The Natural History of Reproductive and Overall Health in Girls and Women With a Pre-Mutation in the FMR1 Gene; Creation of a Patient Registry
The Natural History of Reproductive and Overall Health in Girls and Women With a Pre-Mutation in the FMR1 Gene; Creation of a Patient Registry
Background:

 -  In human DNA, the Fragile X (FMR1) gene helps to regulate the nervous and reproductive
 systems. If the gene is abnormal, it can cause different kinds of problems, such as
 abnormal menstrual periods, decreased fertility, muscle tremors, and mental retardation.
 An abnormal FMR1 gene can also make a person more susceptible to other medical
 conditions, such as thyroid problems, high blood pressure, seizures, and depression.
 More research is needed on how abnormalities in the FMR1 gene can lead to these
 problems, and how often these problems appear in individuals with an abnormal FMR1 gene.

 -  Researchers are interested in developing a patient registry of women who have an
 abnormality in the FMR1 gene. This registry will allow researchers to follow
 participants over time and study possible effects of this abnormality on their general
 and reproductive health.

 Objectives:

 - To develop a patient registry of women with an abnormal FMR1 gene and monitor their general
 and reproductive health.

 Eligibility:

 - Women at least 18 years of age who have an abnormal FMR1 gene on the X chromosome.

 Design:

 -  The following groups of women will be eligible for screening for this study:

 -  Those who have a family member with Fragile X Syndrome or mental retardation

 -  Those who have (or have a family member who has) primary ovarian insufficiency, also
 known as premature menopause

 -  Those who have (or have a family member who has) certain neurological problems such as
 tremors or Parkinson's disease.

 -  Eligible participants will be scheduled for an initial study visit at the National
 Institutes of Health Clinical Center. Participants who have regular menstrual periods
 should schedule the visit between days 3 and 8 of the menstrual cycle; those who do not
 have regular periods may have the visit at any time of the month. In addition, all
 estrogen-based treatments (such as birth control pills) must be stopped for 2 weeks
 prior to the study visit.

 -  Participants will have a full physical examination, provide a medical history, and
 provide blood samples for immediate and future testing. Participants will return for
 yearly visits for the same tests for as long as the study continues.

 -  Participants who have or develop primary ovarian insufficiency related to the FMR1 gene
 will also have tests to measure bone thickness and will have a vaginal ultrasound to
 examine the ovaries. These tests will be scheduled for a separate visit, and will be
 repeated every 5 years for the duration of the study.
Spontaneous 46,XX primary ovarian insufficiency (POI) is a cause of decreased fertility in
 approximately 1% of women before age 40. The most common known genetic cause of 46,XX POI is
 a pre -mutation in the Fragile X Mental Retardation (FMR1) gene. The FMR1 gene is located on
 the X-chromosome and contains a CGG repeat in the un-translated region; this CGG repeat is
 normally present in less than 55 copies, but has a tendency to expand across generations.
 Greater than 200 CGG copies results in Fragile X Syndrome (FXS), the most common form of
 heritable mental retardation. A pre-mutation in the FMR1 gene, defined as between 55 and 199
 CGG repeats, is associated with POI in women and carries a risk of expanding to the full
 mutation in a woman s offspring, resulting in a child with FXS. POI that is associated with
 the FMR1 pre-mutation is known as Fragile X-associated POI ( FXPOI ). Approximately 20% of
 women with an FMR1 pre-mutation develop FXPOI. Importantly, it is not known why some women
 with the pre-mutation develop FXPOI and others do not. The primary objective of this study is
 to characterize the natural history of reproductive function in women who are FMR1
 pre-mutation carriers by creating a patient registry that will allow us to follow them
 longitudinally. Given the relative rarity of this pre-mutation in the general population
 (<1%), a patient registry is necessary for enrollment of an adequate number of patients for
 clinically significant analyses to be performed.

 In order to characterize the natural history of reproductive function in this population, we
 will longitudinally track reproductive health of participants, including menstrual history,
 pregnancy rate, and biological (serum) markers of ovarian function. The FMR1 pre-mutation may
 also be associated with specific general health risks, such as hypertension, thyroid disease,
 neurological disorders, and psychiatric disorders. A patient registry will also allow us to
 track development of these and other common medical conditions to determine if women with the
 FMR1 pre-mutation have increased health risks. Currently, there are no screening guidelines
 regarding reproductive or general health for women who carry the FMR1 pre-mutation, and
 observations from longitudinal data will help to develop such guidelines. Finally,
 standardized guidelines for genetic counseling of women with the FMR1 pre-mutation regarding
 genetic risk to their children do not exist, and data collected in this study will enable
 this.
-  INCLUSION CRITERIA:

 1. Women ages 18 and older

 2. FMR1 CGG repeats numbering between 55 and 199, as determined by standard Southern
 blot and PCR techniques.

 EXCLUSION CRITERIA:

 1. Males

 2. Children

 3. Women who do not have an FMR1 pre-mutation (CGG repeat number <55 or >199)

 4. Inability to make personal medical decisions

 CRITERIA FOR SCREENING FOR THE FMR1 PRE-MUTATION:

 1. Family history of Fragile X syndrome or mental retardation

 2. Personal or family history of primary ovarian insufficiency (or POF or premature
 menopause )

 3. Personal or famiy history of tremor ataxia syndrome or Parkinson s disease