Through its intramural and extramural organizational units, the NICHD supports and conducts a broad range of research on Fragile X syndrome. Short descriptions of selected research studies are included below. NICHD researchers are also studying Fragile X-associated disorders, including Fragile X-associated primary ovarian insufficiency and Fragile X-associated tremor/ataxia syndrome.
Much of the NICHD's research on Fragile X syndrome is supported through its Intellectual and Developmental Disabilities Branch (IDDB). In addition to individual projects, the IDDB supports research on Fragile X through the Fragile X Syndrome Research Centers. The Other Activities and Advances section has information about these centers.
IDDB-supported researchers are currently studying the "mGluR Theory" of Fragile X syndrome: that exaggerated signaling in mGluR (metabotropic glutamate receptor) pathways because of missing Fragile X Mental Retardation Protein (FMRP) leads to the condition's various symptoms.
Using a Fragile X mouse model, researchers generated mice with 50% lower expression of mGluR5. Several aspects of Fragile X were improved, as the risk of seizures was reduced and there was better eye development, brain development, and behavior.1 Current research will test whether inhibiting mGluR5 after birth can prevent Fragile X syndrome in this mouse model. The researchers will also inhibit mGluR5 after Fragile X symptoms are present to investigate whether such an action can reverse the symptoms.
Another recent study investigated a possible shared mechanism for Fragile X syndrome and tuberous sclerosis complex (TSC), another genetic disorder characterized by intellectual disability and autism. Scientists measured brain protein synthesis in mouse models for TSC and Fragile X syndrome and revealed that the Fmr1 mutation in Fragile X causes increased synaptic protein synthesis that can be corrected by inhibiting mGluR5. Interestingly, the Tsc2 mutation in TSC was found to decrease synaptic protein synthesis, and this could be corrected by augmenting mGluR5. The researchers also found that the deficits in the mouse models were ameliorated when the mice were bred to carry both mutations. The findings suggest that deviations in the synthesis of these proteins—in either direction—can lead to behavioral impairments that are shared across genetic disorders. In addition, the findings suggest that therapies designed to correct one cause of ASD are not likely to be effective for all other causes.
In May 2010, a clinical trial of an mGluR5 antagonist began in adults with Fragile X syndrome. If the results from the adult study show promise, the drug can be tested in clinical trials with children. The NICHD, through its Best Pharmaceuticals for Children Act activities, will add its support to that of the National Institute of Mental Health and other Institutes and organizations for the pediatric clinical trials.
Several NICHD-supported research groups are seeking ways to better diagnose and screen newborns for Fragile X mutations and premutations. Early physical recognition of the characteristics of Fragile X syndrome is difficult, and new technology is being designed to detect all categories of Fragile X alleles, including full mutation expansions.2
By the time infants with Fragile X syndrome reach 2 years old, they have a distinct pattern of brain abnormalities. Two-year-olds who have both Fragile X and an autism spectrum disorder (ASD) also have their own unique pattern.3,4
A long-term study is set to discover how these patterns develop and how they are related to the signs and symptoms of Fragile X. Supported by the NICHD's IDDB, the study's researchers are examining early brain development and behavior in infants with Fragile X syndrome. The study will ultimately include 334 infants, some with Fragile X, some with ASD, and some at risk for ASD, as well as a set of control infants. The researchers will perform magnetic resonance imaging (MRI) scans at 6, 12, and 24 months of age and will collect behavioral information as well. This study has the potential to distinguish specific behavioral, genetic, and neurobiological features that characterize infants with Fragile X syndrome as compared to infants at risk for autism without Fragile X syndrome and to those with typical development.5
About 60% of children with Fragile X also have an ASD, but only about 4% of children with ASDs have the FMR1 gene mutation. It is unclear at this point why ASDs affect only a rather small portion of children with Fragile X. One current line of research is to examine the role played by having a mother with an autoimmune disease, such as thyroid disease, lupus, multiple sclerosis, or fibromyalgia.
A recent study6 revealed that children with Fragile X whose mothers had a history of autoimmune disease displayed more problems with tics and a higher rate of seizures than did those whose mothers did not have this history. The children in the first group also had higher scores on measures of behavioral concerns, including aggression, depression, and withdrawal. The groups did not differ on rates of ASD, intellectual disability, head size, or sleep problems. These results suggest that future research should consider how autoimmune disease in mothers may interact with the FMR1 mutation to disrupt brain development in their offspring and make children with Fragile X syndrome more susceptible to seizures, tics, and behavior problems.
Recent research supported by the NICHD has demonstrated how the protein missing in Fragile X syndrome acts as a molecular "toggle switch" in brain cells.7 In Fragile X syndrome, a genetic mutation removes the FMRP from cells, interfering with protein production and signaling at the synapses (the junctions between brain cells where chemical communication occurs). This leads to structural changes and an impairment of the cells' ability to respond to chemical signals, interfering with learning and memory. NICHD-supported scientists determined how the FMRP uses short RNA molecules (microRNAs) to switch on and off the production of other proteins in response to chemical signals. This finding demonstrates the importance of microRNAs in neurological development and diseases such as Fragile X.
NIH-supported researchers have found that a class of drugs called PI3 kinase inhibitors can correct defects in the anatomy of neurons in a mouse model of Fragile X syndrome.8 In Fragile X syndrome, a gene mutation leads to the absence of FMRP, and without FMRP to regulate protein production and signaling, neurons produce excess amounts of certain proteins at synapses. This leads to structural changes and an impairment of the cells' ability to respond to chemical signals, interfering with learning and memory. In the mouse model of Fragile X, using a drug to inhibit the action of the PI3 kinase enzyme dampened the synaptic proteins and could potentially reverse the resulting structural changes. The drug was able to restore normal levels of protein production at synapses, suggesting that PI3 kinase inhibitors could help improve learning and cognition in individuals with Fragile X syndrome.
To achieve its research goals for Fragile X syndrome and associated disorders, the NICHD is involved with a variety of activities. Some of these activities are managed through the components listed above; others are part of NIH-wide or collaborative efforts in which the NICHD participates.
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