Fragile X and the FMR1 gene
Everyone is aware that human being have 23 pairs of chromosomes. One pair, known as the sex chromosomes, is responsible for determining whether you are a male or a female. Females have two X chromosomes. Males have one X chromosome and one Y chromosome. Each chromosome is made up of thousands of genes, all of which have specific function. Many genes produce a single type of protein that functions in the body to accomplish a specific function.
Genes are made up of a series of chemical which are together referred to as DNA. There are four separate chemical components of DNA which are each represented by a single letter G, C, T, and A.
There is a gene on the X chromosome known as the FMR1 gene. It produces a protein called the FMR1 protein. This protein is known to be critical to intellectual development and functioning. Within this gene, there are repeating sequences of DNA known as CGG repeats. Every living person has an FMR1 gene and typically the gene contains approximately 5 to 40 CGG repeats.
Fragile X is a condition in which the number of CGG repeats in the FMR1 gene is higher than normal. Doctors divide people into groups based on how many CGG repeats are present in their FMR1 gene. A “Premutation” results when people who have between 55 and 200 repeats. These individuals are referred to as Fragile X “carriers”. Most Fragile X carriers are unaffected intellectually because they have normal levels of the FMR1 protein. Many of these people will be unaware that they are FX carriers.
In individuals with Fragile X syndrome, the number of CGG repeats is over 200. This expanded number of repeats is called a “full mutation” and it causes the FMR1 gene to “turn off” or not work properly. An FMR1 gene that is turned off doesn’t produce enough, or any, of the FMR1 protein that it is designed to produce.
Females can inherit the Fragile X gene from their mother or their father. Males can only inherit the Fragile X gene from their mother. Approximately 1 in 250 females and 1 in 800 males carry the gene mutation.
Individuals who have the Fragile X premutation have a higher risk of having children with a larger number of repeats. This is because the larger the number of CGG repeats, the more unstable the FMR1 gene becomes. Thus, there can be a family with no history of Fragile X syndrome in which it suddenly appears in a number of offspring.
Problems with the Fragile X gene can result in a number of different health issues.
Fragile X syndrome (FXS)
Fragile X syndrome is the most common cause of inherited mental impairment, ranging from learning disabilities to severe mental retardation including autism or “autistic-like” behavior. Symptoms can include physical characteristics, behavioral deficits, and delays in motor and speech/language development. Approximately 1 in 3,600 males and 1 in 4,000 to 6,000 females have mental impairment due to FXS.
Fragile X–associated tremor ataxia syndrome (FXTAS)
FXTAS is a condition affecting balance, tremor, and memory in carriers older than 50 years; FXTAS primarily affects male carriers but, rarely, female carriers are affected.
Premature ovarian insufficiency (POI)
Premature ovarian insufficiency is a condition in which women experience long periods of time without having ovulation or menstrual periods. blood testing reveals that they have high levels of the pituitary hormone FSH and low levels of the ovarian hormone AMH . In the past, POI was referred to as as premature ovarian failure or primary menopause. These terms are no longer preferred since up to 5% of women with POI may resume ovulation and menstrual cycles and even achieve pregnancy without fertility treatment.
Even with a thorough evaluation, no etiology for spontaneous POI can be identified in 90% of cases. In 13% of affected patients under the age of 30 years, women will be found to have a missing or abnormal X chromosome. Autoimmune oophoritis is the mechanism of POI for approximately 4% of women with POI who have two normal appearing X chromosomes. An FMR1 gene premutation is present in approximately 6% of patients with POI who have two X chromosomes.
Among women who carry the premutation, 16% have premature ovarian insufficiency, or cessation of menses at least 1 year prior to age 40, compared with only 1% in the general population, or a relative risk of 16. Overall, premutation carriers go through menopause 5 years earlier than non-carriers. Interestingly, the CGG repeat sizes that led to the highest risk for POI and earlier age at menopause appear to be in the mid-range of 80–100, not the highest premutation repeat sizes.
Among women with POI, the estimated frequency of women who are premutation carriers is 11.5% in those with a family history of ovarian failure (familial POF) and 3.2% in those without a family history (sporadic POF). This frequency compares to the 1/250 frequency of premutation carriers present in the general population.
Because FMR1 premutation carrier status reveals significant health issues beyond those involving the reproductive system, such as disorders of the nervous system or having a child with fragile X syndrome—which causes inherited mental impairment recent experts have encouraged testing women with POI for Fragile X mutations.
Decreased ovarian reserve
The question has been raised as to whether women who don’t meet the diagnosis of POI but who have evidence for decreased ovarian reserve should have testing of their FMR1 gene. Recent studies have shown that FMR1 carriers have significantly elevated FSH serum concentrations compared with women of the same age who have normal FSH levels. FSH levels were found to be increased even in premutation carriers even if the women had regular menstrual cycles or were using birth control pills. In addition, other studies have found other serum markers indicative of impaired ovarian function.
As of March 2008, doctors around the world are in the process of developing guidelines for testing for FMR1 mutations. The current draft recommends that testing be offered to women who:
- Are diagnosed with POI
- Have elevated FSH levels
- Have had a poor response to gonadotropin stimulation
The following individuals should also consider FMR1 testing to rule out FXS or FXTAS:
- Individuals with mental impairment or autism of unknown cause
- Individuals with significant hyperactivity, learning disabilities, and/or mild cognitive deficits
- Individuals with any of the physical or behavioral features of FXS or FXTAS, regardless of gender or family history
- Any person who has a family member with a diagnosis of FXS or FXTAS, or a family history of mental impairment
- Women with unexplained infertility or primary ovarian insufficiency (also called premature menopause or premature ovarian failure)
In the opinion of the American Society for Reproductive Medicine (ASRM) Practice Committee document released in February 2008, the National Fragile X Foundation recommendation for genetic testing for Fragile X for the indication of “infertility” is unnecessarily broad and not supported by the available evidence because the most common causes of infertility (anovulation, male factor, abnormal female reproductive anatomy) have no relationship to Fragile X. The ASRM Practice Committee supports the NFXF recommendations for FMR1 testing for individuals seeking reproductive counseling having a family history of Fragile X or undiagnosed mental retardation and for women with unexplained premature ovarian failure (also known as “primary ovarian insufficiency”). At the present time, genetic testing for Fragile X is not specifically indicated or recommended for infertile women under age 40 having diminished ovarian reserve; the results of ongoing studies to determine the prevalence of FMR1 premutations and mutations among such women will determine whether genetic testing for Fragile X may be warranted.
FX can be passed on in a family by carriers with no apparent sign of the condition. In some families it has affected numerous family members through the generations, while in others, it initially seems to have caused problems in only one person.
Fragile X testing by preimplantation genetic diagnosis (PGD)
If an intended parent is a Fragile X carrier, their children are at risk for developing a more severe Fragile X problem such as Fragile X Syndrome. Embryos produced from couples who are Fragile X carriers may have varying numbers of CGG repeats. Therefore, identification of those embryos without a large number of CGG can reduce the likelihood of Fragile X associated problems.
A number of PGD techniques have been described to screen embryos for PGD. These are difficult cases. Since women who are carriers tend to have poor response to fertility medications, fewer eggs are obtained and fewer embryos can be produced. This lessens the available pool of embryos that can be tested.