They called him “the singing baby.” As a newborn, Maxwell Wheeler would lie in his crib, whistling shrilly as he breathed in and out. For Cari and Andrew Wheeler of Madera Ranchos, Calif., it was one of the first signs that all was not right with their second child–an infant who didn’t like to be touched, refused to nurse and struggled to keep down formula. At 10 months, when Max was still spitting up more than sitting up, the Wheelers consulted an occupational therapist, who noticed an extra fold above his eyelids, prominent ears and other features she called “dysmorphic.”
“I said, ‘What do you mean dysmorphic?’” Cari recalls. “‘I think he’s cute!’” But she and Andy agreed to have their baby tested for genetic disorders. And so began a medical odyssey that would engulf three generations of the family.
I met the Wheelers at the MIND (for Medical Investigation of Neurodevelopmental Disorders) Institute at the University of California at Davis, where they arrived with Max, now 7, his brother Brockton, 10, and Cari’s parents Mary and Gary Boyer. It was one of many visits for the Wheeler-Boyer clan. Max raced around a visitors’ room, occasionally hugging his mom and trying to pull his beloved granddad up from his chair. Mildly autistic and mildly retarded, Max doesn’t speak much, and he didn’t respond to my overtures. In addition, Max suffers from hyperactivity, low muscle tone, gastrointestinal problems and a tendency to spike scorchingly high fevers. Though he’s doing fine in kindergarten–with an aide–he only recently managed to pass potty-training.
Max wasn’t the only one in the room struggling with a worrisome condition. His grandfather Gary, 70, sat stiffly in his chair, tuning in to and out of the conversation. An architect with a Ph.D. in urban engineering, he has developed a tremor in his left hand, and he’s so unsteady on his feet that he’s taken several falls. “My legs are gone,” he says. “I’m very numb from the knees down.” Perhaps more alarming are the changes in his personality. The first sign was hoarding household items. “Then I started noticing that he became antisocial,” says his wife Mary. “He didn’t want to go out. And he didn’t want to talk when people came over. He would sit on the patio and smoke.”
Cari has been just as stunned by the changes in her once outgoing father, but lately she has had some odd symptoms of her own. Though only 35, she has begun to experience hot flashes, and her menstrual periods have become brief and irregular.
Ten years ago, no one would have connected Max’s autism and other symptoms with Gary’s neurological decline or Cari’s premature signs of menopause. Now, however, researchers realize that all three are caused by changes in the same gene, one that’s related to a disorder called fragile X syndrome (FXS), perhaps the most complicated genetic condition you’ve never heard of. Max has full-blown FXS. The disorder, as its name implies, is the result of a defective gene on the X chromosome, one of the pair of chromosomes that determines gender. FXS affects roughly 1 in 2,500 boys, causing autism spectrum disorders in about half of them. That makes FXS the most common known cause of autism, responsible for roughly 5% of all cases. It is also the most common inherited cause of mental retardation. Though the FXS defect occurs just as frequently in girls, they tend to be less severely affected.
Fragile X has been known for decades, but an explosion of new research, prodded along by advocacy groups like the National Fragile X Foundation and FRAXA, is yielding insights that have implications for understanding and treating autism–and perhaps a number of other conditions too. “Fragile X is leading the autism field in terms of new treatments,” says pediatrician Randi Hagerman, medical director of the MIND Institute. “We know the gene, we know a lot about the biology, and we know how to fix it. That’s pretty exciting!”
In addition, new research has revealed that relatives who carry the fragile X trait, like Max’s mother and grandfather, may themselves be affected by it. At the National Institutes of Health (NIH), a new panel has been charged by Congress to direct research into FXS and related conditions. “We hope to learn lessons that may be applicable to helping people with Huntington’s disease, Alzheimer’s and myotonic dystrophies too,” says Tiina Urv, who heads the panel. Research on the FXS family of disorders may also yield clues to some forms of infertility.
Most of us move through our days with only a vague awareness of our genetic endowment, fretting perhaps over a familial tendency toward heart disease or beaky noses. But families affected by fragile X can discuss their genome with startling specificity. Their key concern is a small strip of DNA on the long arm of the X chromosome. Normally, humans have five to 55 repetitions of the nucleotides CGG (cytosine, guanine, guanine) in this region. But for unknown reasons, the number of CGG repeats can expand beyond normal as the DNA is copied from mother to child.
Cari, for instance, has one normal X chromosome (with 24 repeats), inherited from her mother, and another with an abnormal 85 repeats, inherited from her father, who has 89 repeats. Cari’s son Max has 363. Any number greater than 200 causes full-blown fragile X syndrome (so named because, under a microscope, the expanded X chromosome may look bent to the point of breaking). The reason boys are more likely than girls to develop major symptoms is that girls carry a pair of X chromosomes, which means that if one is defective, the other can compensate. Boys, however, carry an X and a Y, so the damaged chromosome is on its own.
People like Cari and her father, with 55 to 200 repeats, are considered carriers of a fragile X “premutation.” Carriers are relatively common: about 1 in 250 women and 1 in 800 men have the premutation, though some studies suggest the prevalence is higher. Until recently no one worried too much about those numbers, since carriers were thought to be unaffected.
It was pediatrician Hagerman who first noticed in the late 1990s that mothers of kids with FXS often reported that their father was experiencing neurological symptoms. “I thought, This can’t be a coincidence,” she recalls. At an FXS conference in 2000, Hagerman asked some 100 fragile X family members if an older male relative was having problems with balance, tremors or dementia. About a third of the audience members shot their hands into the air. Within a few years, a newly recognized genetic disorder called FXTAS (fragile X–associated tremor, ataxia syndrome) was part of the literature, though the illness is still often mistaken for Alzheimer’s, Parkinson’s or Lou Gehrig’s disease.
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.”
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http://www.time.com/time/magazine/article/0,9171,1818268,00.html
Source: autistic
