Also Known As
FMR1-related disorders
far(X) syndrome
FRAXA syndrome
FXS
Martin-Bell syndrome
X-linked mental retardation and microbrachids
Fragile X-associated tremor and ataxia syndrome (FXTAS)
Fragile X-associated premature ovarian insufficiency (FXPOI)
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This article waslast modified on October 5, 2020.
What is fragile X syndrome?

Fragile X syndrome is an inherited condition associated with a range of developmental delays, learning disabilities, thinking (cognitive) impairment and behavioral issues. It is caused by a pathogenic (disease-causing) expansion of repetitive DNA near the FMR1 gene.

Fragile X syndrome is the most common inherited intellectual disability in males, occurring in about 1 in 4,000 males. It also is a significant cause of intellectual disability in females, occurring in approximately 1 in 8,000 females. Up to half of people with fragile X syndrome also have an autism spectrum disorder (ASD). Fragile X syndrome accounts for about 2 to 5 percent of all people with ASD.

Other FMR1-related disorders include:

  • Fragile X-associated tremor/ataxia syndrome (FXTAS)
  • Fragile X-associated premature ovarian insufficiency (FXPOI)

Genetics
To learn about fragile X syndrome and related disorders, it is helpful to understand some basics about genetics. Our genetic information is made up of chromosomes that are composed of very long double strands of deoxyribonucleic acid (DNA). Normally, everyone inherits 23 pairs of chromosomes (a total of 46 chromosomes), one set from the mother and the other set from the father. There are twenty-two pairs of chromosomes called autosomes, and two sex chromosomes called X and Y that determine your physical sex at birth. Typically, males have one X and one Y chromosome and females have two X chromosomes.

DNA is made up of specific segments called genes that are composed of multiple chemical "bases" that pair together in a specific pattern. There are four bases: adenine (A), cytosine (C), guanine (G), and thymine (T). Genes serve as templates to make (transcribe) ribonucleic acid (RNA). RNA contains the information for making the proteins that govern how the body works.

The FMR1 gene makes instructions for a protein called FMRP that is necessary for normal brain development. The FMRP protein is involved in developing the specialized connections between nerve cells called synapses. When a change (genetic variant or mutation) near the FMR1 gene disrupts FMRP production, leading to absent or low FMRP levels, it affects the development of the nervous system, resulting in fragile X syndrome.

Very close to the FMR1 gene, there is a section of DNA that has multiple repeats of three DNA bases: cytosine-guanine-guanine (CGG). This is called a CGG triplet repeat.

  • Typically, there are between 5 and 44 CGG repeats. This is considered normal. People with this number of repeats are not affected with fragile X syndrome and are not at increased risk of having a child with fragile X syndrome.
  • Any variant with more than 44 CGG repeats is called an expansion. Having 45 to 54 CGG repeats is considered an intermediate variant that does not cause fragile X syndrome. A female with a repeat expansion in the intermediate range has a higher chance of passing a larger triplet expansion (a premutation – see below) to her children.
  • People with CGG expansions of 55 to 200 repeats are said to have an FMR1 premutation or to be an FMR1 premutation carrier. These individuals may have some signs or symptoms similar to individuals with fragile X syndrome, but these are generally mild and may go unnoticed. The premutation is unstable, which means the number of repeats is likely to increase as it is passed from mother to child. If the number of repeats expands into the full mutation range (200 repeats or greater), it can lead to fragile X syndrome in the child.
  • An individual who has more than 200 CGG repeats in this region of DNA is said to have a full mutation. Almost all cases of fragile X syndrome (99%) have an abnormally high number of CGG repeats, usually more than 200. Rarely, fragile X syndrome is caused by a different type of genetic variant, such as an FMR1 gene deletion or a single nucleotide variant. (See the article Genetic Disorders.)

Inheritance
Fragile X syndrome is inherited in an X-linked pattern. The FMR1 gene is located on the X chromosome.

  • Mothers pass on only X chromosomes to their children. About 1 in 250 women carry an FMR1 premutation on one of their X chromosomes. With each pregnancy, mothers who are fragile X premutation carriers have a 50 percent chance of passing the X chromosome with the expanded FMR1 gene to their child. When this happens, there is a chance that the number of repeats will grow larger (expand) and surpass 200 when it is passed on, leading to the full mutation variant and fragile X syndrome. The chance that the premutation will expand to the full mutation range when it is passed on depends on its starting size.
  • Fathers pass on either an X chromosome or a Y chromosome to their children. Fathers with an FMR1 premutation on their X chromosome will pass it to all their daughters. The premutation is not likely to expand when passed on by fathers and it appears that fathers cannot pass on full mutations to their daughters, but scientists don't understand why. Since Y chromosomes do not have the FMR1 gene, fathers do not pass a premutation or full mutation to their sons.

Since most men have one X chromosome and one Y chromosome, a full mutation or premutation usually affects them more seriously than most women who have two X chromosomes because men do not have a second copy of the gene to make a functioning FMRP protein.

Accordion Title
About Fragile X Syndrome
  • Signs and Symptoms

    People with fragile X syndrome or an FMR1 premutation may not have any noticeable symptoms. In people with symptoms, the type and severity of symptoms can vary from person to person or evolve over time. Symptoms may also be more severe in individuals with higher numbers of CGG repeats.

    Males with fragile X syndrome are usually more severely affected by symptoms than females because females typically have two X chromosomes, one of which may have a normal copy of the FMR1 gene. Other unknown biologic factors may affect the severity of the signs and symptoms experienced by each person with fragile X syndrome.

    Some examples of signs and symptoms of fragile X syndrome include:

    • Impaired thinking (cognition), ranging from relatively mild learning disabilities to severe intellectual disability
    • Development delays, such as not learning to sit, stand or walk at about the same age as other children
    • Delay in speech and language skills, especially in boys
    • Attention deficit/hyperactivity disorder (ADHD)
    • Features of autism spectrum disorder (ASD) that affect communication and social interaction
    • Behavioral issues related to ADD or ASD may include hand flapping, biting, anxiety, sensitivity to touch, aggressiveness, irritability, not making eye contact, difficulty paying attention, acting and speaking without thinking, and being very active.
    • Anxiety, depression, aggression, obsessive compulsive disorder (OCD)
    • Seizures
    • Chronic ear infections
    • Distinctive physical features, especially in males as they get older, including a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet and enlarged testicles after puberty

    Fragile X-associated tremor ataxia syndrome (FXTAS)

    Individuals with an FMR1 premutation are at risk for developing fragile X-associated tremor ataxia syndrome. This condition causes "Parkinson-like" tremors. It tends to start after age 50 and symptoms worsen with age. In general, male carriers of premutations are more likely to experience symptoms of FXTAS than women.

    Some examples of signs and symptoms of FXTAS include:

    • Tremors when purposefully moving arms or legs, such as reaching for something (intention tremor)
    • Problems with balance, coordination
    • Parkinson-like tremors when resting, muscle rigidity, slowed movement and slowed speech
    • Numbness, tingling, pain and/or weakness in the legs (peripheral neuropathy)
    • Loss of bladder or bowel control (incontinence) and/or erectile dysfunction
    • Short-term memory loss that may be moderate to severe
    • Problems with planning, problem solving, organization
    • Depression, anxiety, moodiness
    • Women with FXTAS may experience underactive thyroid (hypothyroidism) or fibromyalgia

    Fragile X-associated primary ovarian insufficiency (FXPOI)

    Another condition seen in women with a premutation is fragile X-associated primary ovarian insufficiency. This condition causes a woman's ovaries to stop working before she is 40 years old and leads to early menopause. About a quarter of women with the FMR1 premutation develop FXPOI.

    Signs and symptoms of FXPOI in women who carry the premutation can vary in presence and severity. Some examples include:

  • Testing

    Genetic testing is performed to determine the number of CGG triplet repeats near the FMR1 gene. This testing may be performed for a variety of reasons. Genetic counseling is typically recommended so that you fully understand the implications of results.

    • Diagnosis—genetic testing can confirm a diagnosis of fragile X syndrome (full mutation detection), FXTAS, or FXPOI, or determine premutation carrier status.
      • If your child has signs of autism, intellectual disability, or developmental delay, your healthcare practitioner may order a test for fragile X syndrome. Parents usually notice symptoms of fragile X syndrome first at about 12 months of age for boys and 16 months of age for girls.
      • You may be given a test for fragile X syndrome as an adult if you show symptoms of FXTAS or FXPOI, or if your physician suspects you have symptoms consistent with having an FMR1 premutation, especially if you have a family history consistent with fragile X syndrome.
      • You may be tested as an adult if a family member has been diagnosed with fragile X syndrome or a premutation, or if you have a family history of movement disorders, cognitive, or developmental disabilities.
    • Carrier and prenatal screening may be done to determine whether a pregnant woman and her partner, or couples planning a pregnancy, are at risk for an FMR1-related disorder in their children. This testing may be done if you are a woman who has reproductive or fertility problems, especially if they are part of your family history or if you have a family history of fragile X symptoms.
    • Prenatal diagnostic testing—the American College of Obstetricians and Gynecologists recommends prenatal diagnostic testing for women who are known carriers of the FMR1 premutation and who desire this information prenatally.

    For additional details on testing, see the article on Fragile X (FMR1) Genetic Testing.

  • Treatment

    There is currently no way to cure or prevent fragile X syndrome. Testing and diagnosis are important, however, because there are a number of treatments available to manage some of the symptoms associated with fragile X syndrome. These include educational support and therapy, screening, and treatment for associated medical conditions, and behavioral health treatment. Families may receive genetic counseling, participate in clinical research, and connect with the wider community of people with fragile X syndrome and their family members.

    For more details, see the National Fragile X Foundation webpage on Treatment and Intervention.

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