A genome search using these methods led to a January report by the Boston-based Autism Consortium (a research collaboration involving 14 Boston-area institutions) of an abnormal chunk of chromosome 16 found in several autistic patients. The segment harbors a mixture of gene deletions and extra copies of genes that is estimated to account for 1 percent of unexplained cases of autism spectrum disorder. Several of the genes are known to be expressed in the brain or in early nervous system development. Researchers believe that a large number of rare “copy number variations” such as these may be waiting to be found.

Working with clinical genetics collaborators in several Middle Eastern countries where intermarriage between cousins and large family size are common, HHMI investigator Walsh, a member of the Autism Consortium, has been trying another gene-seeking strategy. He is attempting to find rare recessive gene mutations, which are more likely to be expressed when intermarriage occurs over generations. “My collaborators bring in their tough cases,” says Walsh, who has visited countries including Dubai, Kuwait, Saudi Arabia, and Oman. “Our team of genetic counselors, pediatric neurologists, clinical psychologists, and others provide a second opinion, draw blood for DNA samples, and say that we'll try to figure out the genetic picture.”

Walsh's strategy has begun to pay off. He has found several families in which a member with autism is missing both the paternally and maternally inherited copies of genes, making those genes likely suspects.

“We don't yet know what the deletions do,” he says. But three of the missing genes turned out to be among those being studied by Michael Greenberg, a Children's Hospital Boston colleague. Greenberg is looking for autism clues by studying nervous system genes that are silent until activated, during learning, to make more synapses and are logical candidates for autism research.

Also collaborating with Greenberg at Children's Hospital Boston is Kunkel, who previously discovered the gene for Duchenne muscular dystrophy. He and Children's Hospital colleague Isaac Kohane have devised an unorthodox gene-hunting approach—looking for gene “signatures” of autism in blood cells, rather than in the brain.

“We're using microarrays to see if there is a signature of gene expression in whole blood that distinguishes autism, and we are starting to see such signatures,” says Kunkel. If gene expression in the blood cells is similar enough to that in brain cells to be a useful surrogate measure, researchers could avoid the need to obtain and test brain tissue, which is impossible in living humans. Ultimately, a “proxy” signature for autism could be used diagnostically and in testing candidate drug therapies.

With a variety of intensive behavioral therapies, the capabilities and lives of many autistic children, like Nicole Branconnier, have improved. There is no definitive treatment for the multifaceted, complex disorders of autism, and a cure seems a distant prospect.

However, the biological underpinnings of autism are becoming clearer. And among the recent findings, one in particular may bode well for reversing symptoms with future therapies.

In 2007, Adrian Bird, a geneticist at the University of Edinburgh, showed that Rett syndrome mice with a silenced MECP2 gene could recover many of their lost functions when the gene was reactivated in adulthood. This couldn't be attempted in humans with Bird's experimental methods, but the implications are cause for optimism: apparently the MECP2 mutations don't irreparably harm the neurons themselves, which develop very early; rather, the mutations cause malfunctions in the synapses that form later on.

Bird's finding offers another reason why the synapse makes sense as the culprit in autism, says Walsh. “It may explain the later age of diagnosis of autism, and its preferential effects on later-appearing skills—like language and social behavior—and perhaps its greater likelihood of improvement in some fortunate children,” speculates Walsh. “If we can develop medications to modulate these synaptic changes, we may be able to provide better therapies for this devastating disorder.”

Fischbach agrees: “The possibilities of reversal are very real.” That's encouraging, and so is the quickening pace of gene discovery, which ultimately should shed further light on causative mechanisms. How long this will take, though, is anyone's guess.

“The hunt is on,” says Fischbach, “but it's going to be a while.”

FOR MORE INFORMATION: To learn more about the latest approaches to autism, visit the Websites for the Simons Foundation (http://www.simonsfoundation.org/) and the Autism Consortium (http://www.autismconsortium.org/).

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