What is Fragile X Syndrome?
Fragile X syndrome is a genetic disease characterized by changes in the FMR1 gene that cause developmental, behavioral and mental impairments. It is an X-linked disorder and males are generally more severely affected by fragile X than females. Symptoms of fragile X usually become apparent by the age of 2, when the children start showing delayed development of speech and language. Delayed developmental milestones such as taking longer to sit alone, walk or talk, are some of the earliest detectable features of fragile X syndrome, whereas physical features such as the long face, prominent forehead, large ears and prominent jaw, do not manifest until later on. Individuals who are carriers of the fragile X premutation are at risk later in life of developing fragile X-associated tremor ataxia syndrome, which is a neurodegenerative disease. Female carriers are also at increased risk of infertility, the most extreme form being fragile X-associated primary ovarian insufficiency.
What Causes Fragile X Syndrome?
Fragile X syndrome is caused by defects in the FMR1 gene that makes the protein “fragile X mental retardation protein” (FMRP). FMRP is involved in cognitive development, the development of mental abilities related to knowledge, attention, memory, judgment and reasoning among many other things. It also influences reproductive functions in women. Individuals with fragile X syndrome only produce very little or no FMRP protein. Only one defective copy of FMR1 needs to be inherited to develop the disease.
Genetics of Fragile X Syndrome
Fragile X syndrome is caused by defects in the FMR1 gene. Severity of the disease depends on gender and how much FMRP protein is made. The FMR1 gene is located on the X chromosome. The X and Y chromosomes are known as the sex chromosomes. Men have one copy of the X chromosome and one copy of the Y chromosome and women have two copies of the X chromosome. Although only one defective FMR1 gene is required for disease symptoms to occur, women are generally less affected, due to the slight protectiveness of the normal FMR1 gene on their other X chromosome.
The changes in FMR1 that gives rise to fragile X syndrome occur in a region of the gene that controls how much FMRP will be produced. In individuals with fragile X syndrome, a three-nucleotide sequence (CGG), known as a tri-nucleotide repeat, within the regulatory region of the FMR1 gene is repeated too many times. In a normal individual who is not affected by fragile X associated diseases, CGG is repeated from 5 to 44 times. When the CGG repeat numbers are between 45-54 this is called a “gray zone” or “borderline” change in FMR1. Individuals with this intermediate allele very rarely experience behavioral or psychological symptoms associated with fragile X syndrome.
Individuals who are carriers have the fragile X premutation with repeat numbers between 55 to 200. While these individuals do not have the disorder, they are at higher risk of developing some of the psychological symptoms associated with fragile X syndrome and fragile X-associated disorders. When the repeat number is over 200, these people develop fragile X syndrome. This is because when the repeat number reaches over 200, the cell will turn off the production of FMRP.
Men only have one copy of the X chromosome and will manifest all the symptoms associated with fragile X. However, the two copies of the X chromosome in women makes the genetics a little more complicated. Even though women inherit two X chromosomes, only one of these chromosomes remains active in a given cell. In a process known as X inactivation, one of the two X chromosomes gets inactivated during development and this process is completely random. In a female with a fragile X mutation, some cells will inactivate the X chromosome with the defective FMR1 and others will inactivate the X chromosome with the normal FMR1. There is a 50:50 chance on which version of FMR1 will be turned off in a given cell. This is why fewer women than men are affected by fragile X syndrome. Symptoms in women with fragile X syndrome will also vary because they can still make some FMRP in some of the cells in their body.
A woman with fragile X syndrome, (one defective copy of FMR1), has a 50% chance of passing on the disease to her children (sons and daughters). Research show that fathers with the full mutation can only pass on a premutation, as it appears that sperm are unable to carry X chromosomes with full FMR1 mutations. However, the chance of passing on a premutation to his daughters is 100% and 0% to his sons as they will inherit a copy of his Y chromosome. If a woman carries a premutation, there is a risk that this unstable repeat will expand to a full mutation during egg production, and therefore her child will be affected with fragile X syndrome. This risk of expansion to a full mutation is higher for mothers with premutations that have close to 200 repeats.
How Common is Fragile X Syndrome?
Fragile X syndrome is one of the most common inherited diseases that cause mental impairment. In all races and ethnic groups, 1 in 4000 boys and 1 in 8000 girls are affected by fragile X syndrome. Approximately 1 in 260 women and 1 in 800 men are carriers of the fragile X premutation that increases the risk of developing fragile X-associated disorders.
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Fragile X-associated Disorders. National Fragile X Foundation
Saul RA, Tarleton JC (1998, Updated 2012 Apr 26). FMR1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.