Everyone knows about Down Syndrome but few people know about Fragile X Syndrome; yet it’s the second-most common genetic cause of Mental Retardation (MR), right behind Down Syndrome. The incidence of Fragile X Syndrome is 1 in 4000 males and 1 in 7000 females.

Let’s take a look at what it is. Firstly, we’ve already stated that it’s a genetic disease and, as the name might suggest, is located on the X chromosome; in particular, it originates from the gene FMR1 (Fragile X Mental Retardation 1); a gene that normally has 5 to 45 repeats of the CGG triplet. CGG are, respectively: Cytosine (C) and Guanine (G) repeated twice, or two of the four bricks that comprise DNA. In Fragile X Syndrome, these triplets are considerably more (over 200) and their so called expansion is accompanied by another phenomenon, called methylation of cytosines. These two conditions together (expansion and methylation), cause the inactivation of the gene FMR1 and a physical constriction of the X chromosome. Under a microscope, you can see a real bottleneck that causes the fragility of the X chromosome.

The three forms of Fragile X Syndrome

  • Complete mutation (FXS, Fragile X Syndrome), the FMR1 gene has a complete expansion of the CGG triplets described just a few lines above; the clinical symptoms are intellectual disability, behavioral and learning problems, and distinct physical characteristics.
  • Pre-mutation (FXTAS, Fragile X Syndrome associated with tremor and ataxia), the FMR1 gene mutation is not complete and manifests with tremor, inability to coordinate gait and balance, memory problems, and it occurs after the age of 50.
  • Fragile X-associated primary ovarian failure. This is a form of pre-mutation that’s present only in females, leads to infertility and early menopause before the age of 40.

But if it’s a genetic disease, is it also hereditary?

Yes, it is. But, since the FMR1 gene is present on the X chromosome, this syndrome has some very specific characteristics. First, we must remember that the X chromosome is present in pairs in females, while males have an X and a Y chromosome. What does this mean? It means that in the male, the symptoms of Fragile X are normally more evident because the Y chromosome isn’t able to compensate for the effects of triplet expansion on the X chromosome. In the female; however, if there is a pre-mutation of the gene FMR1 on only one of the two X chromosomes possessed, then there are no obvious symptoms that may indicate the disease. However, in the case of pregnancy, there will be a 50% chance that the pre-mutation will be inherited by the child(ren) and manifest as a complete mutation with greater probability in a male child.

If the boy or girl demonstrates the symptoms of Fragile X Syndrome, and if the couple intends to have a second child, it would be appropriate to perform a simple blood test and contact a specialized center (refer to the link at the end of this article for a list of specialized centers in Italy), in order to determine which of the two parents is the carrier. Calculate the risk with a geneticist and make an informed decision.

How is it possible to diagnose Fragile X Syndrome?

Before conception, this is possible with a genetic test that detects the pre-mutation. However, as stated above, the symptoms are slight (or non-existent) and therefore normally, there are no reasons for the Doctor to prescribe such a test. However, observing one’s own family history, if one identifies relatives who manifest one of the three forms described above, it’s advisable to consult with one’s own Gynecologist or request a direct consultation with a Geneticist. The pre-mutation can be borne by both male and female; however, only in the female is there the instability that makes the pre-mutation expand, and ultimately generate, the syndrome after a few generations. So, a child who has Fragile X Syndrome may have inherited the disease from her grandmother or great-grandmother who had the pre-mutation that has then stretched from generation to generation. But how did the grandmother or great-grandmother generate the pre-mutation? In many cases, it’s generated randomly, as most mutations are generated in nature.

There’s also a prenatal diagnosis that investigates the health status of the embryo or fetus. It’s a diagnosis that is proposed spontaneously by the Doctor to all women who have previously been ascertained a genetic status of pre-mutation or complete FMR1 mutation. Prenatal diagnosis is a molecular analysis that’s conducted, following amniocentesis or villocentesis. There is a modern technique called non-invasive prenatal investigation, which investigates chromosomes 13, 18 and 21 and, upon request, the X and Y chromosomes, but for now we are not able to diagnose Fragile X Syndrome.

In the case of assisted fertilization, a pre-implantation genetic diagnosis can be performed which consists of taking one or two cells from the embryo, on the third day after fertilization. If the diagnosis is negative, the embryo is implanted in the uterus and pregnancy begins.

The last mode of diagnosis of Fragile X Syndrome, involves a pre-conception investigation. It’s assumed that a Fragile X mutation of maternal origin is known, and this justifies the diagnosis. During the maturation phase of the oocyte, the so-called first polar cell is formed. This is a cell that has a genetic makeup mirroring that of the oocyte but will not give rise to an embryo. If the genetic analysis of the first polar cell is positive, showing the presence of the maternal mutation, it means that the oocyte is healthy for that mutation. Conversely, if the first polar cell does not contain the mutation, then it’s assumed that the oocyte has it. From a practical point of view, only the oocytes that have tested negative in the pre-conception test will be used for in-vitro fertilization.

Those who’ve had the joy of having a baby know that within two days of birth, a post-natal diagnosis is routinely performed; however, this diagnosis normally investigates metabolic diseases, and genetic diseases are analyzed only if there are heritable diseases in the family.

Who can you turn to if you need genetic diagnosis or counseling? There are reference centers for the diagnosis of Fragile X Syndrome distributed throughout most of Italy; on this site (in Italian), you can find the list.

Which therapies are available?

Unfortunately, not many — since this is a genetic disease. Pharmacological treatments are available to limit disorders in the psychological area, but these must be integrated-into speech therapy, occupational therapy (for sensory integration), educational plans, and behavioral interventions.

Here, you can view an interesting video (in Italian) about Fragile X Syndrome. Enjoy watching!

This post is also available in: Italiano


Please enter your comment!
Please enter your name here