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Fragile X Syndrome: Which IVF Candidates Should be Tested and How Should Results be Interpreted?

by Dr. Geoffrey Sher on February 8, 2016

Fragile X syndrome occurs in individuals who carry the gene, FMR1 on an X-chromosome. This condition is inherited as a dominant X-linked disorder. With a dominant disorder, the condition results when there is only one copy of the altered gene in each cell.

Fragile syndrome occurs twice as frequently in males (1:1,200) as compared to females (1:2,500) A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. The Fragile X gene, FMR1, can be passed on in a family by individuals who have no apparent signs of this genetic condition. In some families, a number of members appear to be affected, whereas in other families a newly diagnosed individual may be the first family member to exhibit symptoms.

By and large, Fragile X syndrome results from a mutation in the FMR1 gene where a segment, known (CGG triplet repeat), is expanded. Under normal circumstances, the CGG triplet is repeated from 5 to approximately 55 times. In contrast, those who have Fragile X syndrome will have more than 200 repeats. CGG segments prevent the FMR from propagating the formation of a specific protein needed to protect against the development of Fragile X syndrome. Thus over-expression of CGG triplet (>200 times) on an X chromosome represents a degree of loss of this “protective protein” as to lead to the development of fragile X syndrome. Since boys have only one X chromosome, Fragile X syndrome tends to manifest much more severely in males than in females, (who have two X chromosomes).

In a normal population, the number of repeated FMR1 genes varies from 5 to about 55. Those with 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation (carriers”). In women, this is liable to increase to >200 repeats in the developing eggs. Accordingly, such women are at increased risk of having a child with fragile X syndrome. Conversely, when passed by men to the next generation, CGG repeats either remain the same in size or shorten. This is why men with a permutation do not transmit the disease. However they do transmit the permutation which if carried to a subsequent female offspring can result in them transmitting Fragile X syndrome in subsequent generations.

Both males and females with fragile X pre-mutation are by and large intellectually and physically normal in outward appearance. Some may manifest with mild but often socially harmful intellectual or behavioral symptoms,. They are however usually not infertile.

Some men with a premutation are at risk of developing a manifestation of fragile X-associated tremor/ataxia syndrome (FXTAS) a condition characterized by loss of balance, tremors and memory loss. It occurs in some older male carriers of the gene. Heart bone and skin problems are also often present. Age distribution is a s follows: Seventeen percent (17%) of males aged 50-59 years, in 38 percent of males aged 60-69 years, in 47 percent of males aged 70-79 years, and in 75 percent or males aged 80 years or older. Some female premutation carriers may have diminished ovarian reserve (DOR), premature ovarian failure and FXTAS.

It is important to bear in mind that women who have approximately 55 to 200 repeats. There is no clear cut-off between the upper limit of normal and the lower limit of the premutation range. Accordingly, cases with 45-55 repeat copies fall into the so called “gray zone.” In some cases, premutations expand from generation to generation such that over time they ultimately express as full Fragile X syndrome. The larger the premutation in cases that fall in the “gray zone”, the greater is the risk of subsequent expansion to a full mutation in the offspring.

Boys with full FMR1 mutation (Fragile X syndrome) will almost routinely have moderately severe mental retardation. They will tend to have a characteristic facial appearance with a long face, enlarged cranium, protruding ears and an elongated face with a protuberant chin and forehead. Affected boys after puberty tend also to experience enlargement of the scrotum and laxicity of joints. There will also usually be characteristic behavioral problems such as lack of impulse control, temper tantrums, delay in speech and language development and perseverative speech. Hand biting, hand flapping and attention deficit /hyperactivity are other common manifestations. Fragile X syndrome is also the most common known cause of autism or “autistic-like” behaviors.

Girls with Fragile X on the other hand, tend to only have mild mental retardation. Women who have fewer repeats of the FMR-1 gene usually do not have mental retardation but often will have prematurely diminishing of ovarian reserve (DOR) with early menopause and infertility. Both men and women may develop FXTAS.

While most males with full blown clinical fragile X syndrome are mentally retarded and exhibit some or all the physical and behavioral characteristics, only about one third of females are mentally retarded. Another one third are partially mentally impaired, and the remaining third are unaffected.

Fragile X syndrome is diagnosed through DNA testing of cells using one of two methods:

  1. Polymerase Chain Reaction (PCR) or
  2. Southern blot analysis

Both methods exhibit a high degree of interpersonal variability and thus when it comes to interpreting results, there are significant limitations. This is especially the case when diagnosing a “carrier state.” Interpretation is further complicated by the presence of other fragile sites in the same region of the X chromosome.

It is recommended that in the following circumstances, patients undergoing assisted reproduction be tested for Fragile-X:

  • All mentally challenged individuals, those who are autistic, and in cases of developmental delay
  • Women with unexplained premature reduction in ovarian reserve or premature ovarian failure (menopause)
  • Individuals who have physical or behavioral characteristics of fragile X syndrome
  • Those with a family history of fragile X syndrome
  • Those with a family history of mentally challenged male or female relatives where no definitive cause has been ascertained.
  • Offspring of known carrier mothers

Prenatal diagnosis can be made by 2nd trimester amniocentesis, which yields definitive results. In contrast, results obtained from 1st trimester chorionic villus sampling (CVS) should be interpreted with caution, because the status of the FMR1 gene often will not fully manifest in chorionic villi until the second trimester.

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  • Soheil Motamedi - February 8, 2016 reply

    Dear Dr. Sher
    Many thanks for the useful info on your blog. What are your recommendations for a pregnant lady with positive anti-TPO (456 uIU/ml) and high TSH level (40.0 uIU/ml). Would increasing the Levothyroxine dosage be any good to avoid a possible miscarriage. What are the general guidelines when facing similar situations.

    thanks

    Soheil Motamedi

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 8, 2016 reply

    Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies.
    The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects and chromosome X abnormalities. This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.
    It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.
    Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

    Please visit my new Blog at http://goo.gl/4hvjoP , find the “search bar” and type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Ovarian Stimulation for IVF: Comparing “conventional” use of GnRH antagonists to the Agonist/Antagonist Conversion Protocol (A/ACP)
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report)
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • The Role of Nutritional Supplements in Preparing for IVF

    I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoff Sher

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