Fragile X Syndrome
The genetic disorder Fragile X syndrome, which results from mutations in a gene on the X chromosome, is the most commonly inherited form of developmental and intellectual disability. The NICHD supports and conducts research on the diagnosis, treatment, management, prevention, and inheritance of Fragile X and its associated conditions, Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). All three conditions result from changes in the same gene on the X chromosome.
- Fragile X syndrome or Fragile X
Medical or Scientific Names
- Martin-Bell syndrome
Fragile X Syndrome: Condition Information
What is Fragile X syndrome?
Fragile X syndrome is a genetic disorder that affects a person’s development, especially that person’s behavior and ability to learn. In addition, Fragile X can affect:
- Communication skills
- Physical appearance
- Sensitivity to noise, light, or other sensory information
Fragile X syndrome is the most common form of inherited intellectual and developmental disability (IDD)
People with Fragile X syndrome may not have noticeable symptoms, or they can have more serious symptoms that range from learning disabilities to cognitive and behavior problems.
How is a change in the FMR1 gene related to Fragile X & associated disorders?
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.
What causes Fragile X syndrome?
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.
What are the symptoms of Fragile X syndrome?
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.
How do health care providers diagnose Fragile X syndrome?
Health care providers often use a blood sample to diagnose Fragile X. The health care 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.1
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 health care 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 (pronounced am-nee-oh-sen-TEE-sis). A health care provider takes a sample of amniotic (pronounced am-nee-OT-ik) fluid, which is then tested for the FMR1 mutation.
- Chorionic villus (pronounced KOHR-ee-on-ik VILL-uhs) sampling. A health care provider takes a sample of cells from the placenta, which is then tested for the FMR1 mutation.1
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 health care 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.2
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 health care provider can perform developmental screening to determine the nature of delays in a child. If a health care 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.2
What are the treatments 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.1
- 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).
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.
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. The 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 health care provider’s advice. Discuss any questions about medication with a health care provider.
|Symptom||Generic Medication (Brand Name in Parentheses)|
|Attention deficit (with or without hyperactivity)||
(often occurs with ADD/ADHD)
Intermittent explosive disorder
(often occurs with anxiety and/or depression)
ADD: attention deficit disorder; ADHD: attention deficit hyperactivity disorder; TTS: transdermal therapeutic system.
Fragile X Syndrome: NICHD Research Goals
Problems associated with mutation of FMR1 fall into the research portfolios of multiple NIH Institutes, including the NICHD. To help coordinate research on FMR1, the NICHD leads the NIH Fragile X Research Coordinating Group, which includes nine NIH Institutes with research interests in different aspects of Fragile X. The Group consulted with outside experts and in 2008 published a long-term agenda for FMR1 research, the NIH Research Plan on Fragile X Syndrome and Associated Disorders. Finding treatments and supporting families affected by Fragile X and its related disorders are two of the major goals of the Plan.
The NIH is committed to continuing to learn as much as possible about the FMR1 gene and its far-reaching effects. The story of Fragile X might also serve as an effective and useful model for studying other diseases and for moving research discoveries from the laboratory into everyday usage.
Among the Committee’s goals related to Fragile X syndrome are the following:
- Goal I. Advance understanding of the pathophysiology of Fragile X syndrome.
- Goal II. Improve appropriate and timely diagnosis of individuals with Fragile X by conducting population-based screens for the syndrome.
- Goal III. Validate and use functional measures of the manifestation of Fragile X across the life span.
- Goal IV. Initiate a broad-based program of research on the efficacy of treatments for Fragile X syndrome.
- Goal V. Advance understanding of the ramifications of Fragile X syndrome for families.
- Goal VI. Create an infrastructure and resources for research in Fragile X to maximize research efficiencies and promote large-scale research collaborations.
The NICHD’s goals for research on Fragile X syndrome are consistent with those outlined in the NIH Research Plan on Fragile X Syndrome and Associated Disorders. NICHD research efforts related to Fragile X, FXPOI, and FXTAS address each condition specifically as well as more general aspects of Fragile X mutations that may affect all three conditions. Some specific NICHD research goals include the following:
- Understanding how individuals with Fragile X syndrome learn language, process visual information, and react to sensory information. In concert with these studies, other research is detailing brain development in infants with Fragile X to understand how their brains differ from typically developing children and from children with autism and other developmental disorders.
- Finding treatments for the underlying protein dysfunction that causes many of the intellectual and developmental symptoms of Fragile X syndrome, and learning how this dysfunction is involved with Fragile X-associated disorders.
- Understanding which diseases or health problems are associated with the mutated Fragile X gene and determining whether the mutated gene affects risk for other diseases or conditions.
Fragile X Syndrome: Research Activities and Scientific Advances
Through its intramural and extramural organizational units, the NICHD supports and conducts a broad range of research on Fragile X syndrome. Short descriptions of selected research studies are included below. NICHD researchers are also studying Fragile X-associated disorders, including Fragile X-associated primary ovarian insufficiency and Fragile X-associated tremor/ataxia syndrome.
Institute Activities and Advances
Much of the NICHD's research on Fragile X syndrome is supported through its Intellectual and Developmental Disabilities Branch (IDDB). In addition to individual projects, the IDDB supports research on Fragile X through the Fragile X Syndrome Research Centers. The Other Activities and Advances section has information about these centers.
Finding Treatments for Fragile X Syndrome
IDDB-supported researchers are currently studying the "mGluR Theory" of Fragile X syndrome: that exaggerated signaling in mGluR (metabotropic glutamate receptor) pathways because of missing Fragile X Mental Retardation Protein (FMRP) leads to the condition's various symptoms.
Using a Fragile X mouse model, researchers generated mice with 50% lower expression of mGluR5. Several aspects of Fragile X were improved, as the risk of seizures was reduced and there was better eye development, brain development, and behavior.1 Current research will test whether inhibiting mGluR5 after birth can prevent Fragile X syndrome in this mouse model. The researchers will also inhibit mGluR5 after Fragile X symptoms are present to investigate whether such an action can reverse the symptoms.
Another recent study investigated a possible shared mechanism for Fragile X syndrome and tuberous sclerosis complex (TSC), another genetic disorder characterized by intellectual disability and autism. Scientists measured brain protein synthesis in mouse models for TSC and Fragile X syndrome and revealed that the Fmr1 mutation in Fragile X causes increased synaptic protein synthesis that can be corrected by inhibiting mGluR5. Interestingly, the Tsc2 mutation in TSC was found to decrease synaptic protein synthesis, and this could be corrected by augmenting mGluR5. The researchers also found that the deficits in the mouse models were ameliorated when the mice were bred to carry both mutations. The findings suggest that deviations in the synthesis of these proteins—in either direction—can lead to behavioral impairments that are shared across genetic disorders. In addition, the findings suggest that therapies designed to correct one cause of ASD are not likely to be effective for all other causes.
In May 2010, a clinical trial of an mGluR5 antagonist began in adults with Fragile X syndrome. If the results from the adult study show promise, the drug can be tested in clinical trials with children. The NICHD, through its Best Pharmaceuticals for Children Act activities, will add its support to that of the National Institute of Mental Health and other Institutes and organizations for the pediatric clinical trials.
Better Diagnostics and Screening Tools for Fragile X and Premutations
Several NICHD-supported research groups are seeking ways to better diagnose and screen newborns for Fragile X mutations and premutations. Early physical recognition of the characteristics of Fragile X syndrome is difficult, and new technology is being designed to detect all categories of Fragile X alleles, including full mutation expansions.2
Brain Development in Fragile X Syndrome
By the time infants with Fragile X syndrome reach 2 years old, they have a distinct pattern of brain abnormalities. Two-year-olds who have both Fragile X and an autism spectrum disorder (ASD) also have their own unique pattern.3,4
A long-term study is set to discover how these patterns develop and how they are related to the signs and symptoms of Fragile X. Supported by the NICHD's IDDB, the study's researchers are examining early brain development and behavior in infants with Fragile X syndrome. The study will ultimately include 334 infants, some with Fragile X, some with ASD, and some at risk for ASD, as well as a set of control infants. The researchers will perform magnetic resonance imaging (MRI) scans at 6, 12, and 24 months of age and will collect behavioral information as well. This study has the potential to distinguish specific behavioral, genetic, and neurobiological features that characterize infants with Fragile X syndrome as compared to infants at risk for autism without Fragile X syndrome and to those with typical development.5
The Role of Maternal Autoimmune Disease in Fragile X Syndrome
About 60% of children with Fragile X also have an ASD, but only about 4% of children with ASDs have the FMR1 gene mutation. It is unclear at this point why ASDs affect only a rather small portion of children with Fragile X. One current line of research is to examine the role played by having a mother with an autoimmune disease, such as thyroid disease, lupus, multiple sclerosis, or fibromyalgia.
A recent study6 revealed that children with Fragile X whose mothers had a history of autoimmune disease displayed more problems with tics and a higher rate of seizures than did those whose mothers did not have this history. The children in the first group also had higher scores on measures of behavioral concerns, including aggression, depression, and withdrawal. The groups did not differ on rates of ASD, intellectual disability, head size, or sleep problems. These results suggest that future research should consider how autoimmune disease in mothers may interact with the FMR1 mutation to disrupt brain development in their offspring and make children with Fragile X syndrome more susceptible to seizures, tics, and behavior problems.
Protein Missing in Fragile X Uses microRNAs to Act as a "Toggle Switch" in the Brain
Recent research supported by the NICHD has demonstrated how the protein missing in Fragile X syndrome acts as a molecular "toggle switch" in brain cells.7 In Fragile X syndrome, a genetic mutation removes the FMRP from cells, interfering with protein production and signaling at the synapses (the junctions between brain cells where chemical communication occurs). This leads to structural changes and an impairment of the cells' ability to respond to chemical signals, interfering with learning and memory. NICHD-supported scientists determined how the FMRP uses short RNA molecules (microRNAs) to switch on and off the production of other proteins in response to chemical signals. This finding demonstrates the importance of microRNAs in neurological development and diseases such as Fragile X.
New Drug Target Identified for Fragile X Syndrome
NIH-supported researchers have found that a class of drugs called PI3 kinase inhibitors can correct defects in the anatomy of neurons in a mouse model of Fragile X syndrome.8 In Fragile X syndrome, a gene mutation leads to the absence of FMRP, and without FMRP to regulate protein production and signaling, neurons produce excess amounts of certain proteins at synapses. This leads to structural changes and an impairment of the cells' ability to respond to chemical signals, interfering with learning and memory. In the mouse model of Fragile X, using a drug to inhibit the action of the PI3 kinase enzyme dampened the synaptic proteins and could potentially reverse the resulting structural changes. The drug was able to restore normal levels of protein production at synapses, suggesting that PI3 kinase inhibitors could help improve learning and cognition in individuals with Fragile X syndrome.
Other Activities and Advances
To achieve its research goals for Fragile X syndrome and associated disorders, the NICHD is involved with a variety of activities. Some of these activities are managed through the components listed above; others are part of NIH-wide or collaborative efforts in which the NICHD participates.
- The NICHD's IDDB funds three Fragile X Syndrome Research Centers. These centers are geared toward stimulating multidisciplinary, multi-institutional research and translating basic research findings into clinical practice.
- The NIH Fragile X Research Coordinating Group, led by the NICHD, includes nine Institutes with research interests in different aspects of Fragile X or its associated disorders. Several years ago the Group consulted with outside experts and then in 2008 published a long-term agenda for FMR1 research, called the NIH Research Plan on Fragile X Syndrome and Associated Disorders. Finding treatments and supporting families affected by Fragile X and its related disorders are major goals of the Plan.
- The Group recently issued a Request for Information to get feedback on the NIH Research Plan and to seek creative, concrete suggestions from scientific experts in the research and clinical communities, representatives for affected individuals and family members, and pertinent federal agencies. For details, visit http://grants.nih.gov/grants/guide/notice-files/NOT-HD-12-012.html.