Fragile X syndrome

Fragile X syndrome is a genetic condition that runs in families. It is the most common known genetic cause of intellectual disability and the most common known single-gene cause of autism. Fragile X syndrome is caused by a problem (mutation) in the FMR1 (fragile X mental retardation 1) gene; this problem is present in every cell of a person’s body (skin cells, blood cells, etc.). When there is a mutation in the FMR1 gene, a person’s body makes very little or none of the fragile X mental retardation protein (FMRP). The FMRP protein helps create other proteins the body needs and helps develop the synapses, which are the connections between our nerve cells. The lack of this protein affects a person’s development and causes intellectual disability (formerly known as mental retardation), developmental delay, and various physical characteristics. It can affect both males and females, though it generally affects males more severely.

Fragile X syndrome is part of a group known as the FMR1-related disorders. In addition to fragile X syndrome, this group includes fragile X-associated tremor/ataxia syndrome (FXTAS) and FMR1-related primary ovarian insufficiency (FXPOI). All the FMR1-related disorders can affect both men and women, with the exception of FXPOI (women only). All the FMR1-related disorders are passed from one generation to the next through mutation of the FMR1 gene, which is on the X chromosome. The most common cause of these FMR1-related disorders is having too many CGG repeats in the FMR1 gene. Every gene is made up of a string of nucleotide bases in a specific order; the nucleotide bases are A, T, G, and C. The length of each gene and the specific code are different, and sometimes specific parts of the code are repeated. For the FMR1 gene, having up to 44 CGG trinucleotide ("tri" meaning "three", "nucleotide" meaning "nucleotide base") repeats is typical. A person who has between 45 and 54 CGG repeats is considered "gray zone" or "borderline", meaning the potential exists for that repeat to become larger and then be considered a premutation. These individuals do not show any signs of any of the FMR1-related disorders. When a person has between 55 and 200 CGG repeats, they have the premutation and can have either FXTAS and/or FXPOI. If a person has over 200 CGG repeats in their FMR1 gene and it becomes methylated (meaning "turned off"), they have fragile X syndrome, meaning they have the full mutation and will have signs of the disorder. The number of CGG repeats in the FMR1 gene can be determined through molecular testing of the FMR1 gene.

While there is no cure for fragile X syndrome, FXTAS, or FXPOI, there are treatments and strategies to help individuals with FMR1-related disorders and their families. For fragile X syndrome, this can include special education, medicines to help address issues with behavior, and routine treatment of medical problems. Individuals with FXTAS require supportive care for both motor and mental issues. Women with FXPOI should meet with a reproductive endocrinologist, which is a doctor who specializes in hormone-related issues with reproduction/pregnancy. Individuals seeking additional information and support relating to fragile X syndrome should visit the website for the National Fragile X Foundation at https://fragilex.org/.

Fragile X syndrome is also known by the following names:

X-linked mental retardation and macroorchidism
Martin-Bell syndrome
fragile X mental retardation
FRAXA syndrome
fra(X) syndrome
marker X syndrome
Escalante’s syndrome
FXS

There are multiple names for fragile X syndrome, so it is important to make sure families and doctors are on the same page and using the same name. If a doctor is using an unfamiliar term, ask them if they are using a different name for fragile X syndrome. Another reliable source for alternative names for fragile X syndrome is the Genetics Home Reference website, which can be found at Genetics Home Reference Fragile X Synonyms.

Testing of the FMR1 gene has helped estimate how common fragile X syndrome is in the population. Studies have shown that approximately 16 to 25 males in every 100,000 males has fragile X syndrome. Researchers believe the number of females with fragile X syndrome is half the number of males who are affected (approximately 8 to 12 females in every 100,000 females). For another way to look at these numbers, studies have shown that approximately 1 in 3600 males and 1 in 4000 to 6000 females has fragile X syndrome (the full mutations, greater than 200 CGG repeats).

More information and support for those with fragile X syndrome and their families can be found by visiting the National Fragile X Foundation.

Fragile X syndrome is most often abbreviated as FXS.

Frequently Asked Questions About Fragile X syndrome

Who else in my family should be tested for fragile X syndrome?

The following people should be tested for Fragile X syndrome:

Where do I find other people with fragile X syndrome?

The National Fragile X Foundation supports local, independently run Community Support Networks in each state as well as digital support groups for parents, siblings, and self-advocates for persons and families affected by fragile X syndrome. Please visit their Community Support Network page for more information: https://fragilex.org/living-with-fragile-x/community-support/.

What support groups are there for fragile X syndrome?

Helpful support groups and resources for fragile X syndrome include:

What specialist doctors should I see with fragile X syndrome?

Because individuals with fragile X syndrome often have varying degrees of developmental delay, it is recommended that they see a Developmental-Behavioral Pediatrician. It is also recommended that they seek additional guidance from a physician and/or clinic with experience with fragile X syndrome to coordinate their overall care specific to their diagnosis of fragile X syndrome. A list of these clinics can be found at the National Fragile X Foundation website by visiting https://fragilex.org/treatment-intervention/fragile-x-clinics/.

Additional specialists that an individual with fragile X syndrome may need to seek support from include:

What makes fragile X syndrome worse?

How severely a person is affected by fragile X syndrome depends primarily on whether their fragile X mental retardation 1 (FMR1) gene is partially turned off (partially methylated) or fully turned off (fully methylated) and how much fragile X mental retardation protein (FMRP) their body is making. The less protein present in the body and brain, the more severely affected they will be since this protein plays a crucial role in the development of the nerve cells and their connections. External environmental factors (for example, diet, exercise, etc.) will not affect the severity of fragile X syndrome. Early diagnosis of fragile x syndrome can allow for early intervention that may improve quality of life; these interventions may include speech therapy, special education, psychotherapy, and more. For more information about early intervention, please visit the Center for Parent Information and Resources.

What is the usual abbreviation for fragile X syndrome?

Fragile X syndrome is most often abbreviated as FXS.

What is the first sign parents notice in a child with fragile X syndrome?

One of the first delays parents notice in their child with fragile X syndrome is speech delay. This is often treated symptomatically with speech therapy and then testing is done at a later date if the delay continues. Parents also notice stereotypic (repetitive, without function) behaviors such as hand-flapping, gaze avoidance, global developmental delay, and autism-like behaviors. Physically, individuals with fragile X syndrome most notably have a long narrow face with protruding ears, but these features may not be noticeable until puberty or later.

What is fragile X syndrome?

What happens because of the CGG trinucleotide expansion in fragile X syndrome?

In fragile X syndrome, the body silences or turns off the Fragile X mental retardation 1 (FMR1) gene due to the CGG trinucleotide expansion of greater than 200 repeats by a process called hypermethylation. The way that genes work in the body is that the gene serves as a blueprint, and each gene is translated into a protein that ultimately carries out the job of that gene in the body. This process happens multiple times so that the body has the proper amount of that specific protein (which varies depending on which gene and how much is needed).

Because the FMR1 gene is silenced, little to no fragile X mental retardation protein (FMRP) is made. The lack of FMRP leads to abnormal brain development, which causes the cognitive and developmental delay seen in people with Fragile X syndrome. FMRP plays a role in the production of other proteins too; not having the proper amount of these proteins can lead to the other characteristics we see in persons with fragile X syndrome.

What genetic change causes fragile X syndrome?

Fragile X syndrome is caused by a CGG trinucleotide ("tri" meaning "three", "nucleotide" meaning "nucleotide base") repeat expansion of greater than 200 repeats in the promoter region of the fragile X mental retardation 1 (FMR1) gene on the X chromosome and abnormal hypermethylation (turning off of the gene). In very rare cases (1% or less), gene mutations at locations other than the CGG repeat in the FMR1 gene have been described.

Many different genetic testing laboratories are able to analyze the FMR1 gene. To learn what laboratories are currently offering testing, please visit GeneTests and enter "fragile X syndrome" into the search bar.

What diseases look similar to fragile X syndrome?

Fragile X syndrome often looks very similar to Autism Spectrum Disorder (ASD). Developmental delay, cognitive impairment, stereotypic (repetitive, without function) behaviors such as hand flapping and body rocking, and gaze avoidance are features present both in individuals with autism and individuals with fragile X syndrome. Individuals who are suspected to have ASD should be tested for fragile X syndrome. Individuals who have unexplained developmental delay, especially speech delay, and cognitive impairment should also be tested for fragile X syndrome.

The following disorders and syndromes can also be included in the list of possible diagnoses when a person is being evaluated and can look similar to fragile X syndrome:

What are the main physical features and medical issues associated with fragile X syndrome?

Most infants and younger children do not show any obvious physical signs of fragile X syndrome; physical features start to be noticeable around the time of puberty. Some persons with fragile X syndrome have more physical characteristics, and some have fewer.

Common physical features of fragile X syndrome include: a long narrow face, prominent forehead, protruding ears, high-arched palate, flat feet, and macroorchidism (abnormally large testes). Connective tissue (the tissues of the body that bind, connect, and support other tissues and organs) issues can also be seen, including hyperflexibility of the joints (double-jointed) and cardiac issues such as mitral valve prolapse. Strabismus (abnormal alignment of the eyes; cross-eyed), seizures, chronic ear infections, sleep disorders, gastroesophageal reflux, and weight gain are believed to be more common in individuals with fragile X syndrome. There is still some controversy regarding the association of GI disturbances (such as loose stool) and obstructive sleep apnea with fragile X syndrome.

To learn more information and find a fragile X syndrome clinic near you, please visit https://fragilex.org/treatment-intervention/fragile-x-clinics/.

What are the main cognitive and behavior symptoms of fragile X syndrome?

Fragile X syndrome leads to developmental delays including speech delays and intellectual disability (formerly known as mental retardation) of varying degrees from severe cognitive impairment to mild learning disabilities. Individuals with fragile X syndrome can also have extreme anxiety, sensory disorders, social withdrawal, aberrant behavior, aggressive behavior, and stereotypic (repetitive and without function) behaviors like hand-flapping and body rocking. Many of these behaviors, including gaze avoidance, can cause fragile X syndrome to be mistaken for autism. While people with fragile X syndrome can also have autism, fragile X syndrome is a separate disorder with additional signs and symptoms.

What are the first steps after the initial diagnosis of fragile X syndrome?

Once a person is diagnosed with fragile X syndrome, their doctor should discuss a variety of issues with the family, including treatment options, referrals to specialists or a specialty clinic, and genetic counseling for family members. The following is a list of what steps should be taken after a person is diagnosed with fragile X syndrome:

Is there variable expression of fragile X syndrome?

Not all individuals with fragile X syndrome will be affected to the same degree. Individuals who are not making any FMRP protein are generally more severely affected and often present with moderate intellectual disability, autism-like features, and more severe anxiety and ADD. Individuals (male or female) who have more FMRP protein present due to partial methylation (only partial turning off of the gene) may show less signs and have less severe symptoms of fragile X syndrome. Additionally, females, due to the presence of a “good” X chromosome that has an FMR1 gene that is working (turned on), may also be less severely affected and only present with mild learning disabilities. Due to the way that fragile X syndrome is inherited, males with fragile X syndrome tend to be more severely affected than females with fragile X syndrome.

Is there newborn testing for fragile X syndrome?

Testing of the FMR1 gene is available for infants/newborns suspected to have fragile X syndrome. The same blood test that is done for adults is done for children and infants/newborns. The "gold standard" for fragile X syndrome testing has been polymerase chain reaction (PCR) testing to determine the number of CGG repeats and Southern blot analysis, which is another method used to detect the number of repeats that can also determine whether the gene is methylated (turned off) or not. This type of testing must be ordered by a physician or genetic counselor who can interpret the results for the patient and their family.

Fragile X syndrome can be diagnosed prenatally but confirmation of an expanded FMR1 gene in the family is required before testing of at-risk pregnancies can take place. Prenatal testing for fragile X syndrome and be done by testing cells from the amniotic fluid (the liquid in the sac that contains the baby) obtained by amniocentesis (a procedure where a needle is inserted with ultrasound guidance into the belly of a pregnant woman to get amniotic fluid). Another option is to obtain cells for testing by a technique called CVS (chorionic villus sampling), in which a needle is inserted through the belly or vaginally to obtain a tiny bit of the placenta. These cells from the placenta have the same genetic makeup as the baby, and can be tested to determine the number of CGG repeats in the FMR1 gene. However, the test results from cells obtained by CVS need to be interpreted with caution, because methylation status (whether a gene is turned off or not) has not yet been determine at that point in prenatal development. Follow up amniocentesis may be required to clarify an unclear or inconclusive test result by CVS. The collection of cells through amniocentesis or CVS must be done by a physician and the genetic testing must be ordered by a physician or genetic counselor who can interpret the results for the patient and their family. To find a genetic counselor, please visit [link url="www.nsgc.org” target=”_blank”>www.nsgc.org and click the "Find a Genetic Counselor" link to locate a provider in your area.

Is there more than one test for fragile X syndrome?

The "gold standard" for fragile X syndrome testing has been polymerase chain reaction (PCR) testing to determine the number of CGG repeats and Southern blot analysis, which is another method used to detect the number of repeats that can also determine whether the gene is methylated (turned off) or not. Most (greater than 99%) mutations in the FMR1 gene are due to an increased number of CGG repeats. Less than 1% of mutations are due to deletions or duplications in/of the FMR1 gene (this means loss or gain of genetic material) or sequence variants (a small change in the DNA code of the FMR1 gene). The technology used to detect these types of genetic changes include a method called FISH (fluorescent in situ hybridization), deletion/duplication analysis, and sequence analysis.

Protein testing to look at the amount of FMRP (fragile X mental retardation protein) is available but is not performed routinely. This test may be useful to screen males who have intellectual disability (mental retardation) but no diagnosis yet, but this screening test would not provide a definitive diagnosis. Testing of the FMR1 gene would still be needed to confirm whether or not that person has fragile X syndrome.

All of this testing must be ordered by a physician or genetic counselor who can interpret the results for the patient and their family. A full list of the laboratories currently offering testing for fragile X syndrome can be found by visiting GeneTests and entering "fragile X syndrome" into the search box.

Is there clinical research going on for fragile X syndrome?

There are several clinical trials and research opportunities for individuals with fragile X syndrome.
You can find a list of current and past clinical trials occurring in the United States for individuals with fragile X syndrome at [link url="www.clinicaltrials.gov” target=”_blank”>www.clinicaltrials.gov by typing “Fragile X syndrome” in the “search for studies” field.
The National Fragile X Foundation also has a list of open research opportunities for families and individuals with fragile X syndrome at https://fragilex.org/research/clinical-trials-opportunities-for-families/.
FRAXA Research Foundation has a list of ongoing clinical trials for families and individuals with fragile X syndrome at http://www.fraxa.org/toward-a-cure/clinical-trials/.

Is there a difference in testing blood, saliva, or a biopsy for fragile X syndrome?

DNA analysis for fragile X syndrome detecting the CGG trinucleotide repeat expansion in the FMR1 gene can be done on blood, saliva, and skin biopsy samples. All samples can be tested with the same level of accuracy of detection. However, the fastest way to obtain clinical results and the preferred method by laboratories is by testing a blood sample.

Some individuals with fragile X syndrome have mosaicism, meaning they have cells in their body that have a different genetic makeup than other cells. In the case of fragile X syndrome, someone could be less severely affected because they are mosaic, meaning that only some of their body tissues (cells) have the full mutation in the FMR1 gene of greater than 200 repeats. The other body tissues may have FMR1 genes with typical repeat lengths (45 CGG repeats or less). Depending on what tissues of the body have the mutation and which do not, testing by different methods (blood, saliva, or skin biopsy) may give different genetic results.

How is fragile X syndrome inherited?

The Fragile X mental retardation 1 (FMR1) gene is found on the X chromosome, meaning fragile X syndrome is an X-linked disorder and is passed from one generation to the next on the X chromosome. Typical men have one X chromosome and one Y chromosome and typical women have two X chromosomes. When a child is conceived, that child inherits one of their mother’s X chromosomes, and either another X chromosome from their father (resulting in a female child, XX) or the Y chromosome from father (resulting in a male child, XY). Individuals who have 55 to 200 CGG trinucleotide repeats are said to have a premutation and are called premutation carriers. Men who have the premutation will pass their relatively stable repeat size to all of their daughters because they pass their affected X chromosome to their daughters. Any sons of men who have the premutation can NOT inherit the premutation since sons inherit only a Y chromosome from their father. Women who have the premutation can pass any of the following to their sons and daughters who receive the affected X chromosome:

How do I get tested for fragile X syndrome?

Your doctor or genetic counselor can test a person for fragile X syndrome by using their blood to look at their DNA (their genetic blueprint) and test the specific gene that causes fragile X syndrome when it is mutated: the FMR1 gene. There are many different laboratories that offer FMR1 gene testing either as a single gene test or tested alongside other genes. A full list of the laboratories currently offering testing for fragile X syndrome can be found by visiting GeneTests and entering "fragile X syndrome" into the search box. The "gold standard" for fragile X syndrome testing has been polymerase chain reaction (PCR) testing to determine the number of CGG repeats and Southern blot analysis, which is another method used to detect the number of repeats that can also determine whether the gene is methylated (turned off) or not. This type of testing must be ordered by a physician or genetic counselor who can interpret the results for the patient and their family. If the FMR1 gene is the only gene that is tested, the results usually take 1-3 weeks (depending on the laboratory). If other genes are tested in addition to FMR1, then the results could take several weeks longer to come back. The price of genetic testing is ever-changing, and depends on several factors including deductible status, copays, insurance guidelines, financial assistance (if applicable), and current pricing. More recently, technology has brought the cost of genetic testing down dramatically. A physician or genetic counselor can help advise patients and their families as to what the cost of genetic testing would be to them and counsel them on their options and assistance programs (if needed).

To learn more about testing and find a clinic specializing in fragile X syndrome near you, please visit https://fragilex.org/treatment-intervention/fragile-x-clinics/. To find a genetic counselor, please visit [link url="www.nsgc.org” target=”_blank”>www.nsgc.org and click the "Find a Genetic Counselor" link to locate a provider in your area.

How do I find a center of excellence in fragile X syndrome?

The National Fragile X Foundation (NFXF) has an interactive map of fragile X syndrome specialty clinics located around the United States. This includes contact information for clinics that are members of the Fragile X Clinic and Research Consortium and who have demonstrated specialized knowledge of the specific needs of families living with fragile X syndrome and fragile X-associated disorders including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). To learn more information and find a clinic near you, please visit https://fragilex.org/our-research/fragile-x-clinics/.

How do I find a center of excellence in fragile X syndrome if I am not in the United States?

The National Fragile X Foundation (NFXF) maintains a list of international clinics specializing in fragile X syndrome. This information can be found by visiting The National Fragile X Foundation maintains a list of international clinics specializing in Fragile X syndrome. https://fragilex.org/our-research/fragile-x-clinics/international-support-clinics/.

How common is fragile X syndrome?

More information and support for those with fragile X syndrome and their families can be found by visiting the National Fragile X Foundation.

Does the CGG trinucleotide expansion get bigger in each generation in a family with fragile X syndrome?

Fragile X syndrome is an X-linked disorder that follows an inheritance pattern known as the Sherman Paradox. This phenomenon is also referred to as anticipation, where symptoms of a hereditary disease occur earlier (at a younger age) and can be more severe in the next generation. The first CGG trinucleotide mutation that results in a premutation size of 55 to 200 repeats occurs in one generation. As it passes from generation to generation, the premutation can increase in number of repeats (particularly in women). The larger the premutation size, the more unstable it becomes, and the more likely it is to expand to a full mutation in subsequent generations.

For example, a grandfather who has 60 CGG repeats and no FMR1-associated health issues passes on his FMR1 gene premutation to his daughter. In his daughter, the premutation has expanded to 65 repeats in her FMR1 gene; she experiences the symptoms of early menopause associated with FMR1-related primary ovarian insufficiency that can occur in women with the premutation. This daughter has a son, and the premutation expands further and becomes a full mutation of more than 200 repeats in his FMR1 gene. Therefore, her son would have fragile X syndrome and would show some or many of the characteristics associated with the syndrome. For information on what laboratories offer testing for the repeat number in the FMR1 gene, please visit GeneTests.

Do changes in the fragile X mental retardation 1 gene cause fragile x syndrome?

The CGG trinucleotide repeat expansion and hypermethylation (turning off) of the promoter region of the FMR1 gene does not predispose to fragile X syndrome, it causes fragile X syndrome. If a person has the full mutation of greater than 200 CGG repeats, that person has a diagnosis of fragile X syndrome. What symptoms of fragile X syndrome a person shows and how affected they are can vary, even between individuals in the same family. Some persons may be more mildly affected and have fewer symptoms, and some persons may be more severely affected and have many symptoms, but all individuals with greater than 200 repeats in their FMR1 gene are said to have fragile X syndrome. For more information about the signs and symptoms of fragile X syndrome, please visit The National Fragile X Foundation.

Can I donate to help with research for fragile X syndrome?

You can donate money to advance basic scientific research and translational research on fragile X syndrome to the FRAXA Research Foundation at http://www.fraxa.org/donate/.
You can also donate money to the National Fragile X Foundation to support families, research, and advocacy for fragile X syndrome at https://fragilex.org/support-the-nfxf/.

Can fragile X syndrome be treated?

In October 2017, the U.S. FDA granted orphan drug designation for OV101 (Ovid Therapeutics, Inc.) for the treatment of fragile X syndrome. Read more details at https://globenewswire.com/news-release/2017/10/10/1143685/0/en/Ovid-Therapeutics-Receives-Orphan-Drug-Designation-from-the-U-S-FDA-for-OV101-for-Treatment-of-Fragile-X-Syndrome.html.

Intervention also consists of symptom-based treatment, therapy, and support. Individuals with fragile X syndrome can be evaluated and treated for anxiety, ADD/ADHD, and other psychiatric concerns. They can also receive supportive therapies such as speech therapy, occupational therapy, applied behavior analysis, and medical treatment for any medical concerns that present. Early intervention with these treatments and services may help improve development and lives of children living with fragile X syndrome. Treatment currently focuses primarily on behavioral aspects of fragile X syndrome. For more information concerning intervention at any age. please visit the National Fragile X Foundation at https://fragilex.org/treatment-intervention/.

Are there other names for fragile X syndrome?