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January 4, 2011

Reversing Fragile X

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Fragile X and Autism

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An ongoing controversy in the murder-suicide case of pro wrestler Chris Benoit is whether his seven year-old son had a form of mental retardation called "Fragile X Syndrome." The disorder is poorly understood, but as this ScienCentral News video explains, new research suggests there may be a way to reverse it.

Unkempt Neurons

Children with Fragile X Syndrome – the most common, inherited type of mental retardation – have delayed learning and language, poor coordination and repetitive behaviors. Now researchers at MIT have hope of reversing those symptoms after a successful study in mice.

Mansuo Hayashi, lead researcher of the study, explains why a treatment is needed. "With the modern human genetic diagnosis, I think we could identify the genetic disorders prior to birth, but in many cases, with even with the advanced technology, the abnormality won't show up until after birth. … Therefore it's important to find a drug that will treat or delay the symptoms after the symptom appear."

Graphics of Fragile X and Normal Spines of Neurons

Image: MIT
The brain of a Fragile X Child is like an inattentive gardener, letting too many bushy spines grow on brain cells. Normal brains prune these spines to keep the cells' connections strong. The abundance of weak connections in Fragile X causes a kind of static in brain signals.

Reversal of Misfortune

At MIT's Picower Institute for Memory and Learning, Hayashi worked with mice that had the opposite problem of Fragile X: too little spine growths on neurons due to inactivity of a chemical in the brain called PAK. The PAK enzyme controls the growth of neurons in the brain. She decided to breed these mice with Fragile X mice to see if some of the offspring would have normal brains. But Fragile X affects the brain as it grows, and the PAK inhibitor doesn't activate until the mice are several weeks old. Meaning that for it to work, it would have to reverse structural abnormalities in the brain, something that has never been observed.

Her advisor, Nobel laureate Susumu Tonegawa, was skeptical. "When I heard that, I thought that that is a little bit too simple-minded, because, you know, process in the body, in brain, is very complex, and just because you add a plus number with minus number doesn't necessarily become zero."

But it worked. The "double mutant" mice tested close to normal at three different levels, Tonegawa said. "Size and shape and the number of spines, that's one level. Another level is the activity of the transmission of signal through spines. And the third is at the behavioral level."

Susumu Tonegawa talks to fellow researchers.
"Now I started to really believing the significance of this work," he said.

This was the first demonstration of what looks to be a reversal of Fragile X symptoms "We were thrilled," says Hayashi. "[To] identify a completely normal signaling pathway, that's something that could potentially lead to a treatment of the disorder. That's really satisfying."

The Profit of a Cure

The researchers hope that their results, published in the journal Proceedings of the National Academy of Sciences, will lead to new drug development. Though Hayashi used a genetic switch to ameliorate the symptoms of Fragile X, the next step is to test chemicals that are known to inhibit the activity of the PAK enzyme.

Dian Bolling with her son, who has Fragile X Syndrome
Image: FRAXA
Because there is little profit potential in making a drug for a disease that affects only one in 5000 people, it may not attract big pharmaceutical companies. Hayashi thinks clinical trials may eventually be funded by the National Institutes of Health's Office of Rare Diseases, which works with researchers to develop promising treatments for so-called "orphan" diseases, ones that have been left behind by drug companies.

Mansuo Hayashi and Susumu Tonegawa's research is funded by FRAXA Foundation, the Simons Foundation, the Wellcome Trust and the National Institutes of Health.

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