Diane2boys
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(4/7/02 8:00 pm)
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Fragile X Syndrome: Effective treatment may be avail soon
FRAGILE X SYNDROME: EFFECTIVE TREATMENT MAY BE AVAILABLE SOONER THAN EXPECTED
(From ADVANCE for Speech-Language Pathologist & Audiologist)
A new study by Utah and California biologists appears to overturn the long held belief that Fragile X syndrome is too complex to be treated effectively in the foreseeable future. The findings raise hope the existing drugs might be used within a few years to treat the most common inherited form of mental retardation.
The discovery indicates the cause of the disease is much simpler than previously believed, resulting from nerve defects caused by the interaction of only two genes. Biologist Kendal Broadie, PHD, at the university of Utah, and Gerald M.Rubin, PHD, at the University of California, Berkeley, led the research (Cell, Nov 30,2001)
The study involved the fruit fly version of the human fragile gene. When the fruit fly and human genes are mutated, each fails to produce protein, resulting in strikingly similar symptoms in both flies and humans with fragile x syndrome.
The researchers showed how the absence of the fragile x protein in fruit flies causes over-activity of a second gene, resulting in excessive growth of microtubules, tube-like support structures at the end of nerve cells. There, at synapses, nerve signals are transmitted from one nerve cell to another.
The excessive growth of microtubules made nerve-signal transmission go haywire in the flies. That suggests an almost identical process makes nerve-signal transmission malfunction in humans to cause fragile x syndrome.
The scientist cured the flies by using genetic manipulation to eliminate the excessive microtubules. Because excessive microtubules can be broken down with medication such as colchicine , a drug now used to combat certain cancers, the discovery in fruit flies points directly to the possibility of using colchicine or similar drugs to treat mental retardation and other fragile x symptoms in people.
“Something like colchicine at very low doses- much lower than you would give a cancer patient- might serve to counteract the effects of fragile x disease,” said Dr. Broadine, an assistant professor of biology at the University of Utah.
Treatment “could be just a few years away,” he said,” It depends entirely on the side effects of the drug treatments and the dosage of the drug required to counteract the brain defects.”
Treatment with colchicines could cause side effect because normal amount of microtubules is essential to help cells maintain their structure and divide.
However,” in Fragile X the mental retardation is so severe, you might be willing to put up with some side effects,” Dr. Broadie said, noting that the average IQ in this population is 35 or 65 points below normal.
Fragile X Syndrome was identified and named in 1991. It afflicts 1 in 2000 male newborns and 1 in 4000 female newborns in the United States. An estimated 100,000 Americans are affected.
The severity of the symptoms can vary. It is the most common inherited form of mental retardation. Down Syndrome is more common, but not inherited.
Symptoms include elongated ears, a prominent chin, unusually flexible fingers and loose joints, visual problems, flat feet, speech and emotional delays, occasional heart valve abnormalities, and enlarged testicles at puberty. In addition, individuals with fragile x frequently experience anxiety, attention deficit and hyperactivity, shyness, impaired social skills, hypersensitivity to sensory stimulation, overreaction to changes, and behavior resembling autism, including hand flapping, avoidance of eye contact, and hand biting.
Some symptoms can be treated by drugs and speech, occupational, and physical therapy. However, there is no treatment for the syndrome, which is detected through blood test.
The genetic mutation that causes fragile X syndrome occurs in the X chromosome. The syndrome is so named because the long arm of the X-shaped X chromosome looks like it may break off. This is due to extra genetic material, and stuttering-like repeat of a sequence of nucleic acids within the long arm.
Boys with mutant fragile X chromosome always have symptoms, ranging from mild to severe retardation, because they have only one X chromosome. Since the girls have two chromosomes, the normal X chromosome often compensates when the other is mutated. Thus, approximately one-third of girls with fragile X have mental retardation, another 20 % have less severe learning problems, and another have no symptoms.
One in 260 women carries the fragile X chromosome and has a 50-50 chance of passing on the defect to her children, male or female. An estimated one in 800 men carries the defect but can pass it on only to their daughters.
Scientists already knew a human gene called FRM1 carries the code that makes human cells produce the protein FRMP. In people with Fragile X syndrome, the FMR1 gene is mutant, resulting in either reduced amounts or absence of the FMRP protein.
In the new study Dr. Brodie and his colleagues showed a gene called DFXR is the fruit fly equivalent of the human fragile X gene FMR1.When the scientists disabled this gene in fruit files, the result was abnormalities in the synapses where nerve signals are transmitted. Because of the abnormalities, the fruit flies had impaired vision as well as uncoordinated movements that made them fly poorly.
People with fragile X syndrome also have visual problems and trouble coordinating complex behaviors such as movement and learning, Dr. Broadie noted.
In a series of experiments, he and the other researchers showed why the nerve transmission abnormalities and the resulting problems developed in flies. They found that when the gene DFXR was knocked out, there was a resulting increase in activity of another gene that produces futsch. The overproduction of this protein led to excessive growth of microtubules at the synapses, impairing the structure of the synapses and their ability to transmit nerve signals.
To confirm the finding, Dr. Broadie and his colleagues created a double knock-out of fruit flies, in which both the DFXR and futsch genes were disabled. While the disabled DFXR gene led to abnormalities in the flies, disabling the futsch gene prevented excessive growth of microtubules and reversed the abnormalities. The double knock-out flies showed normal behavior, synapse structure and nerve signal transmission.
The equivalent of the futsch gene in humans is MAP1B, which helps form microtubules. Therefore, the researchers concluded that a crippled FMR1 gene in people causes over activity of the MAP1B gene and protein, resulting in the excessive growth of microtubules, nerve synapse abnormalities, and symptoms of Fragile X syndrome.
The human FMR1 and the fruit fly DFXR gene each regulate the formation of hundreds of proteins, Dr. Broadie explained. The big surprise in this study was that the influence of DFXR on only one protein (futsch) causes the fruit fly equivalent of Fragile X syndrome. That implies the disease also has a similar simple cause in humans: the interaction of the FMR1 and MAP1B genes.
Dr. Broadie said his study goes well beyond previous research by investigators from Emory University and Rockefeller University, who showed the human Fragile X protein FMRP normally interacts with a variety of proteins in human brain cells ( Cell, Nov 16, 2001). He explained that his study shows the specific interaction between the DFXR gene and futsch protein in fruit flies, thus implying human Fragile X results solely from the interaction of FMR1 with MAP1B.
Other coauthors of this study are Adina Bailey, at Berkeley, and Yong Zhang, Heinrich Matthies, Robert Renden, Mark A. Smith, and Sean Speese, all of the University of Utah.
For more information contact:
Kendal Broadie, PHD,
synapse.biology.utah.edu
FRAXA Research Foundation:
www.fraxa.org/html/home.htm
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