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BrainStorm (cont.)

Seeking the causes of autism: Bloomberg School researchers Dani Fallin (left) and Peter Zandi. 
Photo: David Colwell
Geneticists are also exploring new models of autism. Finding a gene for autism has challenged these scientists because there is probably no single cause for autism, says genetic epidemiologist Dani Fallin, PhD, a co-investigator with CADDE and an assistant professor of Epidemiology. In addition, the genes involved in autism may not follow conventional rules. Normally, the chemical code inscribed in a stretch of DNA determines a gene’s function. But Fallin and other geneticists now recognize that factors other than a gene’s code can, in some cases, influence that gene’s expression. In one type of interaction called methylation, for instance, chemical units attach to a gene and alter or squelch its expression. If methylation occurs in autism, it may have been foiling geneticists’ attempts to pin down an autism gene. Fallin and other researchers are also investigating the possibility that autism involves a constellation of genes and environmental factors. One candidate gene they are studying is called the beta-2 adrenergic receptor (B2AR) gene.

The researchers hypothesize that various environmental factors—chemicals, drugs, stress—can overstimulate B2AR. They also suspect that some people have a slightly different genetic version of B2AR that makes them more sensitive to these factors.

One drug they are focusing on is called terbutaline. It was brought to their attention by a woman in western Massachusetts named Beth Crowell.

Crowell is the mother of 16-year-old triplets who have all been diagnosed with autism. “Every parent of an autistic child goes through a phase where she asks herself, ‘What did I do?’ ” says Crowell. For Crowell, that question drove her to search the medical literature for answers. Her search led her to terbutaline, an asthma drug also prescribed to prevent premature labor. Crowell, who had taken terbutaline during her pregnancy, was struck by her findings. 

Crowell found studies showing that rats exposed to terbutaline developed neurological problems that, to her, echoed autism. She mentioned her observations to Susan Connors, a physician and mother of an autistic child, and eventually the pair teamed up with Zimmerman to study the connection between terbutaline and autism.

Genes. Environmental factors. Maternal-fetal differences. Multiple pathways could lead to an enigmatic disorder.
The team conducted a small study of fraternal twins drawn from a database of families of autistic children and from autism clinics. They compared twins born to women who had taken terbutaline for at least two weeks during their pregnancies to the twin children of women who had not taken the drug. They then calculated the rate of concordance for each group of twins, with concordance meaning that both siblings in a pair of twins had autism. The study revealed that women who had taken terbutaline were significantly more likely to have two twins who developed autism.

The researchers believe that terbutaline accounts for the increased risk. However, not every child exposed to terbutaline in the womb developed autism, and the researchers have conducted further studies suggesting that a variant of the B2AR gene increases the risk.

Newschaffer calls these findings “an excellent example of how a gene-environment interaction could work” to cause autism. However, he adds, “I don’t want to leap. All of this stuff is very speculative.” He is acutely aware of how easy it is to give people false hope of finding the key cause of autism.

Autism clearly has no single cause. The many factors that contribute to the  disorder may feed into the same pathway—or they may not. There could be multiple pathways. “All of the different disciplines have been looking for a grand unifying theory that explains autism,” says Newschaffer. No one has yet found such a theory. Just as an autistic child might struggle to form words into sentences, autism researchers continue to grope for a meaning that will assemble the scattered fragments of this enigmatic disorder.

Sandy Bush and Pam Gillin don’t know what caused their sons to have autism, and they don’t spend a lot of time thinking about that question. They mainly focus on the here and now.

John Gillin is attending school at the Kennedy Krieger Institute. He is working on learning the verbal and non-verbal skills of social interactions. John has a terrific memory, says his mom. “He can tell you all about Lewis and Clark’s trip. But it’s not conversation.”

Alex Bush attends a public elementary school that has a special autism outreach program. At home, therapists are teaching him occupational skills. Another goal, says Sandy Bush, is to look for ways to help Alex do more of the fun things that other kids do, like riding a bike. When Alex is ready, a new bike is waiting for him. Sandy Bush thinks about how she and her husband will teach Alex to ride. They will start by showing Alex how to operate the hand brake, although Sandy does not know how they will get their son to perform that challenging task. Then, perhaps Alex’s dad will hold onto the handlebars and push Alex along. He will help Alex place his feet on the pedals. Maybe as Alex coasts along, he will get the hang of pedaling.

Big efforts begin one step at a time.

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