Fragile X syndrome (FXS) is an inherited genetic condition characterized by intellectual disability, developmental delays, and distinctive facial features. Cognitive symptoms include developmental delay, intellectual delay (ranging from mild to severe), and learning delays. Individuals with FXS also have a higher chance for behavioral differences, such as attention deficit hyperactivity disorder (ADHD), anxiety, hand biting, hand flapping, poor eye contact, and autism spectrum disorders. Physically, many (but not all) people with FXS have distinctive facial features (protruding ears, long face, prominent forehead and chin, large head), hyperflexible joints, soft skin, and a heart condition called mitral valve prolapse.
FXS is caused by a harmful change (called a pathogenic variant) in the FMR1 gene. The FMR1 gene is responsible for making a protein called FMRP. The FMRP protein is found in many tissues in the body, particularly the brain, testes, and ovaries. In the brain, the FMRP protein works to develop and maintain connections between nerve cells. As we grow and develop, the connections between our nerve cells is constantly shifting. The FMRP protein helps to keep the connections between nerve cells working during this shifting process, which is important for learning and memory.
The FMR1 gene is made up of three letters that repeat themselves over and over (called a trinucleotide). It is normal to have these three letters (CGG) repeated in the FMR1 gene, but how many repeats the gene has is important. Most people have between 5 and 40 CGG repeats in their FMR1 gene. People who have FXS have over 200 CGG repeats. Having too many of these CGG repeats cause the FMRP protein that the gene makes to not work how it’s supposed to. Not having enough of this working FMRP protein is what leads to the signs and symptoms of FXS.
Individuals with number of repeats in the 55 to 200 range are considered to be permutation carriers. While most permutation carriers have no signs or symptoms of FXS, they are at risk for fragile X tremor ataxia syndrome (FXTAS), which causes ataxia, or loss of control of body movements. FXTAS typically occurs in men who are permutation carriers, and can progressively get worse over time.
Women who are permutation carriers are also at an increased risk for fragile X associated primary ovarian insufficiency (FXPOI), which is menopause prior to 40 years of age. FXPOI occurs in about 20% of women who are permutation carriers.
If someone is a permutation carrier, it is possible for the number of CGG repeats to increase when they pass that gene down to any children they have. For example, Sarah is a FXS permutation carrier that has 150 CGG repeats on one of her X chromosomes. She has a son who inherited that X chromosome from her, but when she passed it down to him the number of CGG repeats had increased to 210. This means that he would have FXS. It is difficult to predict how the number of CGG repeats can expand in future generations, but talking with a genetics professional, such as a genetic counselor, can be helpful to gather more detailed information about this.
FXS is inherited in an X-linked dominant pattern because the FMR1 gene is located on the X chromosome. X-linked dominant means that one non-working copy of a gene on the X chromosome is enough to cause FXS. Men only have one copy of their X chromosome, and therefore only one copy of all the genes that are on the X chromosome. If they inherit an X-linked dominant condition, they will be affected. Because women have two X chromosomes, they have one non-working copy of the gene and one working copy of the gene. However, since having only one broken copy of the gene causes X-linked dominant conditions, women who inherit a non-working gene for X-linked dominant conditions often also show symptoms. It is common for men with FXS to be more severely affected than women.
It is estimated that 1 in 4000 males and 1 in 8000 females has FXS.
Currently, there is no cure for FXS. However, life expectancy is not expected to be affected as the health concerns associated with FXS are not usually life-threatening or life-limiting. Management of FXS often focuses on early developmental intervention including specialized education with individualized attention as well as early behavioral and other supportive therapies. There are also specialized FXS clinics in many parts of the country that help guide medication options that may more specifically address the health concerns that are more common in people with FXS.
For individuals with FXTAS, management can include medications, supportive care for gait disturbance, counseling, and rehabilitation treatments. For individuals with FXPOI, endocrine evaluations are recommended along with genetic counseling to discuss reproductive options.