NICHD conducts and supports research on many aspects of FXPOI as well as other Fragile X-associated conditions. Researchers are studying why some women with an FMR1 premutation have FXPOI and others do not, for example. In addition, the Institute is developing a registry of women with FMR1 premutations to study their health over time. Other research is seeking easier, less expensive, and more accurate screening and diagnostic tests that can provide detailed information on a person’s FMR1 status. Another area of NICHD-supported research seeks to substantiate the association between the FMR1 triplet repeat count and infertility phenotype, which can range from diminished ovarian reserve to premature ovarian failure.
NICHD’s goals for FXPOI research are consistent with the NIH Research Plan on Fragile X Syndrome and Associated Disorders. NICHD research efforts related to Fragile X and its associated disorders address each condition specifically, as well as more general aspects of Fragile X mutations that may affect all three conditions. Research goals include the following:
- Identifying model organisms with which to advance the study of FMR1 premutations and FXPOI.
- Advancing understanding of how the FMR1 premutation affects fertility. NICHD pursues long-term studies to determine whether certain conditions lead to POI in premutation carriers. This research could help establish genetic causes of other forms of POI and determine other health risks women with the premutation might face.
- Defining biomarkers that might help predict which premutation carriers will develop POI and how much time they have before the onset of infertility and/or menopause.
- Developing effective strategies for counseling women with an FMR1 premutation and their families. Women with a FMR1 premutation may know that a genetic risk runs in their families, or may be learning about FMR1 for the first time. Genetic counselors and other healthcare providers would benefit from guidelines for discussing the diagnosis of FXPOI, its impact on fertility, and the potential impact on a future child.
Institute Activities and Advances
Through its intramural and extramural organizational units, NICHD supports and conducts a broad range of research on Fragile X-associated disorders, including FXPOI. Short descriptions of some of this research are included below.
NICHD researchers in the Unit on Integrative Reproductive Medicine, in the Division of Intramural Research Program in Reproductive and Adult Endocrinology, are working to understand the causes of female infertility. A main focus is the natural history of reproductive health and fertility difficulties in girls and women with FMR1 premutations.
The unit is developing a registry of women with known or suspected FMR1 premutations. The registry will allow researchers to follow participants over time and study possible effects on reproductive health. The registry will also allow researchers to track development of common medical conditions—such as thyroid disease, psychiatric disorders, hypertension, and neurological disorders—to see if women with an FMR1 premutation have increased health risks.
In addition, there currently are no health or reproductive screening guidelines for women who carry a premutation, nor are there guidelines for the genetic counseling of these women. The registry, and the research it will allow for, soon will enable guidelines to be established1. For details, visit http://clinicaltrials.gov/ct2/show/NCT01187524.
Researchers supported by the Fertility and Infertility Branch (FIB) are studying women with diminished ovarian reserve, including those who have an FMR1 premutation. These women have regular menstrual periods but lower levels of luteinizing hormone, which stimulates the release of eggs from the ovaries. Although fewer than 45 repeats in the FMR1 gene is considered typical, preliminary data show that fewer than one-fifth of women with diminished ovarian reserve have 35 to 44 repeats in the FMR1 gene. Researchers are examining this "high-normal" number of repeats and their effects (if any) on ovarian reserve.2
The Effects of FMR1 Premutations in Children and Adults
Research supported by the Intellectual and Developmental Disabilities Branch (IDDB) is exploring the neurodevelopmental and neurodegenerative effects of the FMR1 premutation in children and adults. Researchers are investigating the relationship between the premutation and cognitive and social deficits in boys, and between the premutation and age-related changes in adults age 40 and older.3
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 would test a small drop of blood on a paper card to detect Fragile X syndrome in newborns.4
Other Activities and Advances
NIH Research Plan on Fragile X Syndrome and Associated Disorders
- In 2009, the NIH developed a research plan to advance the understanding of Fragile X syndrome and its associated conditions: NIH Research Plan on Fragile X Syndrome and Associated Disorders. The plan puts forward goals to guide future research, setting research priorities for each of the conditions. A major priority is to investigate the biological processes underlying all three disorders and how to better diagnose and treat them. Other priorities are studying the prevalence of the gene variations in the population and how the three conditions affect families.
- NICHD's IDDB funds three Fragile X Syndrome Research Centers. The centers are geared toward stimulating multidisciplinary, multi-institutional research and translating basic research findings into clinical practice.
- The Reproductive Medicine Network (RMN), funded through NICHD's FI Branch, carries out large, multicenter clinical trials of diagnostic and therapeutic interventions for infertility and reproductive diseases and disorders. The Network's structure allows investigators to test hypotheses in large numbers of patients who are enrolled in common protocols at multiple centers. This method produces answers more rapidly than working through individual sites. The Network allows external investigators with secured funding to gain access to RMN data and samples on a case-by-case basis, following an external scientific review of the proposed research's relevance to the RMN mission and its scientific significance.
- Trans-NIH Fragile X Research Coordinating Group and Scientific Working Groups. (2008). National Institutes of Health Research Plan on Fragile X syndrome and associated disorders. Retrieved September 12, 2012, from https://www.nichd.nih.gov/sites/default/files/publications/pubs/Documents/nih_fragilex_research_plan_2009.pdf (PDF 440 KB).
- Pastore, L. M. (n.d.). FMR1 CGG repeats in primary ovarian insufficiency women vs. 2 comparison groups. Retrieved September 11, 2012, from https://reporter.nih.gov/project-details/8195141
- Hagerman, R .J. (n.d.). Genotype-phenotype relationships in Fragile X families. Retrieved September 11, 2012, from https://reporter.nih.gov/project-details/8064264
- Latham, G. J. (n.d.). Enabling use of blood spot cards for accurate high-throughput fragile X screening. Retrieved September 11, 2012, from https://reporter.nih.gov/project-details/8124769