NICHD conducts and supports research on many aspects of FXTAS and other fragile X-associated conditions, including what causes them and how they might be prevented or treated. Researchers are seeking factors that explain why some people with the FMR1 premutation have symptoms of FXTAS while others do not. Other studies focus on collecting data from people with known FMR1 mutations and premutations, and from their family members, to see if these mutations or premutations are associated with other diseases or conditions. Research is seeking easier, less expensive, and more accurate screening and diagnostic tests that can provide detailed information on a person’s FMR1 status.
Problems associated with the FMR1 gene mutation fall into the research portfolios of multiple NIH Institutes, including NICHD. To help coordinate research on FMR1, NICHD leads the NIH Fragile X Research Coordinating Group, which includes nine NIH Institutes with research interests on different aspects of fragile X. The group consulted with outside experts and in 2008 published a long-term agenda for FMR1 research, called the NIH Research Plan on Fragile X Syndrome and Associated Disorders. Finding treatments and supporting families impacted by fragile X and its related disorders are major goals of the plan.
The NIH is committed to continuing to learn as much as possible about the FMR1 gene and its far-reaching effects. The story of fragile X might also serve as an effective and useful model for studying other diseases, and for moving research discoveries from the laboratory into everyday life.
Among the group's goals with implications for FXTAS are the following:
- Finding treatments for the underlying protein dysfunction that causes fragile X-associated disorders. Studies in fruit flies and mice have resulted in several promising molecules that are either in human clinical trials today or are on their way.
- Furthering understanding of why FMR1 premutations affect some people but not others. This includes the study of why FXTAS is more common among men than women and how the genetic changes lead to specific symptoms. Research could also help document the frequency of premutations in the general population and improve understanding of when FXTAS develops in families in which FMR1 premutations are common.
- Documenting the different kinds of symptoms that develop and how they change over time. This includes research on defining the neurological, cognitive, behavioral, and emotional symptoms of FXTAS and developing instruments that can measure changes in motor function and other signs. Better instruments and an improved understanding of risk factors could help clinicians identify FXTAS earlier.
- Understanding whether other conditions are linked with fragile X-associated conditions.
- Developing ways to better diagnose and treat FXTAS.
Institute Activities and Advances
The Effects of FMR1 Premutations in Adults and Children
In 2001, researchers supported by the Intellectual and Developmental Diseases Branch (IDDB) discovered FXTAS.
The same NICHD-supported researchers have found that FXTAS is associated with other conditions. For example, sleep apnea is three times more common in people with FXTAS than in the general population. People with FXTAS are also at a higher lifetime risk of mood disorders, including major depressive disorder, anxiety disorder, and post-traumatic stress disorder. In addition, men with FXTAS are more likely to have high blood pressure than men without the FMR1 premutation. (Men with the premutation who don't have FXTAS are not at increased hypertension risk.) (Sources: Hamlin, A., et al. (2011). American Journal of Medical Genetics. PMID: 21932336; Bourgeois, J. A., et al. (2011). Journal of Clinical Psychiatry. PMID: 20816038; and Hamlin, A., et al. (2012). American Journal of Medical Genetics. Part A. PMID: 22528549)
Researchers are studying the protective factors in carriers of FXTAS and the proteins involved in the pathogenesis to determine ways to prevent or reverse the process. They have also found early neurodevelopmental abnormalities in premutation mice, leading to the question of whether it is a lifelong process, and providing hope for the development of early intervention. (Source: Hagerman, P. J., (2012). Current gaps in understanding the molecular basis of FXTAS. Tremor and Other Hyperkinetic Movements; New York: 63.)
Some people with FMR1 premutations experience symptoms in childhood. For example, boys with FMR1 premutations have a higher risk of seizures, compared with boys who do not have premutations. Also, boys who had seizures were also more likely to have an autism spectrum disorder. (Source: Chonchaiya, W. (2012). Human Genetics. PMID: 22001913)
Further research supported by the IDDB aims to explore how the FMR1 premutation affects the development of children and the neurological health of adults. This research includes a study of 500 adults (age 40 years and older) and 150 boys (ages 8 to 16). In the boys, studies will focus on attention deficit hyperactivity disorder and social deficits, including autism spectrum disorder. In the adults, researchers will focus on age-related changes.1
Better Diagnostics and Screening Tools for Fragile X and Premutations
Several NICHD-supported research groups are seeking ways to better diagnose and screen for fragile X mutations and premutations. One potential screening method currently being tested would analyze a small drop of blood on a paper card to detect fragile X syndrome in newborns.
Early physical recognition of the characteristics of fragile X syndrome is difficult, and this method uses new technologies that have been developed that can detect all categories of fragile X alleles, including full mutation expansions.2
Other Activities and Advances
To achieve its research goals for fragile X syndrome and associated disorders, 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 NICHD participates.
- NICHD's IDDB funds three Centers for Collaborative Research in Fragil X and FMR1-related Conditions. The centers are geared toward stimulating multidisciplinary, multi-institutional research and translating basic research findings into clinical practice.
- The NIH Fragile X Research Coordinating Group, led by NICHD, includes nine institutes with research interests on different aspects of fragile X or its associated disorders. The group consulted with outside experts and published a long-term agenda for FMR1 research, called the NIH Research Plan on Fragile X Syndrome and Associated Disorders, in 2008. Finding treatments and supporting families impacted by fragile X and its related disorders are major goals of the plan.
In addition, the plan supports a focus on defining the full range of clinical effects of the FMR1 premutation, its natural course, and the identification of the earliest markers of FXTAS disease in order to facilitate diagnosis and the proper management or prevention of problems experienced by those who have a premutation. This could have a substantial impact on management and genetic counseling for a large number of individuals in the general population.
- Hagerman, R. J. Genotype-phenotype relationships in fragile X families. Retrieved August 21, 2012, from https://projectreporter.nih.gov/project_info_description.cfm?aid=8064264&icde=11603567
- Latham, G. J. Enabling use of blood spot cards for accurate high-throughput fragile X screening. Retrieved August 21, 2012, from https://projectreporter.nih.gov/project_info_description.cfm?aid=8124769&icde=11603103