Cari Wheeler, center, and her dad Gary Boyer, seated, did not know they carried the fragile X trait until Max, center, was born with fragile X syndrome.
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Premature menopausal symptoms like those Cari is experiencing are another recently discovered consequence of the premutation. Known formally as primary ovarian insufficiency, it is believed to affect about 20% of female carriers.
The gene involved in all these disorders codes for a critical brain protein known as the fragile X mental-retardation protein (FMRP). This protein normally acts as a brake on the production of other proteins associated with learning and memory. But when more than 200 CGG repeats are present, the gene for FMRP tends to shut down and production of the other proteins spins out of control. The brain develops too many connections, or synapses, many of them immature and flimsy. The resulting symptoms range from learning disorders to mental retardation and often include autism, epilepsy, anxiety disorders and attention-deficit/hyperactivity disorder (ADHD). "Fragile X is a disorder of excess," explains neuroscientist Mark Bear of MIT. Autism in general seems to involve excessive connections in the brain. Bear and others suspect that drugs that could attack this problem in FXS patients could also prove useful in other types of autism.
The exciting news is that such drugs are already being tested. Hagerman and a team at Chicago's Rush University Medical Center have begun trials with a drug called fenobam, originally designed as an antianxiety medication. MIT's Bear expects to begin trials with two other compounds later this year. The drugs target a receptor on brain cells that the fragile X protein normally helps regulate; the receptor, in turn, regulates proteins involved in learning and memory. "We're looking at a medication to reverse the retardation," says the optimistic Hagerman, "and I think we can achieve it."
Researchers are also working on drugs for FXTAS, which strikes 30% to 50% of all male carriers, usually after age 50. Cindy Mitchell of Huntington Beach, Calif., is haunted by her father's death from the disease two years ago. "He wasted away to 80 lb. He couldn't walk, couldn't keep food down," she says. I met Mitchell, 37, and her husband Bob, 41, at Hagerman's clinic, where they had taken their two sons for evaluation. Mason, 6, has FXS, and Noah, 8, is a carrier, like his mom. Among Mitchell's worries is that she'll die the way her father did, though fewer than 10% of female carriers seem to develop the disease. "And I'm terrified that Noah will get it," she says.
Drugs to treat this adult-onset condition would have to work differently from the ones used to treat fragile X syndrome because the biology of the disease is different too. In fragile X, the key gene is silent; in FXTAS patients, it's too active. "The gene produces up to 10 times more message than normal," explains molecular biologist Paul Hagerman of the University of California at Davis, who together with wife Randi has received an NIH grant to study the disorder. Over time, messenger RNA--the substance that transcribes genes into proteins--accumulates in the nuclei of brain cells, eventually poisoning them.
While scientists work out the molecular pathways that may someday cure FXS and FXTAS, clinicians at more than a dozen centers around the country are devising ways to improve life for affected families. Children with FXS are referred to programs that offer language services, occupational therapy and special education. Randi Hagerman is a believer in drugs to treat anxiety and hyperactivity. For patients with FXTAS, she prescribes exercise and medications already used to treat Parkinson's and Alzheimer's disease.
As research becomes more advanced, the Hagermans hope that more people with suspicious symptoms will choose to be tested for the fragile X mutation and premutation. Many families with an autistic child resist, not wanting to learn that the cause is genetic, but Paul Hagerman urges them to look at things another way. The day is rapidly approaching, he believes, when autism caused by fragile X will be known as the "treatable type."