Notice Number: NOT-HD-08-003
Release Date: January 8, 2008
Response Date: March 31, 2008
National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov)
National Institute of Aging (NIA), (http://www.nia.nih.gov)
National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), (http://www.niddk.nih.gov)
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov)
National Institute of Neurological Disorders and Stroke, (http://www.ninds.nih.gov)
The purpose of this request for information is to seek input from the scientific community, health professionals, patient advocates, and industry related to future research priorities in the genetically related disorders of Fragile X syndrome, Fragile X Tremor Ataxia Syndrome, Premature Ovarian Failure and other relevant conditions associated with FMR1 gene function.
Alterations in the regulation and expression of the Fragile X Mental Retardation 1 (FMR1) gene play a pivotal role in the progression of at least three distinct disease states: Fragile X syndrome (FXS), Fragile X Tremor Ataxia Syndrome (FXTAS) and Premature Ovarian Failure (POF). This diversity of action occurs because: i) FMR1 and its gene product FMRP (Fragile X mental retardation protein) are expressed in a number of tissues and ii) both the loss and gain of FMR1 gene expression can be deleterious. Understanding the function and regulation of FMR1 is the focus of attention for a diverse set of researchers, and the information gleaned from one field is likely to be beneficial for an understanding of all three of the disorders. To that end NIH has created a series of working groups with the goal of synergizing research both within each field, and across the spectrum of FMR1-associated disorders. This RFI seeks input into that process.
FXS is the most studied of the three FMR1 associated disorders. It is the most common cause of inherited mental retardation and results from a loss of FMRP expression in the brain during development. FXS occurs as a result of a large expansion of CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene preventing the expression of fragile X mental retardation protein (FMRP). In individuals where less than ~50 CGG repeats are present in the 5’ region, FMRP expression is normal. Full mutations (more than 200 repeats) generally result in hypermethylation of the CpG repeats and the adjacent promoter region, transcriptional silencing, and the loss of FMRP expression. Full mutations with associated mental retardation (MR) have been estimated to occur in approximately 1 in 4,000 males and in 1 in 6,000 females and have been found across racial and ethnic groups. Clinically, FXS has a broad spectrum of phenotypes. Neurologically, the FXS includes a severely disabling neurodevelopmental disorder involving both neurocognitive, and emotional characteristics. Other physical characteristics are also present.
There are also individuals with an intermediate number of repeats (~55-200 repeats) who are known as premutation carriers. It has been estimated that approximately 1 in 259 females and 1 in 810 males carry the premutation. Individuals carrying the premutation are at risk of developing physical, neurocognitive, and emotional characteristics through the course of their lifespan.
There are two primary disorders associated with premutations. The first is FXTAS, an adult onset neurological disorder with associated tremor, ataxia and cognitive decline/dementia. FXTAS primarily affects males, consistent with an X-linked recessive disorder. The second disorder is known as “premature ovarian failure (POF).” POF is more accurately an ovarian insufficiency that leads to a continuum of altered ovarian function and affects approximately 15% of women who carry the premutation. Symptoms include a loss of regular menstrual cycles, infertility, and ovarian hormone deficiency not normally observed until the age of menopause. Other conditions that have been associated with premutation carriers include anxiety and autism in young children, symptoms of ADHD, and academic learning disabilities during adolescence. Collectively these FMR1-associated disorders have far reaching implications for individuals and families and represent a major adverse health burden.
In recent years there has been a surge in the number of research projects related to FMR1 associated disorders both supported and conducted across Institutes at NIH. To coordinate research efforts and facilitate collaboration the NIH Fragile X Research Coordinating Group was instituted in the spring of 2007. This group consists of individuals representing both extramural and intramural research at the National Institute of Child Health (NICHD), the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the National Institute of General Medical Sciences (NIGMS), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Deafness and Other Communication Disorders (NIDCD), and the National Cancer Institute (NCI).
In order to maintain the momentum of discovery and further develop research relevant to FMR1- associated Disorders, the NIH and the Fragile X Coordinating Group welcome your comments on current Fragile X syndrome research activities. We would particularly like your opinion on the future directions in research related to FMRP Associated Disorders. This information will be used to assist in the development of an FMR1 Associated Disorders Research Plan being developed in accordance to Appropriations Language for FY2008 from the House Committee Report on Labor-HHS-Education Appropriations (H.Rept.110-231) and the Senate Committee Report on Labor-HHS-Education Appropriations (S.Rept.110-107).
The NIH is especially interested in creative, concrete suggestions to the following questions, for strengthening the long term research plan.
1a. What tools and research resources are presently available and which are the most helpful for any of the disorders? Which are underutilized?
1b. What tools and research resources not presently available need to be developed (or developed further) and which of these would be most useful for any of the disorders?
Response will be accepted until March 31 2008. Responses should be limited to 10 pages and marked with this RFI identifier NOT-HD-08-003. Responses are preferred in electronic format and can be e-mailed to NICHD_FMR1RFI@mail.nih.gov. The collected information will be analyzed, but the results will not be made available to the public. Responses will be held in a confidential manner. Any proprietary information should be so marked.
Respondents will receive an email confirmation acknowledging receipt of their response, but will not receive individualized feedback.
Inquiries regarding this notice may be directed to:
Tiina K. Urv, Ph.D.
Health Scientist Administrator
Mental Retardation and Developmental Disabilities Branch
Center for Developmental Biology and Perinatal Medicine
National Institute for Child Health and Human Development, NIH
6100 Executive Blvd.
Rm4B09D, MSC 7510
Bethesda, MD 20892-7510
Email : firstname.lastname@example.org
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