...the tough case of fragile X

Early signs, late detection

he May family, from Fairfax, Virginia, was the first to sign up with Bailey's original study in 1991. Now they're helping him to create an online FXS resource guide, available through the FPG web site and supported by a grant from the Ronald McDonald House Charities.

.: Sam May, who has fragile X syndrome, in science class with teacher Cathy Thornton. Photo courtesy Kathleen May; click to enlarge. :.

This web guide will include the developmental and behavioral signs that parents can watch for in their children. These include avoidance of eye contact, nervousness, a long or wide forehead, protruding ears, and limited motor imitation — such as clapping, waving and banging (see some signs of fragile X, below, for a longer list). A family history of mental retardation, autism, or learning problems is an important warning. And yet, many of these signals can't always be differentiated from other developmental disorders. This lack of clear symptoms makes it difficult to diagnose fragile X accurately.

That's why Bailey recruited occupational therapist Grace Baranek, associate professor of allied health sciences, to the FXS team. Baranek is an expert in detecting early signs of autism through observation of home videos, and Bailey suggested that she apply those skills to the study of FXS.

"We're looking for some early symptoms or behaviors that might be able to help us identify children with fragile X earlier than they're being identified by their pediatricians or other health care providers," Baranek says.

he uses a technique called retrospective video analysis. The families of eleven children previously diagnosed with FXS lent hundreds of hours of their home videos, showing the children during the ages nine to twelve months. Baranek meticulously viewed this footage, looking for autistic behaviors and other developmental delays such as repetitive movements or an unusual posture. "A lot of fragile X children tend to have lower muscle tone," she says.

Baranek's preliminary findings suggest that there are some fragile X symptoms that do show up early, and with these in mind, she's been able to correctly classify 73 percent of the children in the videos. "However, it's always easier to find things in retrospect," she says. Still, she hopes that her work with autism and FXS can identify behaviors that can be translated into a parental questionnaire or an observational form that a pediatrician could use in screening children around age one.

.: Some of the researchers working on fragile X at FPG. Photo by Steve Exum; click to enlarge. :.

Don Bailey, Jane Roberts, and Deborah Hatton have already proposed one comprehensive checklist that could be useful in detecting FXS in infants and toddlers. But a checklist might not be enough, they suggest.

Newborn screening

ow Bailey and his colleagues are preparing to focus on yet another area, one that will put Carolina prominently at the intersection of genetic research and social policy. The National Institutes of Health awarded a grant to FPG to plan a study involving newborn screening of one million babies for FXS.

While there are hundreds of disorders that can be genetically tested, most states only screen babies for a handful. That's because the traditional criterion for deciding which disorders to screen for has been the availability of a treatment. For example, all states screen for phenylketonuria, a genetic metabolism disorder that leads to mental retardation. A simple dietary change, however, can prevent that, and so the cost of screening is well worth it.

But the Human Genome Project is enabling scientists to screen for hundreds or even thousands of disorders and susceptibilities to diseases. As testing becomes cheaper and consumer demand grows, screening may increasingly tell people about genetic characteristics for which there are no cures.

There is no cure for fragile X syndrome. But newborn screening, says Bailey, could help provide access to early intervention programs. Moreover, it could provide families with important information about their own reproductive risk. In past studies, Bailey learned that more than half of parents have additional children before fully understanding that the first child has the syndrome. Because of this, many families have two children with the full FXS mutation. Parents in the FPG cohort have told Bailey that they wish they had known their own FXS carrier status earlier. "Parents say that the best time to offer genetic screening is preconception," he says.

Learning from families

ebra Skinner, a cultural anthropologist, studies how parents make meaning of this genetic disorder and how the knowledge of the disorder affects family relationships. She's especially eager to study the concept of genetic identity — as we increasingly learn to think of ourselves in terms of our genetic instructions, she asks, what can fragile X families teach us?

Bailey says, "We all have multiple identities, but most of us think of genetics as being part of who we are right now. In the next decade, people with a genetic disorder may have that as their defining identity, and that identity will permeate their self-conception."

FXS, with its clear single-gene cause, is a good prototype for other genetic screening, Bailey says. "This puts us in the forefront of many policy issues. Fragile X screening is a model of what's to come."

Meanwhile, other research at Carolina focuses on the biology of FXS. Joe Piven, of the Neurodevelopmental Disorders Research Center and the Department of Psychiatry, in conjunction with researchers at Duke and Stanford universities, received a $3.5 million grant earlier this year to study the brain development of young boys with FXS. The study will use MRI (magnetic resonance imaging) scans at ages two and four to compare fragile X brains with typically developing brains.

uch answers aren't yet available, so Kathy May is making do with her powers of creativity. She's seen that early intervention and developmental therapies — such as special education and home environment training — can be effective. But she and her husband, John, found something easier. Something for their home. Something fun for Sam as well as Mom and Dad.

They bought a trampoline.

"It attracted the neighborhood kids to the back yard," Kathy says. It helped Sam with his balance, and it helped him with his social life. "It was just much more useful than sitting in a therapist's office."

Genetic science uncovered the tiny reasons fragile X syndrome appears in families. But it's the Carolina Fragile X Project that is discovering just how those families live with it, how they bounce back from the shock of learning about the disorder.

"Yes, there have been some extremely difficult times," May says. But when she hears Sam laughing in the back yard, her son doesn't seem disadvantaged at all.

some signs of fragile X

.: a family history of autism, mental retardation, or learning problems
.: stiffening of the limbs when anxious or excited
.: avoidance of eye contact with parent
.: hand flapping
.: defensive to touch
.: limited ability to mimic movements such as clapping, waving, and banging
.: lack of pointing
.: lack of social play
.: long or protruding ears
.: long or wide forehead
.: high, arched palate

Anton Zuiker studies medical journalism in the School of Journalism and Mass Communication. His articles about innovation are at www.unc.edu/~zuiker.

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