in a single gene called the FMR1 gene. Every human being has this gene. Some people have only a small change in this gene (referred to as a
) and may not show any symptoms associated with Fragile X. Persons with the premutation are called
and are at risk to develop other related conditions (see FXTAS and FXPOI below). Other people may have bigger changes in the gene (called a
Fragile X is inherited, which means it is passed down from parent to child. The changes in the gene can become greater when passed from mother to child, so a woman who has no symptoms related to Fragile X can have a child affected with Fragile X Syndrome. A male carrier can only pass the premutation, and will pass it to all of his daughters, but none of his sons. Fragile X affects people of all ethnicities, races, and socio-economic backgrounds. Fragile X is named because of the appearance of the X chromosome where the gene mutation occurs, not because individuals with the FMR1 mutation are in any way "fragile".Fragile X Syndrome (FXS)
Normally, the FMR1 gene makes a protein the body requires for brain development. When there is a full mutation in this gene, the body makes only a little bit or none of the protein, which can cause the symptoms of Fragile X Syndrome, or FXS. FXS is the most common single-gene cause of intellectual disability, and can also cause behavioral challenges and assorted physical characteristics.
- Intellectual/Learning - Many people with FXS have intellectual disabilities. These problems can range from mild learning disabilities to more severe intellectual disability. Girls with FXS are typically less affected than males, though about one-third do have significant intellectual disability. A small percentage of females with the full mutation do not show any symptoms of FXS at all - intellectually, physically, or behaviorally.
- Behavioral - Most children with FXS have behavior challenges. This can include ADD or ADHD, autism and autistic-like behaviors, anxiety, hand-biting/flapping, aggression (especially in males), poor eye-contact, and sensory issuessuch as difficulty with bright light, loud noises, being touched by others, or the way something feels (e.g. clothing, certain foods, etc). Though usually less-severely affected, girls can still have emotional/mental-health issues and general and/or social anxiety.
- Communication - Most boys with FXS have challenges with speech and language. They may have trouble speaking clearly, stutter, leave out pieces of words, have unusual rhythm/cadence to their speech, or perseverate (uncontrollably repeat words and/or phrases over and over again). They may also have problems understanding nonverbal cues when talking with others, such as the tone of voice or a person's body language. Girls with FXS typically do not have severe problems with speech or language.
- Physical - Persons with FXS may have large ears, a long face, soft skin, and for males, large testicles. Other associated physical issues can include recurring ear infections, flat feet, high arched palate, and double-jointedness and/or hyper-flexible joints. Physical features such as a long face and large testicles are more common after puberty.
FXS is the leading known cause of autism; approximately 2-6 percent of individuals with autism have FXS as the cause. Approximately 15-33 percent of individuals with FXS also have autism; this range may be so large because of changes in the diagnostic criteria for autism and the methods used to diagnose it.Because of the known link between FXS and autism, and because of the implications that a genetic condition like FXS can have for families, it is recommended that all individuals diagnosed with autism be tested for FXS.
Although individuals with FXS do face significant challenges, they can be involved, productive, and important members of their families, communities, schools, and workplaces. Individuals with FXS are also often gifted with wonderful traits as well;they can be highly-empathetic and loving, have a great sense of humor, have a strong desire for social interaction, and can be very good imitators.Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
FXTAS is a neurodegenerative disorder that affects carriers of the FMR1 premutation. It affects males more often, and more severely, than females, and typically does not appear until after the age of 50. FXTAS symptoms progress at different rates for different individuals, and most individuals diagnosed with FXTAS had no related problems prior to the onset of symptoms.
- Balance problems (calledataxia).
- Intention tremors (during intentional movements such as writing).
- Memory loss (usually short-term).
- Irritability/moodiness, personality changes, other psychiatric symptoms.
- Parkinson's-like symptoms (FXTAS is often misdiagnosed as Parkinson's).
- Dementia (FXTAS is often misdiagnosed as Alzheimer's).
- Cognitive decline (loss of math, reading, and verbal comprehension skills).
FXTAS is most often diagnosed by a neurologist, movement disorder specialist, psychiatrist, orgeneticist. A person who has any of the above symptoms, whether already known to be an FMR1 premutation carrier or not, should be evaluated.Fragile X-Associated Premature Ovarian Insufficiency (FXPOI)
FXPOI is a condition that affects female carriers of the FMR1 premutation, in which a woman's ovaries do not function at normal capacity. Common symptoms include absent/irregular periods, menopause symptoms (e.g. hot flashes), early menopause, and infertility. It is important to note that FXPOI is not early menopause; women with FXPOI can become pregnant because their ovaries can occasionally function enough to release viable eggs, whereas women who have gone thorough menopause will not. In addition, women with FXPOI can also experience a return of menstrual periods. Any woman who experiences the symptoms of FXPOI, whether a known FMR1 premutation carrier or not, should talk to her physician.
Prevalence of Fragile X Premutation, Full Mutation, and Related Conditions
- Premutation carriers - Although regional studies vary on the prevalence of the FMR1 premutation, the current internationally-accepted prevalence rate is that1 in 260 females and 1 in 800 males are carriers of the premutation.
- Full mutation (FXS) - The current prevalence of Fragile X Syndrome is 1 in 3600 to 4000 males, and 1 in 4000-6000 females. The lower incidence in females is due to the fact that some females with the full mutation do not have any of the intellectual, behavioral, or physical symptoms of FXS.
- FXTAS - Current studies have found that approximately 33 percent of men over age 50 who carry the FMR1 premutation will develop some symptoms of FXTAS. Approximately 5-8 percent of women who carry the FMR1 premutation will develop some symptoms of FXTAS, though these symptoms are usually fewer and more mild than typically occur in males.
- FXPOI - Approximately 20-25 percent of female FMR1 premutation carriers will develop FXPOI.
Fragile X is diagnosed with a simple DNA blood test, the FMR1 gene test, which has been available since 1991 and is 99% accurate in detecting Fragile X. If you are asking your physician for a referral for Fragile X testing, you must be certain that they are ordering the FMR1 gene test and not the older, less-accurate chromosome test. One easy way to tell if you are getting the DNA test is that the person drawing the blood will use a vial with a lavender colored top. The chromosome test uses a tube with a green top.
The test generally costs between $300 and $600 and it takes about two weeks to get the results back. If you have private health insurance or public insurance such as Medical, it may cover the cost of the test. If you are paying for the test out of pocket, please contact the National Fragile X Foundation or the Fragile X Treatment and Research Center at UC Davis MIND Institute for information on finding a genetic counselor and an experienced, reputable lab to process your test.
Testing for Fragile X only detects whether a person has the FMR1 gene mutation, and whether it's the full mutation or the premutation. It can not determine the degree to which an individual with the full mutation will be affected intellectually, behaviorally, or physically, or whether an individual with the premutation will be affected with FXTAS or FXPOI.
For more information on Fragile X and associated conditions, including more detailed explanations of the genetics/biology involved and available reproductive options for carriers, please visit the National Fragile X Foundation website.