Study: Fragile X treatment a possibility

SALT LAKE CITY, Nov. 28 (UPI) -- The most common inherited form of mental retardation, Fragile X disease, is not too complex to be treated, research released Thursday said.

This discovery, published in the Nov. 30 issue of the journal Cell, indicates the source of the disease -- much simpler than previously believed -- is nerve defects caused by the interaction of only two genes.

"Fragile X syndrome causes profound mental retardation in at least 100,000 Americans,"

Kendal Broadie, co-researcher and assistant professor of biology at the University of Utah

in Salt Lake City, told United Press International.

"The cognitive defect is caused by improper development of synaptic connections -- the communication links through which information flows between nerve cells," he said. "All previous work has suggested that the cause of Fragile X syndrome is complex -- the incorrect regulation of many hundreds of proteins in nerve cells -- certainly too complex to offer hope of an effective treatment in the foreseeable future."

Broadie said the new research suggests "misregulation of only a single protein may cause most or all of the brain defects in Fragile X syndrome."

Broadie's co-researcher is Gerald Rubin, professor of genetics at the University of California at Berkeley. They conducted the research at labs in Salt Lake City and Berkeley.

Broadie and Rubin studied the fruit fly version of the human Fragile X gene. When fruit fly and human genes mutate, they fail to make a protein, resulting in similar symptoms in flies and in humans with Fragile X.

The researchers found lack of the Fragile X protein in fruit flies causes over-activity

of a second gene and excessive growth of structures named "microtubules" at the ends of nerve cells, where signals are transmitted from cell to cell.

"The cause of the disease might be a great deal simpler than previously supposed and, most important, possibly treatable with available medications," Broadie said.

The scientists cured the flies of Fragile X by using genetic manipulation to eliminate the

excessive growth of microtubules. Such growth also can be stopped with medications, such as colchicine which is used for cancer.

The research with fruit flies suggests the possibility of using colchicine or similar drugs to treat mental retardation and other Fragile X symptoms in human beings.

"Potential drugs include an extract of autumn crocus (colchicine), an extract of periwinkle (vinblastine) and various anti-fungal drugs such as nocodazole," Broadie said. "These drugs act to destabilize cellular skeletons and are currently used to treat a variety of medical problems, including cancer. Low dosages of these drugs would be predicted, from our study, to counteract the underlying cause of Fragile X."

He added treatment could be just a few years away, depending on the side effects of drug treatments and the dosage required to counteract the brain defects.

"It's encouraging that the molecular biology is being worked out well enough to consider a drug treatment," said Jack Tarleton, director of Fullerton Genetics Laboratory in Asheville, N.C. "But the development of the human brain is very complex and the developments in a fruit fly may not translate into a human being. The brain may not be flexible enough to allow it to return to a state where normal learning can occur. But this is certainly exciting research in a totally new direction."

The genetic mutation that causes Fragile X occurs in the X chromosome. Women have two X chromosomes. Men have one X chromosome and one Y chromosome. Fragile X is so named because the long arm of the X-shaped X chromosome looks like it may break off.

Boys with the mutant Fragile X chromosome always have symptoms -- ranging from mild to severe retardation -- because they have only one X chromosome. Girls have two X chromosomes, so the normal X chromosome often compensates when the other one is mutated. Thus, about one-third of Fragile X girls suffer mental retardation, another 20 percent have less severe learning problems and other have no symptoms.

One in 260 women carries the Fragile X chromosome and has a 50-50 chance of passing the defect to her children, male or female. About one in 800 men carries the defect, but can pass it only to daughters, not to sons.

(Reported by Bruce Sylvester from West Palm Beach, Fla.)