Research Frontiers: Unlocking the Fragile X Mystery

Kennedy Krieger Scientists Explore Syndrome's Effect on Neural Proteins

Kennedy Krieger recently received a major grant from the National Institutes of Health to further investigate Fragile X syndrome, the second most common cause of intellectual disability. The two-year, $300,000 grant will help a team led by Kennedy Krieger's Dr. Walter Kaufmann learn more about how the disorder manifests itself, which could make treating the symptoms of Fragile X easier.

Unlike Down syndrome, which can involve hundreds of genes, Fragile X occurs when a single gene on the X chromosome fails to produce FMRP, a protein that regulates the synthesis of other proteins. Scientists already know some of the proteins and neurological processes controlled by FMRP, but that's only part of the story, Dr Kaufmann says. "If the group of affected proteins were the same in each child, the syndrome would be very homogeneous," he says. Instead, individuals with Fragile X demonstrate a wide variety of manifestations of the disease: some have autism, others have ADHD, others have language delays. Most have a combination of manifestations in varying degrees.

The NIH grant will fund a study, "Lymphocytic Targets and Behavior in Fragile X," dedicated to uncovering why the disorder varies so widely from person to person. The study will use blood tests to examine lymphocytes (white blood cells from lymph tissue) from 100 boys with Fragile X syndrome and 20 who don't have the disorder. The reason for the focus on boys: Fragile X occurs two to four times less often in girls, who have an extra X chromosome that often compensates for the mutated one. Dr. Kaufmann's team will measure the level of several proteins known to be affected by the Fragile X mutation in each boy's lymphocytes. The team will also evaluate the boys in terms of overall cognitive function, language impairment, attention control and impulsivity, autistic features and fine motor function.

The study hypothesizes that boys with abnormal levels of proteins typically present in the neocortex and limbic system regions of the brain will be more prone to language delays and/or autistic behavior. Why? Those two regions control language and other communication functions. In the same vein, the study also expects to confirm that boys with unusually high or low levels of proteins found in the cerebellum, a brain region responsible for motor control, will have disproportionately high occurrences of motor coordination disabilities. The study predicts similar correlations between abnormalities in several other types of proteins and the manifestations of Fragile X syndrome.

Learning more about the role that the Fragile X gene plays in proteins critical for brain development and function opens up the possibility of intervention by addressing the areas of the brain that rely on those proteins. For example, Dr. Kaufmann's earlier research on boys with Fragile X suggests that reduced amounts of a protein called MUNC13 increase the likelihood of attention disorders in Fragile X. While MUNC13 helps control glutamate release, Ritalin, a popular medication for treating attention disorders, controls dopamine release. That could explain why only about 60 percent of boys with Fragile X and attention disorders respond to Ritalin. Further research on the connection between glutamate release and attention disorders could prompt the development of a drug that targets glutamate levels.

Understanding how an individual's levels of MUNC13 and other proteins can vary may help provide an objective way to anticipate that individual's responses to particular treatments says Dr. Kaufmann: "Now, we have a window to the brain that we didn't have before."