Imagine you’re listening to the radio. You hear music. But there’s a lot of static, too—noise that butts in from all over the place and muddies the signal. The static is distracting and frustrating and no matter how you mess with the dial, it won’t go away. Now imagine you can’t turn the radio off. That’s sort of what it’s like inside Adam Strom’s brain.
Adam has fragile X syndrome, a genetic condition that can be synonymous with a lot of things: learning disabilities, intellectual disability, seizure disorders. A third of children diagnosed with fragile X, including Adam, also have autism. The syndrome is made up of a chaotic medley of symptoms that are different for each person. You could meet someone who has fragile X and never know it. That’s one reason scientists have misunderstood it for so long.
One of Adam’s symptoms is the static—the unending zap of stimulation from the sights and sounds around him, each of which demands the same attention from his brain regardless of importance. A typical human brain can tune out unimportant things in favor of more immediate concerns—an ongoing conversation, for example, rather than a squeaky door in the other room or a fly buzzing at the window.
Each of those things is a stimulus, a signal to the brain that sets off a flurry of synaptic activity and forges connections between nerve cells. When the brain recognizes a signal as something it doesn’t need to pay attention to, the nerve cells calm down and stop producing the pay-attention protein they had begun to pump out. This synaptic activity is how we learn throughout our lives, and it’s especially crucial for young, developing brains. But for children with fragile X syndrome, the cells don’t calm down. The result is overstimulation, under-connectivity between nerve cells, and incessant static.
“There can be four things going on in a room, and Adam can’t help but keep track of them all,” says Steve Strom, Adam’s dad. “He’s aware of every detail of each of those things.”
Adam started to show symptoms just after his first birthday, when he stopped learning new words and started losing muscle tone. “His skin got so loose, he looked like an old man,” Steve says. Adam was still a happy baby, though, and didn’t have a lot of the other developmental problems many babies with fragile X have—jerky movements, poor eye contact, incessant crying. There can be speechlessness, anxiety, aggression, hyperactivity, and tantrums that go on for hours. Some kids repeat phrases or sounds over and over again, rock back and forth, flap their hands, chew on themselves and their clothes. Some have what doctors call sensory defensiveness, which means, among other things, that they don’t like to be touched. Then others, like Adam, are serial huggers.
The “fragile X gene” that scientists talk about wasn’t discovered until 1991, just a few years before Adam was born. “For many years in this business, we just sort of lumped children and people together as having developmental delay or intellectual disability,” says Joe Piven, who studies the neural mechanisms involved in autism. “Being able to identify a gene that’s responsible for this whole set of behavioral, cognitive, and medical problems really catapulted the whole field forward. Fragile X is a huge window of opportunity for understanding not only intellectual disability but also autism.”
Researchers all over the world think a fragile X cure—or the nearest thing to it—could be as little as ten years away. And researchers at UNC are getting closer to it.
In the family
Everyone has the fragile X gene, also known as FMR1—it’s situated on the tip of the X chromosome. But an alteration in the gene can cause it to expand and mutate beyond its normal range, causing that spot on the chromosome to swell. Under a microscope, the tips of the X look fragile, like they’re about to break off. This mutation is what leads to the syndrome.
Over a million people in the United States alone have the altered gene, although most of them don’t know they’re carriers. Other than a known family history of fragile X, there are few or no warning signs that lead people to get tested. Fragile X can hide in families for generations as carriers unknowingly pass the altered gene along to their children. But eventually, somewhere in the family, a baby is born who has a fully mutated version of the gene, which leads to the syndrome. That’s what happened in Adam’s mother’s family.
Teresa Strom’s grandparents were farmers in east Tennessee whose tenth child, Teresa’s uncle, was known to be “a little slow.” The doctors told his mother that it was probably because she’d had asthma during her pregnancy. Not until 1995, after Teresa’s uncle was in his fifties, was he finally diagnosed. “He went to a new doctor for a change in his medication,” Teresa says. “The doctor walked into the room and knew at first glance that he had fragile X.”
Without the benefit of a blood test, many doctors don’t recognize fragile X syndrome in babies or young children. Most kids who have it don’t look different from others their age. But as kids with fragile X get older, they often develop a distinctive look: long faces, protruding ears, wide head circumferences.
No one in Teresa’s family had ever heard of fragile X, but soon they learned that two of her first cousins also had it.
“We had been trying to get pregnant at that point,” Teresa says. She’d had two miscarriages, which scientists now know are a common problem for women who are fragile X carriers. When she mentioned her newly discovered family history, her ob-gyn told her there was no reason to be concerned. But that was in the early days of fragile X research. There was a lot of misinformation going around.
Teresa found out she was a carrier (just like her father) around the time she found out she was pregnant with Adam. Then during the amniocentesis Teresa and Steve learned that, despite her doctor’s reassurances, the child she was carrying had the full mutation. He would have fragile X syndrome when he was born.
Steve sighs. “That was agonizing,” he says.
The autism link
No one really knows all the various causes of autism. But the discovery of the fragile X gene in 1991 changed everything for researchers all over the world. Suddenly they had an indisputable culprit for up to 6 percent of autism cases. Fragile X is now the most common known cause of autism.
“The issue with autism is that it’s not one thing,” Piven says. “We call it autism, but some people in the field are starting to call it ‘the autisms.’ Say somebody shows up at your doorstep and they’re short of breath. You don’t know if they’ve just run a race, or they just smoked a carton of cigarettes, or they have pneumonia, or they’re having a heart attack. That’s the situation with autism. We’re now discovering that they don’t all have the same thing.”
Piven and his colleagues at UNC and Stanford just finished a study of brain images that show the differences between the developing brains of toddlers with autism caused by fragile X syndrome (like Adam) and toddlers who have autism with no known cause.
They looked at two MRI brain scans for each of fifty children, one at age two and another at age four. On an individual level, the MRIs didn’t reveal much, says psychologist Heather Cody Hazlett, who worked on the study with Piven. To any radiologist, the brains would look normal. But Hazlett and her colleagues used computers to process the images and convert them into quantitative data. That way Hazlett’s team could measure the volume of various parts of the children’s brains and compare the numbers across the group.
“With the two-year-olds,” Piven says, “you wouldn’t know the difference without a blood test. You might just think they had autism. Behaviorally, they were really similar.” But the scans showed the real differences. The two-year-olds who had fragile X syndrome had larger-than-normal caudates, a part of the brain that is associated with repetitive behaviors. They also had smaller-than-normal amygdalae, which mediate social behaviors.
This is good news for researchers and for pharmaceutical companies. Knowing where in the brain the fragile X gene is expressed means scientists are one step closer to having a target for pharmaceutical treatments. Some of those treatments are in clinical trials now, including one at UNC.
Adam visits Linmarie Sikich on a regular basis while he takes part in a clinical trial for the drug Arbaclofen. Sikich has been running clinical trials for developmental disorders, autism, and early-onset schizophrenia for fourteen years. Arbaclofen can clear away some of the static for kids with fragile X, she says. UNC is one of a handful of hospitals across the country enrolling patients who want to try the drug.
Until about four years ago, most treatments for fragile X were behavior therapies and strictly controlled environments. “That was all we had to offer,” Sikich says. Doctors tried to help by prescribing ADHD and anxiety drugs, but none have been quite right for fragile X patients. Now pharmaceutical companies are working to develop drugs specifically for fragile X, Sikich says, and Arbaclofen could be one of them. Sikich’s trial may determine whether the drug improves patients’ ability to learn, alleviates their irritable behaviors, eases their anxiety and repetitive tendencies, and—maybe most important—helps them function in social situations.
Interacting with others can be tough for kids with fragile X. Studies have shown that they have increased levels of cortisol—a stress hormone—during social interactions. Helping a child learn how to have a conversation can not only improve his cognitive functions (people tend to learn during social interactions) but also make things easier for the family. Here’s an example, Sikich says: Say a family with a child with fragile X syndrome is going to a party. He might ask fifty times, “What are we going to do? Who are we going to see? When are we going to leave?” As his anxiety intensifies on the way to the party, so do his repetitive phrases and movements—rhythmic hugging, slapping, pushing, or crying. And once he gets to the party, the real overstimulation sets in. A meltdown becomes inevitable.
“Once they arrive, the child’s repetitive behaviors are likely to become so intense and disruptive that the family has to leave abruptly,” Sikich says. “But the same child, after treatment with Arbaclofen, may only ask ‘What are we going to do?’ five times instead of fifty. And he may have been able to talk to three or four people while they’re at the party and even stay two hours without any meltdowns. In a couple of cases, there have been kids who have asked their parents for the first time, ‘Do you want to play a game with me?’ and kids who can provide a sentence or two in response to, ‘What did you do in school today?’ It’s a huge difference for a family.”
Developmental milestones loom large in many parents’ minds. Baby should sit up at seven months, baby should babble at eight months, baby should use simple sentences by twenty-four months. Doctors often pooh-pooh first-time parents who get concerned if their baby is off-schedule. For babies with fragile X, this can have lifelong consequences. (Read one mother’s story.) Steve and Teresa Strom were lucky. They knew that Adam had fragile X before he ever started to show symptoms. Most parents don’t find out until their babies turn into toddlers.
As soon as Adam’s symptoms started, his doctors helped Steve and Teresa enroll him in various therapies that were tailored to his needs. One was speech therapy, which helped Adam communicate through sign language. Steve says, “When I came home one day after work, Teresa said, ‘Come here, I want to show you something.’ She read a book to Adam, and Adam signed the word ‘more,’ telling her he wanted her to read it to him again. That opened a lot of doors for Adam.”
Another was occupational therapy, the purpose of which for kids is the same as for adults: to help them function better at their jobs. A child’s job is to play. It’s how children learn, how they stimulate and understand their senses, and how they improve their motor skills. Adam’s occupational therapist helped him play in a tire swing, which helped stop his muscle loss. Even today Adam loves to watch YouTube videos of other kids in occupational therapy sorting toys by color, scooting around on tricycles, playing on exercise balls. Sometimes he shows the videos to his own occupational therapist and asks for the same treatments.
All babies born in the United States are eligible for state-based early interventions—individualized therapy regimens that are tailored to each child’s needs based on the severity of their impairments. Getting these therapies early, while a child’s brain is in its crucial stages of development, can improve quality of life for children and their families for the rest of their lives. And although a simple blood test can screen babies for fragile X just after they’re born, the testing isn’t standard, so most families miss out on early treatments. At UNC Hospitals, researchers are now offering testing as part of the Fragile X Newborn Screening Study.
“Adam was a jumper from early on,” Steve Strom says. “He would stand up in his crib and jump and jump and jump.” Eventually, after they upgraded from the crib to a bed, they bought Adam a mini trampoline to spare the new mattress. Sheryl Moy, who runs UNC’s Mouse Behavior Phenotyping Laboratory, has seen the same kind of jumping in mice that were bred to have symptoms of autism and fragile X. One of her study videos shows a mouse vaulting up and down in the corner of its enclosure. “We call that jackhammer jumping,” Moy says. “We counted up to eight hundred jumps during a single testing session. It’s extremely athletic.”
There are only two animal models for fragile X syndrome: mice and flies. In flies, the syndrome manifests itself mostly as a loss of circadian rhythm—the flies can’t tell when it’s day and when it’s night. (Many kids with fragile X tend to wake up in the middle of the night.) Scientists can now completely eliminate symptoms in the fly model—in other words, cure them. Moy and her colleagues are now studying the more complex mouse model to see if we can do the same with them.
“Autism seems to be increasing in prevalence,” Moy says, “and fragile X mice are one of the few genetic models that we can use to look at autism in a broader context. Of course, there’s no way we’d be able to take something as complex as autism or fragile X syndrome and think that a mouse would show all of those symptoms, so we would never say, ‘We have an autistic mouse.’ But we can look at behaviors that are relevant.” Figuring out how to treat symptoms and behaviors in the mouse models can teach us how to treat humans, she says.
Moy creates and runs behavioral tests for mice. She uses different strains of mice that were bred to have specific profiles and looks at how well they balance as they run along elevated beams, how they care for their young, where they like to sit in their enclosures. In the past, most tests for mouse social behavior were designed to look at aggression, sexual behavior, and maternal behavior. “But there wasn’t a test to ask ‘Does a mouse like social contact? Does it have social motivation?’ And that’s one of the problems with autism,” she says. “It’s not so much that the kids are aggressive. It’s more that, in some cases, they’re not interested in social interaction. They don’t find it rewarding.”
Moy and her colleagues created a test for the autism mice to find out whether they would rather be alone or with a mousy companion. The test—now standard in the field—begins when the mouse enters the middle room in a three-chambered box. From there it has three choices: it can a) stay in the middle room by itself; b) pass through a door to the left, where it will find another mouse, referred to as the stranger, sitting inside a wire cage; or c) pass through a door on the right, where it will find an empty wire cage. (The empty cage is there to make sure the mouse isn’t just drawn to the strange structure rather than the stranger inside it.) The chamber doors are equipped with photo beams that track how much time the mouse spends on each side and how many times it skitters back and forth.
The researchers found that most normal mice choose to hang out in the “social” chamber, where they can be with another mouse. They rear up, sniff at the cage, rattle their tails, or box (a show of aggression). “You can see the normal mice really seem to use this as an opportunity for social investigation,” Moy says. The fragile X and autism mice generally don’t show that social preference—they explore all the rooms equally.
Researchers also found that one strain of mice with autism-like behaviors, known as BALB/cJ, have smaller corpus callosums. This may be tied to their lack of social preference, Moy says, and it could provide a model for the same kind of brain under-connectivity that occurs in children with autism. She and other UNC researchers are now starting studies to find out if oxytocin, a hormone that’s important in maternal behavior and social cognition, could promote social interaction. The researchers are still in the beginning stages, but tests so far suggest that mice treated with oxytocin spend more time sniffing and being sociable with other mice. “To us, this is extremely exciting,” Moy says. “It suggests that this model could be used to develop therapeutic agents.”
While clinical trials can offer hope and relief, not everyone has access to them. Teresa’s uncle and cousins in Tennessee are five hours away from UNC Hospitals. And enrolling in a trial is a big commitment, Sikich says—it means frequent office visits, daily diaries, and the risk of being assigned a placebo rather than a new drug. But so far, the Arbaclofen has made a huge difference for Adam, Steve says. Adam is one of Sikich’s long-term patients, so the Stroms will be among the first to know when new treatments become available.
“I’m not comfortable using the word ‘cure’ yet,” Sikich says, “but I think we’re very close to something that could modify the course of the disease. Not something that just slightly damps down symptoms, but that really changes learning, changes the anxiety. What can we do to provide the best treatments possible? How safe are the treatments? Unless we do the research at both the basic level and at the clinical-trial level, we’ll never really know.”
Adam is fourteen now. He’s in eighth grade at a public school in Wake County where he’s enrolled in an Autism 3 class. At school he goes to speech therapy, and outside of school he goes to occupational therapy and group singing therapy with Voices Together, a local nonprofit that serves people with developmental disabilities. “That’s been fantastic for improving his performance in school,” Steve says. “He’s better at taking turns, answering questions, and helping other students. He’s a trooper.”