A UC Riverside-led team of researchers says it has found conclusive evidence that a naturally produced enzyme in the body is responsible for autism and other neurological disorders in people with Fragile X syndrome.

Fragile X is a mutation of the X chromosome associated with obsessive-compulsive and repetitive behaviors as well as learning deficits. People affected by Fragile X have been shown to have structural differences in brain cells, such as underdeveloped neural receptors.

One in 5,000 males is born with the disorder; females can be affected, but to a lesser degree. About 40 percent of cases of autism are associated with Fragile X syndrome.

The study is the cover story for the latest edition of the Journal of Neuroscience.

In 2007, Iryna Ethell, a UCR biochemist, found that overactivity of an enzyme called MMP-9 was connected with Fragile X. Her team recently identified MMP-9 as a major culprit in symptoms associated with Fragile X in mice.

By eliminating a gene that activates MMP-9, the researchers found that even with the presence of Fragile X syndrome, the mice showed no symptoms of autistic behavior. They measured sociability, anxiety and other behaviors, as well as examining individual brain cells.

Often, such discoveries are the first step in a long process. Just understanding a mechanism for a particular disease or disorder doesn’t necessarily mean a treatment is imminent. Effective therapies or drugs can be many years away.

In recent years, however, it was discovered that minocycline, an existing approved form of tetracycline, works as an MMP-9 inhibitor. Human studies using the drug have been done, most recently by researchers at UC Davis’ MIND Institute.

Dr. Randi Hagerman is medical director of the institute. She called Ethell’s study “extremely exciting.”

Hagerman said the results would help her researchers at UC Davis justify further study of the effects of minocycline on suppressing MMP-9. The Davis study showed children 6 to 17 years old with autistic symptoms associated with Fragile X improved while taking the drug. But she suspects it may have greater benefit for younger children.

“I think this gives us information to take this to a younger age,” she said of Ethell’s results.

Brain cells, as well as other cells in the body, produce MMP-9. The enzyme, which resides in the matrix between cells, is normally dormant. In healthy people, it is activated when the brain is injured in some way.

“It cleaves the extracellular matrix so new cells and new connections can be formed,” replacing lost functions, Ethell said.

In Fragile X syndrome, the overactive MMP-9 – more than two to three times as in a normal brain – is thought to be responsible for prohibiting connections on the brain cell’s splayed dendrites from maturing. These “spines” are thinner, unable to function normally and thought to be responsible for many of the symptoms observed in autism.

Ethell said when MMP-9 activity is suppressed in Fragile X mice, the spines achieve a normal state.

Dr. Michael Tranfaglia is medical director of the FRAXA Research Foundation, a Newburyport, Mass., organization focused on a cure for Fragile X. The foundation has been helping to fund Ethell’s research since 2007.

“Iryna’s finding is really interesting,” Tranfaglia said. “This is really important for our understanding of how the brain works in general.”

Tranfaglia said that when he first heard about the connection between minocycline and MMP-9, he was skeptical.

“My first thought was this is kind of interesting, but it’s too good to be true. The funny thing is, it has really held up. It actually does offer the possibility of off-the-shelf treatment for Fragile X and related forms of autism.”

Tranfaglia said he has been providing the drug to some of his affected patients. The results have been inconsistent, he said, but “I’ve seen some really amazing responses.”

While it may apply only to certain kinds of autism, Tranfaglia said, “this study shows that just the MMP-9 effect is sufficient to correct the problem.”

Ethell said she has been studying the proteins that allow cells to communicate for most of her career. Her husband, Douglas Ethell, head of molecular neurobiology at Pomona’s Western University of Health Sciences, is a co-author of the study.

“We were talking to each other about this and decided it would be a good study to do,” Ethell said.

UCR graduate students Harpreet Sidhu and Lorraine Dansie did the bulk of the laboratory work, Ethell said.

She’s hoping the study will lead to more effective medication for suppressing MMP-9.

“With knowing what this drug is doing,” she said, referring to minocycline, “maybe we can find something better.”

Contact the writer: 951-368-9595 or mmuckenfuss@pe.com