Fragile X syndrome is the most common form of inherited developmental disability. A problem with a specific gene causes the disease. Normally, the gene makes a protein you need for brain development. But the problem causes a person to make little or none of the protein. This causes the symptoms of Fragile X.

People with only a small change in the gene might not show any signs of Fragile X. People with bigger changes can have severe symptoms. These might include

• Intelligence problems, ranging from learning disabilities to severe intellectual disabilities
• Social and emotional problems, such as aggression in boys or shyness in girls
• Speech and language problems, especially in boys

A genetic blood test can diagnose Fragile X. There is no cure. You can treat some symptoms with educational, behavioral, or physical therapy, and with medicines. Getting treatment early can help.

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.

Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.

Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.

Fragile X syndrome (FXS) is a genetic disorder. Because of changes in their genetic material (specifically the FMR1 gene), people who have FXS do not make a protein called FMRP, which is needed for normal brain development. People who have other fragile X-associated disorders also have changes in the FMR1 gene, but usually make some of the FMRP protein.

Signs and symptoms of FXS include:

• Developmental delays (not sitting, walking, or talking at the same time as other children the same age);
• Learning disabilities (trouble learning new skills); and
• Social and behavior problems (such as not making eye contact, anxiety (fear, worry), trouble paying attention, hand flapping, acting and speaking without thinking, and being very active).

Having FXS is associated with an increased chance of intellectual disability, particularly in males, and of having autism spectrum disorder (ASD).

#1 FXS is genetic but there isn’t always a family history.

FXS means that a particular part of person’s FMR1 gene is much larger than usual. This part of the FMR1 gene ranges in size from person to person and can become bigger from one generation to the next. Therefore, many people with FXS have no family members with FXS symptoms. In some people who do not have FXS, this part of the FMR1 gene is a little larger than usual. These people are said to have a “premutation” in the FMR1 gene. FMR1 premutations run in families, and women with a premutation may give birth to children with FXS. Some people with a premutation have symptoms of fragile X-associated disorders, such as tremors and, in women, early menopause, although these symptoms are most commonly due to other causes.

#2 Babies aren’t routinely tested for FXS so families might not find out about FXS for a few years.

FXS requires a special blood test that is not usually included in the genetic tests that a pregnant woman gets or in the tests that are routinely done right after a baby is born. The only way to diagnose FXS is with a special blood test called the “FMR1 DNA Test for Fragile X.” The American Academy of Pediatrics recommends that children diagnosed with general developmental delays, intellectual disability, or autism spectrum disorder receive a genetic test for FXS.

#3 Not everyone who has FXS has the same symptoms, and FXS doesn’t just affect boys.

Both boys and girls can have FXS. FXS is more common in boys, and the symptoms are usually more severe in boys than in girls. Boys with FXS usually have some degree of intellectual disability, whereas girls range from normal intelligence to having an intellectual disability. But both boys and girls can have symptoms that range from mild to severe.

#4 There is no cure for FXS, but an early diagnosis can still help.

Even though there is no cure for FXS, there are educational, behavioral, and therapeutic services which can help. A diagnosis may also help families with family planning and connecting with support groups of other families affected by FXS. Learn more.

#5 CDC works with researchers and the fragile X community to improve the lives of people with the condition and their families.

To help individuals and families affected by FXS, we need to learn more about other conditions that commonly occur with FXS, the day-to-day lives of people living with FXS and their families, and the types of intervention and support that are most effective for individuals with FXS and their families.

Fragile X syndrome (FXS) is the most common known cause of inherited intellectual disability.FXS affects both males and females. Females often have milder symptoms than males.The exact number of people who have FXS is unknown, but a review of research studies estimated that about 1 in 7,000 males and about 1 in 11,000 females have been diagnosed with FXS.

• Among people affected with FXS, intelligence quotient (IQ) scores decline noticeably with age: adolescents and adults consistently score lower on IQ tests than young children.
• Young children with FXS often take longer than their peers without FXS to reach early developmental milestones and to develop nonverbal communication (communication without words, typically through gestures, facial expressions, and body language).
• Boys with FXS have an average IQ score under 55, significantly lower than the average IQ score of the general population, which is 100.

Fragile X Diagnosis

• The average age of FXS diagnosis for boys is 35 to 37 months. Girls are diagnosed at an average age of 42 months. [Read article]
• Parents are usually the first to notice symptoms of FXS at about 12 months of age for boys and 16 months of age for girls. [Read article]
  • Parents reported repeat healthcare visits before their healthcare provider diagnosed developmental delay at an average age of 20 months for boys and 26 months for girls.
  • Health professionals typically diagnosed FXS about 16 months after confirming a developmental delay.
• About 4 in 10 families reported that they visited a health professional at least 10 times before their child was diagnosed with FXS. [Read article]

Co-Occurring Conditions and Characteristics

• A national parent survey found that most people with FXS had been diagnosed or treated for other conditions that occur together (co-occurring) with FXS. [Read scientific summary]

• A study of 557 people with FXS between 3 and 21 years of age found that
  • Just over 4 in 10 people had both FXS and autism spectrum disorder (ASD).
  • People with both FXS and ASD were about 3 times more likely to experience seizures than people with FXS alone.
  • Approximately 4 in 10 people with both FXS and ASD had sleep problems that required treatment, compared to 3 in 10 people with FXS alone.
  • There was a higher proportion of attention problems, hyperactivity, hypersensitivity/over reactivity, perseverative/obsessive compulsive behavior, and irritability/aggressive behavior/agitation/ self-injury among those with both FXS and ASD as compared to those with FXS alone.
  • Aggressive/disruptive behavior was the only behavior treated with medicine more often in people with both FXS and ASD compared to those with just FXS. About 4 in 10 people with both FXS and ASD were treated with medicine for aggressive/disruptive behavior compared with less than 2 in 10 people with FXS alone.
  • Compared to children who only have ASD, children with both FXS and ASD may be less likely to receive Behavior Therapy.
• About 3 in 10 boys with FXS but only 2 in 10 typically-developing boys are obese.

Adult Life of Men and Women with FXS

• Among adults with FXS, men are less likely than women to be able to read books with new words or ideas, speak using complex sentences, or speak at a typical speed.

• • A national family survey of adults with FXS showed that
    • About 4 in 10 women with FXS achieved a high or very high level of independence in adult life compared to about 1 in 10 men.
    • About 4 in 10 women with FXS lived independently, often with a spouse or romantic partner, compared to 1 in 10 men who lived independently, and rarely with a spouse or romantic partner.
    • About 8 in 20 women with FXS required no assistance with activities of daily living compared to 1 in 20 men.
    • The majority of women with FXS had at least a high school diploma; the majority of men did not have a high school diploma.
    • Almost half of women with FXS had full-time jobs, compared to 2 in 10 men.

Premutation

People with a fragile X premutation do not have fragile X syndrome but might have another fragile X-associated disorder. Some people with fragile X premutations have noticeable symptoms, and others do not.

• The exact number of people who have a fragile X premutation is unknown. Studies estimate that between 1 in 148 and 1 in 291 females and 1 in 290 and 1 in 855 males in the United States may have a fragile X premutation.
• These numbers are important because both men and women are at risk for having symptoms related to fragile X-associated disorders.
  • Women with a premutation reported their last menstrual cycle at an earlier age (on average, 48 years) than women without a premutation (on average, 51 years).
  • Men and women with a premutation were more than four times as likely to report dizziness or fainting and more than twice as likely to report numbness compared to people without a premutation.
• People with a premutation are almost twice as likely to have a child with a disability as people without a premutation.
• A national parent survey found that males and females with fragile X premutation were more likely to have been diagnosed or treated for other conditions that occur together with FXS compared to people who did not have a premutation.

Costs

A study analyzing the employment impact and financial burden experienced by families of children with FXS found that

• With each additional condition occurring with FXS, there was greater financial burden for the family.
• About half of families reported that FXS caused a financial burden.
• In more than 6 in 10 families, parents changed work hours, stopped working, or turned down a job because of having a child with FXS.
• Families reported that therapies accounted for about one-third of their FXS-related out-of-pocket expenses. An additional third of out-of-pocket expenses went to medicines and other medical costs, including genetic testing and developmental evaluations.

Fragile X syndrome is an inherited intellectual disability caused by a mutation in the FMR1 gene.

What is fragile X syndrome?

Fragile X syndrome is the most common form of inherited intellectual disability in males and is also a significant cause of intellectual disability in females. It affects about 1 in 4,000 males and 1 in 8,000 females and occurs in all racial and ethnic groups.

Nearly all cases of fragile X syndrome are caused by an alteration (mutation) in the FMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment inactivates (silences) the FMR1 gene, which prevents the gene from producing a protein called fragile X mental retardation protein. Loss of this protein leads to the signs and symptoms of fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely.

What are the symptoms of fragile X syndrome?

A boy who has the full FMR1 mutation has fragile X syndrome and will have moderate intellectual disability. They have a particular facial appearance, characterized by a large head size, a long face, prominent forehead and chin and protruding ears. In addition males who have fragile X syndrome have loose joints (joint laxity), and large testes (after puberty).

Affected boys may have behavioral problems such as hyperactivity, hand flapping, hand biting, temper tantrums and autism. Other behaviors in boys after they have reached puberty include poor eye contact, perseverative speech, problems in impulse control and distractibility. Physical problems that have been seen include eye, orthopedic, heart and skin problems.

Girls who have the full FMR1 mutation have mild intellectual disability.

Family members who have fewer repeats in the FMR1 gene may not have intellectual disability, but may have other problems. Women with less severe changes may have premature menopause or difficulty becoming pregnant.

Both men and women may have problems with tremors and poor coordination.

What does it mean to have a fragile X premutation?

People with about 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation (an intermediate variation of the gene). In women, the premutation is liable to expand to more than 200 repeats in cells that develop into eggs. This means that women with the FMR1 premutation have an increased risk of having a child with fragile X syndrome. By contrast, the premutation CGG repeat in men remains at the same size or shortens as it is passed to the next generation.

Males and females who have a fragile X premutation have normal intellect and appearance. A few individuals with a premutation have subtle intellectual or behavioral symptoms, such as learning difficulties or social anxiety. The difficulties are usually not socially debilitating, and these individuals may still marry and have children.

Males who have a premutation with 59 to 200 CGG trinucleotide repeats are usually unaffected and are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS). The fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by late-onset, progressive cerebellar ataxia and intention tremor in males who have a premutation. Other neurologic findings include short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.

The degree to which clinical symptoms of fragile X are present (penetrance) is age related; symptoms are seen in 17 percent of males aged 50-59 years, in 38 percent of males aged 60-69 years, in 47 percent of males aged 70-79 years, and in 75 percent or males aged 80 years or older. Some female premutation carriers may also develop tremor and ataxia.

Females who have a premutation usually are unaffected, but may be at risk for premature ovarian failure and FXTAS. Premature ovarian failure (POF) is defined as cessation of menses before age 40 years, has been observed in carriers of premutation alleles. A review by Sherman (2005) concluded that the risk for POF was 21 percent in premutation carriers compared to a 1 percent for the general population.

How is fragile X syndrome diagnosed?

There are very few outward signs of fragile X syndrome in babies, but one is a tendency to have a large head circumference. An experienced geneticist may note subtle differences in facial characteristics. Intellectual disability is the hallmark of this condition and, in females, this may be the only sign of the problem.

A specific genetic test (polymerase chain reaction [PCR]) can now be performed to diagnose fragile X syndrome. This test looks for an expanded mutation (called a triplet repeat) in the FMR1 gene.

How is fragile X syndrome treated?

There is no specific treatment available for fragile X syndrome. Supportive therapy for children who have fragile X syndrome includes:

• Special education and anticipatory management including avoidance of excessive stimulation to decrease behavioral problems.

• Medication to manage behavioral issues, although no specific medication has been shown to be beneficial.

• Early intervention, special education and vocational training.

• Vision, hearing, connective tissue problems, and heart problems when present are treated in the usual manner.

Is fragile X syndrome inherited?

This condition is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. In most cases, males experience more severe symptoms of the disorder than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Fragile X results from a change or mutation in the Fragile X Mental Retardation 1 (FMR1) gene, which is found on the X chromosome. The gene normally makes a protein called Fragile X Mental Retardation Protein, or FMRP. This protein is important for creating and maintaining connections between cells in the brain and nervous system. The mutation causes the body to make only a little bit or none of the protein, which often causes the symptoms of Fragile X.

Not everyone with the mutated FMR1 gene has symptoms of Fragile X syndrome, because the body may still be able to make FMRP. A few things affect how much FMRP the body can make:

• The size of the mutation. Some people have a smaller mutation (a lower number of repeats) in their FMR1 gene, while others have big mutations (a large number of repeats) in the gene. If the mutation is small, the body may be able to make some of the protein. Having the protein available makes the symptoms milder.
• The number of cells that have the mutation. Because not every cell in the body is exactly the same, some cells might have the FMR1 mutation while others do not. This situation is called mosaicism (pronounced moh-ZAY-uh-siz-uhm). If the mutation is in most of the body’s cells, the person will probably have symptoms of Fragile X syndrome. If the mutation is in only some of the cells, the person might not have any symptoms at all or only mild symptoms.
• Being female. Females have two X chromosomes (XX), while males have only one. In females, if the FMR1 gene on one X chromosome has the mutation, the FMR1 gene on the other X chromosome might not have the mutation. Even if one of the female’s genes has a very large mutation, the body can usually make at least some FMRP, leading to milder symptoms.

Normal Function

The FMR1 gene provides instructions for making a protein called FMRP. This protein is present in many tissues, including the brain, testes, and ovaries. In the brain, it may play a role in the development of connections between nerve cells (synapses), where cell-to-cell communication occurs. The synapses can change and adapt over time in response to experience (a characteristic called synaptic plasticity). FMRP may help regulate synaptic plasticity, which is important for learning and memory. The protein's role in the testes and ovaries is not well understood.

Researchers believe that FMRP acts as a shuttle within cells by transporting molecules called messenger RNA (mRNA), which serve as the genetic blueprint for making proteins. FMRP likely carries mRNA molecules from the nucleus to areas of the cell where proteins are assembled. FMRP also helps control when the instructions in these mRNA molecules are used to build proteins, some of which may be important for functioning of the nerves, testes, or ovaries.

One region of the FMR1 gene contains a particular DNA segment known as a CGG trinucleotide repeat, so called because this segment of three DNA building blocks (nucleotides) is repeated multiple times within the gene. In most people, the number of CGG repeats ranges from fewer than 10 to about 40. This CGG repeat segment is typically interrupted several times by a different three-base sequence, AGG. Having AGG scattered among the CGG triplets appears to help stabilize the long repeated segment.

Health Conditions Related to Genetic Changes

Fragile X-associated primary ovarian insufficiency

A trinucleotide repeat expansion in the FMR1 gene increases a woman's risk of developing a condition called fragile X-associated primary ovarian insufficiency (FXPOI). In this condition, the CGG trinucleotide repeat in the FMR1 gene is repeated about 55 to 200 times, which is referred to as a premutation. Women who develop FXPOI may experience irregular menstrual cycles, an inability to have children (infertility), early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH). About 16 to 20 percent of women with a premutation have FXPOI, which leads to abnormal menstrual cycles and elevated FSH levels before age 40 and often causes infertility.

For unknown reasons, the premutation leads to the overproduction of abnormal FMR1 mRNA that contains the repeat expansion. Researchers believe that the abnormal mRNA causes the signs and symptoms of FXPOI. It is thought that the mRNA attaches (binds) to other proteins and keeps them from performing their functions. In addition, the repeats make producing protein from the blueprint more difficult, and consequently, some people with the FMR1 gene premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (described above), such as prominent ears, and may experience emotional problems such as anxiety or depression.

Fragile X-associated tremor/ataxia syndrome

Men, and some women, with an FMR1 gene premutation are at increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is characterized by progressive problems with movement (ataxia), tremor, memory loss, reduced sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes. The disorder usually develops late in life and worsens over time.

As in FXPOI (described above), the premutation causes overproduction of abnormal FMR1 mRNA containing the expanded repeat region, and researchers believe that this abnormal mRNA causes FXTAS. The abnormal mRNA has been found in clumps of proteins and mRNA (intranuclear inclusions) that are found in brain and nerve cells in people with FXTAS. Some researchers speculate that the proteins found in the inclusions cannot perform their normal functions, which could lead to the signs and symptoms of FXTAS. Another hypothesis is that the inclusions could cause the death of nerve cells important for movement and mental function. However, the exact role the inclusions play in the development of the disorder is unknown.

Fragile X syndrome

Almost all cases of fragile X syndrome are caused by an expansion of the CGG trinucleotide repeat in the FMR1 gene. In these cases, CGG is abnormally repeated more than 200 times, which makes this region of the gene unstable. As a result, the FMR1 gene is turned off (silenced) and makes very little or no protein. A loss or shortage of FMRP disrupts normal functions of nerve cells and, consequently, the nervous system, causing severe learning problems, intellectual disability, and the other features of fragile X syndrome. About one-third of males with an FMR1 gene mutation and the characteristic signs of fragile X syndrome also have features of autism spectrum disorders that affect communication and social interaction.

Fewer than 1 percent of all cases of fragile X syndrome are caused by other changes in the FMR1 gene. Mutations may delete part or all of the gene or change one of the building blocks (amino acids) used to make FMRP. These genetic changes alter the 3-dimensional shape of the protein or prevent any protein from being produced. The abnormal or missing protein disrupts nervous system functions, leading to the signs and symptoms of fragile X syndrome.

Other disorders

The FMR1 gene premutation (55 to 200 CGG repeats) is associated with a variety of neurological problems grouped as fragile X-associated neuropsychiatric disorders (FXAND). Children with a premutation can have learning disabilities, attention-deficit/hyperactivity disorder (ADHD), intellectual disability, or developmental disorders that affect communication and social interaction (such as autism spectrum disorder). Some adults with a premutation have emotional or psychiatric problems, such as depression, anxiety, obsessive-compulsive disorder, extreme tiredness (fatigue), chronic pain, or difficulty sleeping (insomnia). It is estimated that approximately half of people with a premutation have one or more of these problems. The neuropsychiatric abnormalities are thought to be caused by an abundance of abnormal FMR1 mRNA that impairs the function of other proteins.

Other Names for This Gene

• FMR1_HUMAN
• FMRP
• FRAXA
• Protein FMR-1

Genomic Location

Fragile X syndrome and its associated conditions are caused by changes (mutations) in the FMR1 gene found on the X chromosome. This mutation affects how the body makes the Fragile X Mental Retardation Protein, or FMRP. The mutation causes the body to make only a little bit or none of the protein, which can cause the symptoms of Fragile X.

In a gene, the information for making a protein has two parts: the introduction, and the instructions for making the protein itself. Researchers call the introduction the promoter because of how it helps to start the process of building the protein.

The promoter part of the FMR1 gene includes many repeats—repeated instances of a specific DNA sequence called the CGG sequence. A normal FMR1 gene has between 6 and 40 repeats in the promoter; the average is 30 repeats.

People with between 55 and 200 repeats have a premutation of the gene. The premutation may cause the gene to not work properly, but it does not cause intellectual and developmental disability (IDD). The premutation is linked to the disorders FXPOI and FXTAS. However, not all people with the premutation show symptoms of FXPOI or FXTAS.

People with 200 or more repeats in the promoter part of the gene have a full mutation, meaning the gene might not work at all. People with a full mutation often have Fragile X syndrome.

The number of repeats, also called the “size of the mutation,” affects the type of symptoms and how serious the symptoms of Fragile X syndrome will be.

Inheriting Fragile X Syndrome

Fragile X syndrome is inherited, which means it is passed down from parents to children. Anyone with the FMR1 gene mutation can pass it to their children. However, a person who inherits the gene mutation may not develop Fragile X syndrome. Males will pass it down to all of their daughters and not their sons. Females have a 50/50 chance to pass it along to both their sons and daughters. In some cases, an FMR1 premutation can change to a full mutation when it is passed from parent to child. Read more about how FMR1 changes as it is passed from parent to child.

Fragile X syndrome (FXS), is caused by changes in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. In addition to FXS, there are other fragile X-associated disorders that are caused by changes in FMR1. The FMR1 gene usually makes a protein called FMRP that is needed for brain development. Changes in the gene determine whether someone makes less or none of this protein, depending on how much the gene is changed. Fragile X-associated disorders include:

• Fragile X syndrome
• Fragile X-associated primary ovarian insufficiency
• Fragile X-associated tremor/ataxia syndrome

Fragile X Syndrome (Full Mutation)

Fragile X syndrome (FXS) is one of the most common causes of inherited intellectual disability. People who have FXS do not make the protein FMRP. In these people, the FMR1 gene has been turned off. Fragile X syndrome often results from a full mutation of the FMR1 gene.

Other Fragile X-Associated Disorders (Premutation)

People who have other fragile X-associated disorders (not FXS) have changes in their FMR1 gene but usually make some FMRP. In these people, the FMR1 gene is not turned completely off, but the gene does not function normally. Fragile X-associated disorders can be caused by this type of partial change, called a premutation of the FMR1 gene. People with a premutation of the FMR1 gene do not have FXS but may have another fragile X-associated disorder. Some people with a premutation may have noticeable symptoms, and others may not.

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) is a cause of infertility and early menopause among adult women. Women with a condition called primary ovarian insufficiency stop having menstrual cycles and have symptoms of menopause before 40 years of age. Women who have a premutation in their FMR1 gene are at higher risk for primary ovarian insufficiency and are at higher risk for having children who have FXS.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) is a disorder of the nervous system that can cause tremors and problems with walking, balance (also called ataxia), memory, and mood disorders among older adults. FXTAS can be caused by a premutation in the FMR1 gene.

Fragile X syndrome (FXS) is a genetic disorder. A genetic disorder means that there are changes to the person’s genes. FXS, or the risk for developing FXS, can be passed down from parents to children through genes.

Many people who have a family member with FXS may wonder what this means for their own health or for the health of other family members. If you are concerned or wish to learn more, you may want to talk to a healthcare provider or genetic counselor.

Below is some information to help you understand how FXS and some related conditions can be passed down through genes.

Genes

Each cell in the human body contains thousands of genes. Genes determine many things about the person. For example, what the person will look like and whether he or she is likely to have certain illnesses. In addition, genes have instructions for making proteins in the cells. Proteins are needed for the body to work correctly.

FXS is caused by a change (mutation) in a gene that scientists called the FMR1 gene. The FMR1 gene makes a protein the scientists called FMRP that is needed for brain development.

Chromosomes

Genes are found on chromosomes. Every human cell contains 23 pairs of chromosomes. People get their chromosomes from their parents. People get one of each pair of chromosomes from their mother and one of each pair from their father. The chromosomes that form the 23rd pair are called the sex chromosomes. They decide if a person is male or female. Females have two X chromosomes (XX), and males have one X and one Y chromosome (XY).

The FMR1 gene is on the X chromosome.

DNA

The chromosomes and genes have a special code called DNA. DNA has four chemical letters, called “bases”: A, C, T, and G. The order of the letters determines the information carried in each gene, like the way that a specific pattern of letters makes up the words in a sentence.

How FXS is Inherited

To understand how FXS is inherited, it helps to know about the changes in the FMR1 gene that cause FXS and other fragile X-associated disorders. There is a place in the FMR1 gene where the DNA pattern of the chemical letters, CGG, is repeated over and over again. Different people have different numbers of these CGG repeats, but most people have less than 45 repeats. People with FXS nearly always have more than 200 repeats, many more than normal. Having more than 200 repeats causes the FMR1 gene to “turn off” so that it can’t make FMRP (the protein made by the FMR1 gene). When a person’s FMR1 gene has more than 200 repeats, so that it can’t make FMRP, the person has FXS.

Each person is in one of the four groups shown below based on the number of CGG repeats in the person’s FMR1 gene. The number of CGG repeats that a person has can be determined by a blood test ordered by a healthcare provider or genetic counselor. People with different numbers of CGG repeats have different risks of developing fragile X-associated disorders and of having children with FXS.

A female has two copies of the FMR1 gene, one on each of her two X chromosomes. The number of CGG repeats on each copy of the FMR1 gene is usually different. For example, a female might have 30 CGG repeats on one copy of her FMR1 gene, but 70 CGG repeats on her other copy. The group a female is in (normal, intermediate, premutation, or full mutation, as shown below) is based on her FMR1 gene copy with the greatest number of CGG repeats. A male has only one copy of the FMR1 gene on his only X chromosome, so the group a male is in is based on the number of CGG repeats in that one copy.

Normal: 5 to 44 Repeats

Most males have about 5 to 44 repeats of the chemical letters, CGG, in their FMR1 gene and most females also have 5 to 44 repeats in each of their FMR1 genes. This is considered a normal number of repeats. People with a normal number of repeats do not have FXS and do not pass a higher chance for having FXS to their children.

Intermediate: 45 to 54 Repeats

People who have an intermediate number of repeats (45 to 54) do not have FXS and are not at risk for having children with FXS. However, they may have a slightly higher chance of having some symptoms related to other fragile X-associated disorders and may pass the slightly higher chance of having these disorders to their children.

Premutation: 55 to 200 Repeats

People who have 55 to 200 repeats are said to have a “premutation” in the FMR1 gene. They do not have FXS but they might have, or may later develop, other fragile X-associated disorders. In addition, people with a premutation can have children with a premutation or full mutation (FXS). However, the chances of having a child with a premutation or a full mutation are different for women with a premutation than they are for men with a premutation, as described below.

• The number of repeats in the egg cells of a woman with a premutation can increase from the premutation range (55 to 200 repeats) to the full mutation range (more than 200 repeats). Therefore, a woman with a premutation can pass on a full mutation. The more CGG repeats a woman with a premutation has, the more likely her child will inherit an FMR1 gene with a full mutation and, therefore, have FXS. With each pregnancy, a woman with a premutation in one of her FMR1 genes has a 50% chance of passing on either the premutation or a full mutation to her child (daughters or sons), and a 50% chance of not passing on either the premutation or the full mutation.
• A man with a premutation will pass on his premutation to his daughters, but not to his sons. A man with a premutation will not pass on a full mutation to any of his children.

Full Mutation (FXS): More than 200 Repeats

People with a full mutation (more than 200 repeats) have FXS.

• With each pregnancy, women have a 50% chance of passing fragile X on to their child (sons or daughters).

People with Fragile X do not all have the same signs and symptoms, but they do have some things in common. Symptoms are often milder in females than in males.

• Intelligence and learning. Many people with Fragile X have problems with intellectual functioning.
  • These problems can range from the mild, such as learning disorders or problems with mathematics, to the severe, such as an intellectual or developmental disability.
  • The syndrome may affect the ability to think, reason, and learn.
  • Because many people with Fragile X also have attention disorders, hyperactivity, anxiety, and language-processing problems, a person with Fragile X may have more capabilities than his or her IQ (intelligence quotient) score suggests.
• Physical. Most infants and younger children with Fragile X don’t have any specific physical features of this syndrome. When these children start to go through puberty, however, many will begin to develop certain features that are typical of those with Fragile X.
  • These features include a narrow face, large head, large ears, flexible joints, flat feet, and a prominent forehead.
  • These physical signs become more obvious with age.
• Behavioral, social, and emotional. Most children with Fragile X have some behavioral challenges.
  • They may be afraid or anxious in new situations.
  • They may have trouble making eye contact with other people.
  • Boys, especially, may have trouble paying attention or be aggressive.
  • Girls may be shy around new people. They may also have attention disorders and problems with hyperactivity.
• Speech and language. Most boys with Fragile X have some problems with speech and language.
  • They may have trouble speaking clearly, may stutter, or may leave out parts of words. They may also have problems understanding other people’s social cues, such as tone of voice or specific types of body language.
  • Girls usually do not have severe problems with speech or language.
  • Some children with Fragile X begin talking later than typically developing children. Most will talk eventually, but a few might stay nonverbal throughout their lives.
• Sensory. Many children with Fragile X are bothered by certain sensations, such as bright light, loud noises, or the way certain clothing feels on their bodies.
  • These sensory issues might cause them to act out or display behavior problems.

Healthcare providers often use a blood sample to diagnose Fragile X. The healthcare provider will take a sample of blood and will send it to a laboratory, which will determine what form of the FMR1 gene is present.

Prenatal Testing (During Pregnancy)

Pregnant women who have an FMR1 premutation or full mutation may pass that mutated gene on to their children. A prenatal test allows healthcare providers to detect the mutated gene in the developing fetus. This important information helps families and providers to prepare for Fragile X syndrome and to intervene as early as possible.

Possible types of prenatal tests include:

• Amniocentesis. A healthcare provider takes a sample of amniotic fluid, which is then tested for the FMR1 mutation.
• Chorionic villus sampling. A healthcare provider takes a sample of cells from the placenta, which is then tested for the FMR1 mutation.

Because prenatal testing involves some risk to the mother and fetus, if you or a family member is considering prenatal testing for Fragile X, discuss all the risks and benefits with your healthcare provider.

Prenatal testing is not very common, and many parents do not know they carry the mutation. Therefore, parents usually start to notice symptoms in their children when they are infants or toddlers. The average age at diagnosis is 36 months for boys and 42 months for girls.

Diagnosis of Children

Many parents first notice symptoms of delayed development in their infants or toddlers. These symptoms may include delays in speech and language skills, social and emotional difficulties, and being sensitive to certain sensations. Children may also be delayed in or have problems with motor skills such as learning to walk.

A healthcare provider can perform developmental screening to determine the nature of delays in a child. If a healthcare provider suspects the child has Fragile X syndrome, he/she can refer parents to a clinical geneticist, who can perform a genetic test for Fragile X syndrome.

There is no single treatment for Fragile X syndrome, but there are treatments that help minimize the symptoms of the condition. Individuals with Fragile X who receive appropriate education, therapy services, and medications have the best chance of using all of their individual capabilities and skills. Even those with an intellectual or developmental disability can learn to master many self-help skills.

Early intervention is important. Because a young child’s brain is still forming, early intervention gives children the best start possible and the greatest chance of developing a full range of skills. The sooner a child with Fragile X syndrome gets treatment, the more opportunity there is for learning.

Most children with Fragile X can benefit from special education services that are tailored to their particular strengths and weaknesses. Educational treatments should take the child’s specific symptoms of Fragile X into account to promote the best learning environment.

Eligibility for Special Education

Most children with Fragile X are eligible for free, appropriate public education under federal law. Although a medical diagnosis does not guarantee access to special education services, most children with Fragile X will have certain cognitive or learning deficits that makes them eligible for services. Parents can contact a local school principal or special education coordinator to learn how to have a child examined to see if he or she qualifies for services under the Individuals with Disabilities Education Act.

Suggestions for Working with Individuals with Fragile X

Everyone with Fragile X is unique. However, those with this disorder often share some particular behaviors and intellectual characteristics. For example, children with Fragile X can easily become overwhelmed by crowds, noise, and touch. Other common characteristics include weak abstract thinking skills and poor quantitative (measuring and counting) skills. However, these children often have unique strengths as well, including visual memory. By taking these unique strengths and weaknesses into account, teachers can promote the best learning for these children.

Suggestions:

• Know the learning style of the individual.
• Develop a consistent daily schedule or routine.
• Use visual signs (pictures, sign language, logos, words) and concrete examples or materials to present ideas, concepts, steps, etc.
• Prepare the individual for any changes in routine by explaining these changes ahead of time, possibly by using visual signs.
• Include functional goals with academic goals; for instance, teach the individual the names of different pieces of clothing as well as how to dress himself/herself.
• Provide opportunities for the child to be active and move around.
• Use computers and interactive educational software.
• Provide a quiet place where the child can first retreat and then regroup.

Teachers can use the National Fragile X Foundation’s Lesson Planning Guide for Fragile X to learn more about the best strategies for teaching children with Fragile X.

What Type of Classroom

In general, there are three options for the classroom placement of a child with Fragile X, based on that child’s specific abilities and needs:

• Full inclusion in a regular classroom
• Inclusion with “pull-out” services
• Full-time special education classroom

Placement decisions should be based on each child’s needs and abilities.

The Individualized Educational Plan (IEP)

If a child with Fragile X syndrome qualifies for special services, a team of people will work together to design an IEP for the child. The team may include parents or caregivers, teachers, a school psychologist, and other specialists in child development or education. The IEP includes specific learning goals for that child, based on his or her needs and capabilities. The team also decides how best to carry out the IEP. It reaches a consensus on classroom placement for the child, determines any devices or special assistance the child needs, and identifies the specialists who will work with the child.

The special services team should evaluate the child on a regular basis. The team can chart progress and decide whether changes in treatment are needed (for instance, changes to the IEP, in classroom placement, or in the services provided).

To this point, the Food and Drug Administration (FDA) has not approved any drugs specifically for the treatment of Fragile X or its symptoms. But in many cases, medications are used to treat certain symptoms of Fragile X syndrome, as shown in the chart below. NICHD does not endorse or support the use of any of these medications in treating the symptoms of Fragile X syndrome, or for other conditions for which the medications are not FDA approved.

Medication is most effective when paired with therapy designed to teach new coping or behavioral skills. Not every medication helps every child.

Please note that some of these medications carry serious risks. Others may make symptoms worse at first, or they may take several weeks to become effective. Doctors may have to try different dosages or combinations of medications to find the most effective plan. Families, caregivers, and doctors need to work together to ensure that a medication is working and that the medication plan is safe.

This chart is meant for reference ONLY and should not take the place of a healthcare provider’s advice. Discuss any questions about medication with a healthcare provider.

ADD: attention deficit disorder; ADHD: attention deficit hyperactivity disorder; TTS: transdermal therapeutic system.

A variety of professionals can help individuals with Fragile X syndrome and their families manage the symptoms of the disorder. Those with Fragile X might benefit from services provided by several different specialists:

• Speech-language therapists can help people with Fragile X syndrome improve their pronunciation of words and sentences, slow down their speech, and use language more effectively.
• Occupational therapists help find ways to adjust tasks and conditions to match a person’s needs and abilities.
• Physical therapists design activities and exercises that help build motor control and improve posture and balance.
• Behavioral therapists try to understand why someone with Fragile X acts out, and they create ways and strategies for avoiding or preventing these situations from occurring while also teaching better or more positive ways to respond to situations.

Fragile X Syndrome (FXS) often occurs with other conditions. Some of these conditions include anxiety, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, depression, difficult peer relationships, intellectual disabilities, and learning disorders.

Anxiety

There are many different types of anxiety disorders with many different causes and symptoms. These include generalized anxiety disorder, panic disorder, separation anxiety, selective mutism, and different types of phobias. Separation anxiety is most common among young children. These children feel very worried when they are apart from their parents.

Attention-Deficit/Hyperactivity Disorder (ADHD)

Children with attention-deficit/hyperactivity disorder (ADHD) have trouble paying attention and controlling impulsive behaviors. They might act without thinking about what the result will be and, in some cases, they are also overly active. It is normal for children to have trouble focusing and behaving at one time or another. However, these behaviors continue beyond early childhood (0-5 years of age) among children with ADHD. Symptoms of ADHD can continue and can cause difficulty at school, at home, or with friends.

Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a developmental disability that can cause significant social, communication and behavior challenges. People with ASD handle information in their brain differently than other people.

ASD is a spectrum disorder which means that ASD affects each person differently and can range from very mild to severe. People with ASD may share some similar symptoms, such as problems with social interaction but there are differences in when the symptoms start, how severe they are, and the specifics of the symptoms.

Depression

Everyone feels worried, anxious, sad, or stressed from time to time. However, if these feelings do not go away and they interfere with daily life (for example, keeping a child home from school or other activities, or keeping an adult from working or attending social activities), a person might have depression. Having either a depressed mood or a loss of interest or pleasure for at least two weeks might mean that someone has depression. Children and teens with depression might be irritable instead of sad. Depression can be treated with counseling and medication.

Difficult Peer Relationships

FXS can have many effects on a child’s development. It can make childhood friendships, or peer relationships, very difficult. These relationships contribute to children’s immediate happiness and may be very important to their long-term development.

Children with FXS might have difficulty in their peer relationships, for example, being rejected by peers or not having close friends. In some cases, children with peer problems may also be at higher risk for anxiety, behavioral and mood disorders, substance abuse and delinquency as teenagers.

Intellectual Disability

People with intellectual disability have a significantly below-average score on a test of mental ability or intelligence and limitations in the ability to function in areas of daily life, such as communication, self-care, and getting along in social situations and school activities.

Children with intellectual disability can and do learn new skills, but they develop more slowly than children with average intelligence and adaptive skills. There are different degrees of intellectual disability, ranging from mild to severe. A person’s level of intellectual disability can be defined by their intelligence quotient (IQ), or by the types and amount of support they need.

Learning Disorders

There are many kinds of learning disorders (also called learning disabilities). They can range from mild to severe and affect each person in different ways. Learning disorders may affect a person’s ability to read, write, listen, talk, reason, do math, and follow instructions, or stay organized.

Read one family’s story of living with fragile X syndrome and find out what CDC is doing about this condition.

Ask Ruth what it’s been like having two sons with full mutation fragile X syndrome, and she’ll tell you. “It’s been so hard. But it’s changed my life. I love it all. Even the struggles have been strengthening.”

Fragile X syndrome (FXS) is the most common known cause of inherited intellectual disability. Males with FXS usually have some degree of intellectual disability which can range from mild to severe and females range from normal intellectual ability to moderate intellectual disability. Individuals with full mutation fragile X may also experience a range of behavioral and health challenges from anxiety, depression, sensory issues (problems receiving and responding to sensory information, such as seeing, hearing, smelling, tasting, and touching), and autism, to ear infections, difficulty sleeping, seizures, and gastrointestinal problems like diarrhea and gastric reflux.

A Day in the Life of Fragile X

Ruth’s two sons, John and David, are both middle-aged. John is about to turn 50. He’s the higher functioning of the two. He’s worked for 29 years as a dishwasher at a cafeteria that’s walking distance from his home. Ruth recalls the time John’s boss asked him to come to work 30 minutes earlier the next day. “They need a face clock. They can see the hands going around, but telling John to come to work earlier the next day doesn’t mean anything. John’s boss needs to tell me or tell the job coach, and we make the adjustment. We take his clock and put it on the copier with the hands where they need to be for him to leave. Then we copy it and put it up beside his other clock. After one day, he’s got it. He knows what it’s supposed to look like.”

Then there’s the time a policewoman picked John up while he was walking to work. She stopped to question him and he ran. When she chased him, he hit her with his gym bag. She locked him in the police car and took him home. Ruth says the officer simply had no idea she was dealing with someone with a disability, nor could the officer have predicted the work Ruth would have to do with John to get him comfortable with police officers again.

David, age 47, is John’s younger brother. He worked for nine years in the kitchen of an inn before he started having trouble with anxiety. The anxiety developed into a panic disorder and he became unable to work. For a few years, the family never went out of town together. Familiar activities like his day program or going to church were fine, but unfamiliar activities and places would send David into panic mode. These days David does volunteer work as part of a day program. He packs bags with necessities for a battered women’s shelter or works in different thrift stores around town. Throughout the day, David is with staff members he knows. Ruth says “he feels secure that whoever is with him is someone who won’t push him into a situation he can’t handle.”

After a lot of waiting and a little luck, John and David now live together with a third roommate in an independent setting. Monday night is grocery shopping, Tuesday is swimming, Wednesday is bowling, Thursday is floor hockey, and Friday is pizza and movie night with their friends. Saturday is dinner out. Every other weekend John and David go home with Ruth and her husband Earl. At each of these activities they have support.

Ruth and Earl raised their sons before there was a diagnosis of fragile X syndrome. Ruth says the school put a lot of pressure on John and David—thinking their challenges were a result of bad behavior—instead of managing the environment so they didn’t get anxious and upset. Ruth says if there was one thing she could change for John and David, it would be eliminating that anxiety. She says her sons seldom have meltdowns anymore, but it’s that anxiety that hurts their lives.

Ruth and Earl don’t talk with John and David about what will happen when they’re gone. They know their sons will ask them where they’re going and when. Ruth says her sons understand that somebody is going to need to take care of them. She has two nieces that are younger than John and David. The four cousins grew up together. The nieces will step in when Ruth and Earl can’t. Ruth says they know they’re in training and one of them closely watches what Ruth does when there’s a problem, and asks lots of questions.

Ruth says she would tell parents of younger children with FXS that it does get better. She says her sons have gained more control and become more flexible as they’ve gotten older. It’s no longer a catastrophe if their routine changes. “Doors will open. We walk through them and wait for the next one.”