A New Approach to Correcting Autism

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(c) UC Regents

Parker Roos (right) and his sister Allison, both of whom have fragile X syndrome, wait for evaluations and check-ups at the UC Davis M.I.N.D. Institute.

The causes of autism remain largely shrouded in mystery, but there are some types of the disorder that can be traced to specific gene defects. The most common of these — responsible for roughly 5% of autism cases — is a flaw in the X chromosome that causes a condition known as Fragile X Syndrome. Because the defect has been studied on a molecular level, it provides a unique window into understanding autism — and treating it. And that is why a paper published in this week's issue of the journal Neuron is bound to generate excitement, even though the work was done in rodents. It shows that wide-ranging symptoms of Fragile X, which include epilepsy, impaired mental functioning, aberrant brain structure and other abnormalities, can be reversed. The work, researchers say, holds enormous promise for humans with Fragile X and probably for other forms of autism as well.

Roughly 1 in 3,600 people have Fragile X Syndrome, with boys more severely affected than girls. People with the disorder tend to have elongated faces and prominent ears; about half of them fall somewhere on the autism spectrum and most are mentally retarded or learning disabled as well. Fragile X occurs when the brain fails to produce normal quantities of a chemical known as the Fragile X mental retardation protein, or FMRP. This protein appears to act as a brake on the production of other proteins in the brain, including those associated with learning and memory. Without enough FMRP, protein production spins out of control, like a runaway train. The brain develops an abnormally dense number of connections, resulting in a variety of physical, mental and behavioral problems. "Fragile X is a disorder of excess," explains Mark Bear, lead author of the Neuron paper. "There are too many synapses, accelerated body growth, excessive protein synthesis, and excessive excitability, which leads to epilepsy."

Scientists have suspected that FRMP exerts its braking action by attaching to receptors on the surface of brain cells, known as mGluR5 receptors (the Glu is for glutamate, a key signaling agent in the brain). They reasoned that it would be possible to correct the excesses of Fragile X by blocking these receptors, which act as accelerators of protein production. To test this idea, the researchers produced a special breed of mice that had the Fragile X trait but only half the normal number of mGluR5 receptors. The result, explains Bear: "We were able to correct the excesses [of Fragile X], taking our foot off the accelerator."

What was especially remarkable was the number of ways the intervention reversed Fragile X symptoms. The specially bred mice had fewer seizures, more normal brain structure, a more typical rate of body growth and they performed better on a learning task than mice with uncorrected Fragile X. The experiment suggests that treating Fragile X with a drug that inhibits mGluR5 receptors could have similarly healing effects.

"This gives the whole field of autism a lot of hope for targeted treatments that can be beneficial," says Dr. Randi Hagerman, medical director of the MIND Institute and director of the Fragile X Research and Treatment Center at the University of California, Davis. "It's likely that the mGluR5 pathway may be involved in other kinds of autism," she says. That means that a drug that works on this pathway could have broad application in treating autism.

As it happens, drugs that block the mGluR5 receptor already exist. Hagerman's group and a team at Rush University in Chicago are about to test one such drug, fenobam, as a treatment for Fragile X. Bear, meanwhile, has founded a company called Seaside Therapeutics that hopes to begin human safety tests of another drug as early as next year. Both researchers believe that a safe and effective mGluR5 inhibitor would help both children and adults with Fragile X Syndrome, though drug treatment early in childhood would seem to offer the most promise.

Hagerman, one of the nation's leading researchers on Fragile X, hopes that the current explosion of interest in the disorder will lead more people with autism and their relatives to be tested for the Fragile X defect. Just being a carrier of the disorder can have health implications, including an elevated risk of premature menopause for women and tremors and cognitive decline in older men. Theoretically, a drug that treats Fragile X could lower risks for carriers as well. Says Hagerman: "It's a very exciting time."