Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)
Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset condition (occurs in people older than age 50) that develops in some men and women with an altered form of the fragile X gene. Those with FXTAS do not have the intellectual or developmental disabilities common in fragile X syndrome.
NICHD-supported researchers were the first to identify FXTAS and link it to changes in the FMR1 gene, which causes fragile X syndrome. The Institute is one of several federal agencies working to understand FXTAS and other conditions caused by changes in the FMR1 gene.
- Fragile X-associated tremor and ataxia syndrome (FXTAS)
Medical or Scientific Name
- FXTAS (pronounced FAX-tass)
Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS) : Condition Information
What is Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
FXTAS is a condition that develops in some men and women who have an altered form of a specific gene. People with FXTAS have a change or mutation in a gene called the Fragile X Mental Retardation 1 (FMR1) gene. This gene is found on the X chromosome. To learn more, visit the How is a change in a gene related to FXTAS? section.
FXTAS occurs later in life (in people older than age 50) and is characterized by tremors when making purposeful movements, balance problems, Parkinson's-like symptoms such as muscle stiffness or rigidity, and memory loss. Most people have no symptoms until the onset of the condition later in life.
FXTAS is less common among women, and their symptoms are often milder, but having the FMR1 premutation still puts them at risk for FXTAS.1
How is a change in the FMR1 gene related to Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
People with FXTAS have a change or mutation in the FMR1 gene found on the X chromosome.
In the 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 causes the gene to not work properly, but it does not cause intellectual and developmental disability (IDD). FXTAS occurs in some people who have the premutation.
The premutation is also related to fragile X-associated primary ovarian insufficiency (FXPOI).
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 most common inherited form of IDD. Individuals with the full mutation are not at risk for FXTAS.
Anyone with the FMR1 gene mutation can pass it to their children. However, a person who inherits the gene may not develop FXTAS. 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 addition, parents can have children with a condition associated with Fragile X even if the parents do not have that condition themselves.1
What causes Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
Because FXTAS occurs only in those who have the premutation on the FMR1 gene, the premutation is related to the condition.
If the premutation was the only cause of FXTAS, then everyone with the premutation would develop FXTAS after age 50. However, it is still not clear why some people with the premutation develop FXTAS while others do not. This topic is an active area of study.
What are the symptoms of Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
Although FXTAS affects individuals differently, the symptoms of the disorder are similar to those of Parkinson's or Alzheimer's disease, including memory loss, slowed speech, tremors, and a shuffling gait.1 Some people will have many symptoms that appear quickly and get worse over time. Others have only a few mild symptoms.2
Men have slightly different symptoms of FXTAS than women do. Symptoms of FXTAS in men include3:
- Balance problems, called ataxia (pronounced uh-TAK-see-uh)
- Intention tremor (shaking when trying to perform purposeful movements, such as touching one's nose or grabbing something)
- Parkinson's-like symptoms, such as muscle stiffness or rigidity, a shuffling gait or walk, and slowed speech
- Memory loss, including forgetting how to do things that were once done easily (such as balancing a checkbook), getting lost going to familiar places, or forgetting the names of everyday objects
- Irritability and moodiness
- Low blood pressure
- Numbness or burning in the hands and feet
- Loss of reading skills and math skills
- Difficulty learning new things
Women with FXTAS may have the following symptoms3:
- High blood pressure
- Balance problems, called ataxia
- Premature ovarian failure
- Intention tremors
- Seizure disorders
- Thyroid problems (usually an underactive thyroid gland, called hypothyroidism)
- Muscle pain such as fibromyalgia
Symptoms of FXTAS usually develop after age 50. The average age of people newly diagnosed with FXTAS is about 61.2
How do health care providers diagnose Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
Health care providers can order a blood test to determine if a person who has symptoms of FXTAS is a carrier. A laboratory will conduct the tests to determine what form of the FMR1 gene is present.1 (Read a detailed explanation of the genetics of the FMR1 gene in the section How are genes altered in fragile X-associated disorders?)
However, FXTAS is often misdiagnosed. The condition was identified only recently―in 2001—so it is not as familiar to health care providers as other common disorders in seniors, such as Alzheimer's disease and Parkinson's disease. The similarity of symptoms can lead some health care providers to pursue those conditions before considering FXTAS. Many of the FXTAS symptoms, such as memory problems and balance problems, may also be seen as natural parts of aging.
A health care provider may use a combination of a blood test, symptoms, and information from brain imaging, such as magnetic resonance imaging (MRI), to confirm a FXTAS diagnosis.2 In about one-half of men and one-fifth of women with FXTAS, MRIs show white matter lesions (areas of dead cells) in the middle cerebellar peduncle of the brain.3
What are the treatments for Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS)?
Certain medications and therapies are helpful for treating symptoms of FXTAS and may help slow its progression. However, no treatment can stop FXTAS from progressing and none is considered a cure.
Symptoms of FXTAS differ from person to person, and treatment should address a person's individual needs. Health care providers may work as a team to provide appropriate treatment, such as physical therapy for difficulty with movement and balance, medication for tremors, and psychological counseling and support services for the individual and family. Other therapies may include rehabilitative treatments such as speech and occupational therapy and gait training. A urologist may be consulted regarding sexual health.1
In addition, the children of FXTAS patients may want to confirm their FMR1 gene status and to discuss their situation with a genetic counselor.
In many cases, medications have been used to treat symptoms associated with FXTAS,2 as shown in the table below.
Please note that the NICHD does not endorse or support the use of any of these medications in treating symptoms of FXTAS, or for other conditions for which the medications are not approved by the U.S. Food and Drug Administration.
|Problems with thinking and memory||Most medications for FXTAS-associated cognitive problems and dementia are off-label uses of therapies used for Alzheimer's disease.|
|Psychiatric symptoms such as anxiety, irritability, agitation, hostility, obsessive-compulsiveness, apathy, and depression||
Other medications for urinary urgency, bowel incontinence, difficulty swallowing, dizzy spells, high blood pressure, pain, and thyroid dysfunction may also be used.3
Fragile X-Associated Tremor & Ataxia Syndrome (FXTAS): NICHD Research Goals
Problems associated with the FMR1 gene mutation 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 on different aspects of fragile X. The group consulted with outside experts and 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 impacted by fragile X and its related disorders are 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 life.
Among the group's goals with implications for FXTAS are the following:
- Finding treatments for the underlying protein dysfunction that causes fragile X-associated disorders. Studies in fruit flies and mice have resulted in several promising molecules that are either in human clinical trials today or are on their way.
- Furthering understanding of why FMR1 premutations affect some people but not others. This includes the study of why FXTAS is more common among men than women and how the genetic changes lead to specific symptoms. Research could also help document the frequency of premutations in the general population and improve understanding of when FXTAS develops in families in which FMR1 premutations are common.
- Documenting the different kinds of symptoms that develop and how they change over time. This includes research on defining the neurological, cognitive, behavioral, and emotional symptoms of FXTAS and developing instruments that can measure changes in motor function and other signs. Better instruments and an improved understanding of risk factors could help clinicians identify FXTAS earlier.
- Understanding whether other conditions are linked with fragile X-associated conditions.
- Developing ways to better diagnose and treat FXTAS.
Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Research Activities & Scientific Advances
The Effects of FMR1 Premutations in Adults and Children
In 2001, researchers supported by the Intellectual and Developmental Diseases Branch (IDDB) discovered FXTAS.
The same NICHD-supported researchers have found that FXTAS is associated with other conditions. For example, sleep apnea is three times more common in people with FXTAS than in the general population. People with FXTAS are also at a higher lifetime risk of mood disorders, including major depressive disorder, anxiety disorder, and post-traumatic stress disorder. In addition, men with FXTAS are more likely to have high blood pressure than men without the FMR1 premutation. (Men with the premutation who don't have FXTAS are not at increased hypertension risk.) (Sources: Hamlin, A., et al. (2011). American Journal of Medical Genetics. PMID: 21932336; Bourgeois, J. A., et al. (2011). Journal of Clinical Psychiatry. PMID: 20816038; and Hamlin, A., et al. (2012). American Journal of Medical Genetics. Part A. PMID: 22528549)
Researchers are studying the protective factors in carriers of FXTAS and the proteins involved in the pathogenesis to determine ways to prevent or reverse the process. They have also found early neurodevelopmental abnormalities in premutation mice, leading to the question of whether it is a lifelong process, and providing hope for the development of early intervention. (Source: Hagerman, P. J., (2012). Current gaps in understanding the molecular basis of FXTAS. Tremor and Other Hyperkinetic Movements; New York: 63.)
Some people with FMR1 premutations experience symptoms in childhood. For example, boys with FMR1 premutations have a higher risk of seizures, compared with boys who do not have premutations. Also, boys who had seizures were also more likely to have an autism spectrum disorder. (Source: Chonchaiya, W. (2012). Human Genetics. PMID: 22001913)
Further research supported by the IDDB aims to explore how the FMR1 premutation affects the development of children and the neurological health of adults. This research includes a study of 500 adults (age 40 years and older) and 150 boys (ages 8 to 16). In the boys, studies will focus on attention deficit hyperactivity disorder and social deficits, including autism spectrum disorder. In the adults, researchers will focus on age-related changes.1
Better Diagnostics and Screening Tools for Fragile X and Premutations
Several NICHD-supported research groups are seeking ways to better diagnose and screen for fragile X mutations and premutations. One potential screening method currently being tested would analyze a small drop of blood on a paper card to detect fragile X syndrome in newborns.
Early physical recognition of the characteristics of fragile X syndrome is difficult, and this method uses new technologies that have been developed that can detect all categories of fragile X alleles, including full mutation expansions.2
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 (FXSRCs). The 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 on different aspects of fragile X or its associated disorders. The group consulted with outside experts and published a long-term agenda for FMR1 research, called the NIH Research Plan on Fragile X Syndrome and Associated Disorders, in 2008. Finding treatments and supporting families impacted by fragile X and its related disorders are major goals of the plan.
In addition, the plan supports a focus on defining the full range of clinical effects of the FMR1 premutation, its natural course, and the identification of the earliest markers of FXTAS disease in order to facilitate diagnosis and the proper management or prevention of problems experienced by those who have a premutation. This could have a substantial impact on management and genetic counseling for a large number of individuals in the general population.
The group recently issued a Request for Information (RFI) 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.3