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Autism Disorder Reversed in Mice
By Michael Smith, MedPage Today
February 09, 2007

EDINBURGH, Scotland, Feb. 9 -- Rett syndrome -- a relatively rare autism spectrum disorder -- may be reversible, if experiments in mice are borne out in humans.

The syndrome, which affects about one in 10,000 girls, is caused by mosaic expression of mutations in the X-linked gene MECP2 and destroys speech, normal movement, and use of the hands, although there is no loss of neurons, according to Adrian Bird, Ph.D., of the University of Edinburgh.

But in a mouse model of the syndrome, symptoms could be reversed completely, even in animals that were severely affected, Dr. Bird and colleagues reported online in the Feb. 9 issue of Science.

"The general perception in the field is that once you have damage in the brain, it's very difficult to go backwards," Dr. Bird said. "What we found is that (Rett syndrome is) reversible."

The finding is both the "most desirable (and) the most unexpected result" of the experiments, Dr. Bird said in a statement.

Huda Zoghbi, M.D., of Baylor College of Medicine in Houston -- who discovered that the syndrome is caused by MECP2 mutations -- called the findings "extraordinary."

And, since MECP2 mutations are now being seen in some cases of childhood schizophrenia, classic autism and learning disabilities, the results may have a wider application than just to Rett syndrome, she said.

"If we can develop therapies to address the loss of MECP2 we may be able to reverse neurological damage in children and adults with Rett, autism and related neuropsychiatric disorders," said Dr. Zoghbi, who was not involved with the Edinburgh research.

However, the researchers cautioned that the "experiments do not suggest an immediate therapeutic approach" to Rett syndrome.

Dr. Bird and colleagues made the discovery using genetically engineered mice, whose MECP2 gene was silenced by a so-called stop cassette. The silencing could be reversed at will by administering the estrogen analog tamoxifen.

The researchers measured symptoms in the mice with observational tests for such things as gait, tremor, irregular breathing, and poor ability to clasp with the hind limbs. A wild-type mouse would score zero for all symptoms, while mice with the syndrome would score one if a symptom was present and two if it was severe.

The key experiment, Dr. Bird and colleagues said, was in female mice that had developed symptoms:

• Wild-type littermates had no symptoms, as expected.
• Untreated experimental animals had symptom scores averaging above four. • Mice treated with tamoxifen over a four-week period (thus slowly reactivating their MECP2 gene) saw their symptom scores progressively reduced, to one or below.
• The difference in symptom scores between the two groups of experimental mice was significant at P<0.002.

The researchers also measured neuronal signaling in the mice, and particularly long-term potentiation (LTP), which is thought to be the cellular basis for learning and memory.
In female experimental mice, the onset of symptoms coincided with a reduction in LTP, compared with wild-type mice, the researchers found. However, after treatment to restore the gene function, LTP in the experimental mice was indistinguishable from wild-type.

"Like many other people, we expected that giving MECP2 to mice that were already sick would not work," Dr. Bird said. "The idea that you could put back an essential component after the damage to the brain is done and recover an apparently normal mouse seemed farfetched."

Yet, he added, "the results are gratifyingly clear, and must give hope to those who are affected by this distressing disorder."

The research was supported by the Rett Syndrome Research Foundation, the Wellcome Trust, and the Rett Syndrome United Kingdom/Jeans for Genes. The researcher did not report any conflicts.

Source reference:
Guy J et al. "Reversal of Neurological Defects in a Mouse Model of Rett Syndrome." Science 2007;doi 10.1126/science1138389.
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