X is clear, the ways it is expressed in children range considerably. Some children show subtle developmental delays while others have major impairments. Boys with fragile X tend to be more affected than girls.

Bailey says his introduction to the syndrome dovetailed nicely with his earlier work with families, and he's built on that. Since 1992, he's nurtured a multidisciplinary team of researchers, each scientist approaching FXS from a different perspective. "We've got anthropology, speech and language pathology, audiology, neuropsychology, developmental psychology, occupational therapy, and special education," Bailey says. The team is currently working on seven different grants totaling more than $2.2 million per year.

The children

ur primary focus in the last ten years," Bailey says, "has been on accounting for the variability within fragile X. Why are some kids severely delayed and some are not?"

In 1992, Bailey received his first grant, from the U.S. Department of Education, to study the early development of boys with fragile X. Very little about early development had been described, and children were routinely diagnosed late — after age three — or not at all.

"We also wanted to learn about how families found out about fragile X syndrome, what experiences they had, what signs they had observed," Bailey says. "We wanted to track the kids longitudinally to see what kind of services they were getting and what schools they were placed in." The team started with a group of seventy-five boys in North Carolina, South Carolina, and Virginia and have followed them ever since; these boys are now in late elementary or middle school.

Bailey's team has accounted for some of the variability in children's development through the study of the protein FMRP. They found that the amount of that protein in the blood does correlate to the level of cognitive development. But this accounts for only part of the severity, so something else must be at work.

Part of the answer may lie in understanding the association between fragile X and a range of other conditions such as anxiety, attention deficits, hyperactivity, and autism. Bailey's team has shown that at least 25 percent of children with FXS also have autism, and that those with autism are much more severely delayed.

umerous other researchers are striving to find the genetic cause or causes of autism, which is diagnosed through a variety of behaviors. Deborah Hatton was a doctoral student when Bailey received his first grant. She's been deeply involved with the project ever since as a principal investigator and will lead a new study of how families adapt to the temperaments of FXS children.

"Most families and teachers in our sample seem more concerned with behavior problems than with cognitive deficits," she says. "Although we are researchers, we have an obligation to study issues that can improve the quality of life for these children and their families, their teachers, and their therapists."

Kathy May appreciates those efforts. "It's interesting to learn what they see happening to Sam in his life. I get positive feedback that I am doing an okay job with this kid."

next page: what can fragile X families teach us?

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