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Study Aims to Develop First Medications for Fragile-X Syndrome, Leading Inherited Cause of Mental Retardation

Proposed Medications also May Reveal Treatments for Autism

Science Update

A new NIMH grant is enabling scientists to begin testing safety and effectiveness of potential medications for fragile-X syndrome, the most common inherited form of mental retardation. No effective medications are available for the disorder. The animal studies currently underway are designed to lay the groundwork for the first human clinical trials in subsequent phases of the research.

People with other developmental disorders that share some of the same brain mechanisms which lead to fragile-X syndrome, including some cases of autism, also may benefit from this research. The purpose of the study is to advance promising laboratory findings into treatments for patients.

The grant will total $3.37 million over three years. Randall Carpenter, M.D., of Seaside Therapeutics (Cambridge, Massachusetts), is the principal investigator.

The National Institute of Mental Health (NIMH) is the primary funder of the project, with additional support from two other institutes of the National Institutes of Health: the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Two private organizations, the Fragile X Research Foundation and Cure Autism Now, also contributed funding.

What Is Fragile-X Syndrome?

Full-blown fragile-X syndrome affects one in 4,000 males and one in 6,000 females in the U.S. It may result in mental retardation ranging from moderate to severe and often is accompanied by anxiety, attention-deficit disorder, seizures, and physical deficits, such as joint problems, accelerated growth, and abnormal facial features. Other symptoms may include behavioral and social abnormalities.

The number of less severe cases is unknown, but they include learning disabilities, emotional problems, and some degree of mental retardation.

Like fragile-X syndrome, some forms of autism can be profoundly disabling, while others are less so. Autism is more common than fragile-X syndrome. A recent study by the Centers for Disease Control and Prevention estimated that autism occurs in 1 of every 150 children eight years old1.

What Causes Fragile-X Syndrome, and How Is It Linked to Autism?

The root cause of fragile-X syndrome is a gene mutation also strongly associated with some cases of autism. The two disorders sometimes occur together.

The mutation is in a gene that makes a protein called FMRP. However, this gene mutation isn't the target of the compounds being tested; the targets are receptors on brain cells, called mGluR5 receptors. The gene mutation is thought to have trickle-down effects that include mGluR5 receptors, which lead to the symptoms of fragile-X syndrome.

How Do the Compounds Being Tested Work?

Because of the gene mutation that causes fragile-X syndrome, people with the disease don't have the FMRP protein. Scientists theorize that, without FMRP, brain cells produce too much of certain other proteins, and that the mGluR5 receptor plays a key role in this process.

Researchers suggest that excess production of these other proteins contributes to the weakened connections between brain cells seen in people with fragile-X syndrome. The compounds being tested in this study partially block mGluR5 receptors to correct the problem.

Why Target mGluR5 Receptors?

Recent studies in animals suggest that targeting mGluR5 receptors could prevent or treat fragile-X syndrome. A report in the December 20 issue of Neuron adds compelling evidence from NIMH-funded researchers Mark Bear, Ph.D., Director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, and colleagues, with scientists from Brown Medical School and India's National Institute of Mental Health and Neuroscience and National Center for Biological Sciences.

Using a genetics technique, these researchers reduced the number of mGluR5 receptors in living mice. The mice had features of fragile-X syndrome, because they had been engineered previously to lack the FMRP protein. Reducing mGluR5 in these fragile-X-like mice had the following effects.

  • Brain cells that had not responded properly to environmental demands, such as visual demands, began responding properly in the mice. Cellular responses to environmental demands are especially crucial in the developmental phase of life, because they result in biochemical events that help shape normal brain development.
  • Reducing mGluR5 receptor levels in the mice reduced abnormalities in areas of brain cells called dendritic spines. The abnormalities are characteristic of people with various kinds of mental retardation, including fragile-X syndrome.
  • The fragile-X mice had too much protein in the area of the brain, the hippocampus, that is the hub of memory. This excessive protein level dropped when the researchers reduced mGluR5 receptor levels.
  • The brain normally extinguishes some memories, a necessary function. The mice extinguished memories more than is normal, but this improved when the researchers lowered the number of mGluR5 receptors.
  • The seizures and rapid body growth characteristic of fragile-X syndrome were prevented in the mice.

What's Next?

In the current study, researchers will determine if compounds that partially block mGluR5 receptors are safe for animals. Earlier animal studies had yielded preliminary evidence that they are safe and effective. If the additional testing in this study confirms the compounds' safety in animals, the scientists will request a Food and Drug Administration permit to conduct research that will determine dosage and safety in normal, human volunteers. Pending the results of that research, the compounds will be tested in clinical trials of people with fragile-X syndrome.

Where Can I Get More Information?

To learn more about fragile-X syndrome, visit the NICHD  web site.

For more information about autism, visit the NIMH web site.


Dölen G, Osterweil, Rao BSS, Smith GB, Auerbach BD, Chattarji S, Bear MF. Correction of fragile X syndrome in mice.

1 Autism and Developmental Disabilities Monitoring (ADDM) Network, Centers for Disease Control and Prevention, 2007.