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FXTAS

Fragile X–associated tremor/ataxia syndrome (FXTAS) is an “adult onset” neurodegenerative disorder, usually affecting males over 50 years of age. Females comprise only a small part of the FXTAS population, and their symptoms tend to be less severe.FXTAS affects the neurologic system and progresses at varying rates in different individuals.

All individuals with FXTAS are carriers of what is called a “premutation” of the FMR1 (Fragile X) gene (also known as “premutation carriers”).

In its “full mutation” form the FMR1 gene causes Fragile X syndrome (FXS), a different, but genetically related disorder that is present from birth but is often undiagnosed or misdiagnosed for many years.

Female “premutation carriers” can also be affected by Fragile X-associated primary ovarian insufficiency (FXPOI), another of the conditions associated with the change in the FMR1 gene.

What Is FXTAS?

As mentioned, all individuals with FXTAS are premutation carriers of the FMR1 gene (CGG repeats 55-200). The “job” of the FMR1 gene is to make protein (FMRP) that is important in brain development.

Researchers believe that (for unknown reasons) having the premutation leads to the overproduction of FMR1 mRNA (which contains the expanded repeats). They believe that the high levels of mRNA are what cause the signs and symptoms of FXTAS, but more research is needed.

Note: Not all premutation carriers will develop FXTAS, but all individuals with FXTAS have an FMR1 premutation. Researchers are investigating what other factors might contribute to FXTAS in FMR1 premutation carriers.

Faces of FX - Matthew

Symptoms in Males

Both the type and severity of FXTAS symptoms vary among individuals. Some will have multiple symptoms that progress rapidly, others few symptoms that remain mild over many years. The most common symptoms in males are:

“Intention” or “action” tremor (trembling hands that occur when one reaches for something or is otherwise using one’s hands. The tremor is not as noticeable at rest).

  • Balance problems, called “ataxia,” which might result in occasional or frequent falls or the need for the person to hold on to a railing or use a cane.
  • “Parkinsonism,” which can include general shaking of body parts, muscle rigidity, a shuffling gait and slowed speech.
  • Cognitive/intellectual decline, including short-term memory loss, loss of math or spelling skills, difficulty making decisions, and other intellectual functions.
  • Numbness or burning of the hands and feet (neuropathy).
  • Low blood pressure (orthostatic hypotension).
  • Personality or mood changes, which might include increased irritability, outbursts of anger, and inappropriate or impulsive behavior not typical of or consistent with the person’s previous personality.
  • Difficulty with organizing, planning, anticipating, and carrying out of everyday life tasks and activities (“executive function skills”).
  • Difficulty learning new tasks.
  • In advanced cases, loss of bowel or bladder control, impotence (autonomic dysfunction).
  • Specific findings on a brain MRI called “increased signal intensity in the middle cerebellar peduncles (MCP) sign”. These findings are evident to neuroradiologists (radiologists with additional expertise in neurological conditions).
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Symptoms in Females

Females can experience the same neurological symptoms as males, but almost always with less severity. Most affected women have some degree of tremor and/or ataxia. While the psychiatric and mood disorders are also less frequent in females, they are at higher risk for anxiety and depression in general. Additional symptoms affecting some females include:

  • Fibromyalgia and/or generalized muscle pain.
  • Thyroid disorders, usually hypothyroidism.
  • Seizure disorders.

 

With FXTAS being a relatively new disorder, there may not appear to be as many services and professionals available as there is for other medical conditions. However, a number of support services and informational materials may be of value to those impacted by FXTAS, some of which address symptoms common to other medical conditions such as Parkinson’s.

The National Fragile X Foundation is on the lookout for more services and will continue to update this list below. In the meantime, we would welcome reader’s recommendations.

Movement Disorder Society
International Guide to Movement Disorder Patient Advocacy Groups and Foundations
Caregiving recommendations for those with FXTAS from the Colorado Fragile X Consortium

 

Treatment of Fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems

FXTAS – Clinical Features, Genetics & Testing Guidelines
An in-depth professional article covering all aspects of FXTAS. A great resource for doctors and professionals, but also provides great insight for family members.

Fragile X-associated Tremor-Ataxia Syndrome Consensus Documents on Clinical Practices
Fragile X-associated Tremor-Ataxia Syndrome (2012-Oct)
Guidelines for best practices generated by consensus of all the physicians working on Fragile X. A great resource for doctors and professionals, but also provides great insight for family members.

Fragile X Clinics and Referrals

The National Fragile X Foundation offers free resources such as referrals to clinics and specialists.

Email: treatment@fragilex.org
Phone: 800-688-8765
Facebook Support Group for people living with FXTAS and their caregivers.

Physicians

Physicians practicing in a number of disciplines may encounter patients who are potentially at risk for or have been diagnosed with FXTAS. Given the multi-system nature of this condition, a patient may be under the care of multiple or varying specialists. These include but are not limited to:

  • Neurologists (for tremor, ataxia, memory loss)
  • Psychiatrists (for personality change, depression, mood disorders)
  • Psychologists (for cognitive impairment)
  • Movement disorders specialists (for tremor, ataxia)
  • Medical geneticists (for any of the above, positive family history)
  • Internists, Urologists (for hypertension or impotence)
  • Orthopedists (for neuropathy, gait abnormalities)
  • Physiatrists (for rehabilitation)

Since FXTAS shares many symptoms with other conditions, patients with FXTAS are often misdiagnosed with Parkinson’s disease, Alzheimer’s, psychiatric disorders, dementia, stroke, other ataxias, and peripheral neuropathy.

If a patient has any of the symptoms of FXTAS, it is imperative to establish their FMR1 status. This is done by ordering the FMR1 DNA test. There is a systematic diagnostic protocol for FXTAS developed by specialists around the globe.

In order to utilize this diagnostic criteria, the patient should have:

  • FMR1 testing
  • Brain MRI imaging
  • A neurological evaluation.

Because patients with FXTAS may have family members with either Fragile X syndrome (FXS) or Fragile X-associated primary ovarian insufficiency (FXPOI), physicians should take a family history and inquire about the following:

  • Adult onset neurological symptoms described in FXTAS in other adult family members.
  • Female relatives with infertility or early menopause.
  • Male and female relatives with intellectual disability, autism, developmental, behavioral, language or learning disorders.

Next Steps

  • If you are a physician whose primary patient population does not include those with movement disorders or neurological problems (such as a urologist, internist, orthopedist, etc.), any patient with symptoms similar to FXTAS should be referred to a neurologist or movement disorders specialist.
  • If FXTAS is confirmed in your patient, genetic counseling by a board-certified genetic counselor is highly recommended. The children, grandchildren and other relatives of the patient may be at risk for other Fragile X conditions and positive carrier status. Additionally, there are often female relatives who unknowingly may have Fragile X-associated primary ovarian insufficiency (FXPOI) and are undergoing expensive and extensive fertility treatments not knowing they are at risk to have a child with Fragile X syndrome (FXS).
  • Most metropolitan and many community medical centers employ genetic counselors. If there is not one in your referral network you can find one through the National Society of Genetic Counselors.
  • There are clinics around the country dedicated to serving those with one of the Fragile X. Patients can be referred to the clinic nearest them. Visit our Fragile X Clinics to find a clinic nearest your patient and/or their family.

Additional Medical Information

For more medical information and important articles pertaining to FXTAS click here.

Genetic Counselors

Though many genetic counselors are familiar with Fragile X syndrome, it is less common for those outside the neurology setting to be familiar with Fragile X-associated tremor/ataxia syndrome (FXTAS).

If you suspect adult patients may have FXTAS, it is first and foremost essential that you confirm they are FMR1 premutation carriers by conducting molecular testing.

In the evaluation/counseling of patients with confirmed or suspected FXTAS, a detailed three-generation pedigree should include inquiries regarding:

  • Adult onset neurological symptoms described in FXTAS (see “What is FXTAS ”) in patient and other adult family members,
  • Female relatives with infertility, early menopause,
  • Male and female relatives with intellectual disability, autism, developmental, behavioral, language or learning disorders.

If a patient is diagnosed with FXTAS the following issues should be addressed:

  • In a male patient:
    • The patient’s mother is an obligate carrier.
    • All daughters of the male patient with FXTAS will have inherited the premutation and are at risk to have children with Fragile X syndrome (FXS). These daughters are also at increased risk to have ovarian dysfunction and fertility problems related to primary ovarian insufficiency (FXPOI). A female family member could be undergoing (often expensive and invasive) fertility treatments while unaware that she may be a carrier of the premutation and at risk of having an affected child.
    • Relatives of the patient and relatives of his mother, including children, grandchildren, nieces, nephews and cousins, are at risk for FXTAS, Fragile X syndrome, learning disabilities, mental health issues, or to be carriers of the FMR1 premutation.
    • Siblings of the patient are at risk to present with FXTAS. Therefore, ataxia, psychiatric and neurological problems need to be identified.
    • All grandchildren through daughters of the male patient with FXTAS are at a 50 percent risk to inherit the FMR1 pre- or full mutation.
  • All children of both genders of the female patient with FXTAS are at a 50 percent risk to inherit the FMR1 pre- or full mutation.

When providing genetic counseling services to a family with a newly diagnosed member with FXTAS, cascade testing for individuals at risk to be premutation carriers or affected with a full mutation should take place within the genetic counseling services, or a referral should be made to counseling/testing services local to the at-risk family members.

It is important to keep in mind the cognitive and psychiatric issues common in individuals with FXTAS when reviewing the genetic and familial implications of this diagnosis.

  • Many patients may experience confusion and emotional reactions to learning the genetic nature of their condition as well as the implications for their children and other relatives.
  • It is important to involve the caregiver in these sessions, along with other family members who can absorb and communicate important genetic information.

FXTAS only occurs in individuals who have a Fragile X (FMR1) premutation. Therefore, it is essential that anyone being considered for this diagnosis is tested for and confirmed as a premutation carrier. This involves DNA testing of the individual’s FMR1 (Fragile X) gene.

Diagnosing FXTAS

The symptoms of FXTAS are divided into “minor” and “major” clinical and MRI findings. The diagnosis is then categorized into “definite,” “probable” or “possible” FXTAS. The criteria were developed primarily as a reflection of the presenting symptoms in men. As we learn more about FXTAS in females, the diagnostic criteria may become different for females, since they usually have milder symptoms.

Also, there are symptoms of FXTAS that are considered “co-morbid,” which means they often occur in individuals with FXTAS but aren’t used to confirm the diagnosis (just as a sore throat is a symptom of strep throat, but cultures, fever, etc. are also used to make the diagnosis).

Major FXTAS Symptoms

  1. Intention tremor: A tremor of the hand when using utensils, writing instruments, reaching for or pouring something. The tremor is not as apparent at rest.
  2. Gait ataxias: Balance problems which may include falling, needed support when walking or going up/down stairs, trouble stepping on/off curbs, generalized instability, or display of a “wide-based” gait.
  3. MRI findings strongly associated with (but not unique to) FXTAS. These findings include “white matter lesions involving middle cerebellar peduncles”, or “MCP” signs.
  4. Neuropathology findings called “FXTAS inclusions” within brain cells.

Minor FXTAS Symptoms

  1. Parkinsonism (resting tremors).
  2. Short -term memory problems. This can be difficult to determine since it is natural for short-term memory to deteriorate as we age. However, in FXTAS it can change more rapidly than normal or may be more dramatic, such as forgetting what one ate, said or did shortly after the event.
  3. Problems with “executive function” and decision-making. Executive function includes the ability to initiate and complete an activity, to adapt and change behavior as needed, and to anticipate and plan for new tasks and situations. Executive function allow us to anticipate outcomes, solve problems, and generalize from one situation to the next.
  4. MRI findings that are more general than those listed above, referred to as “lesions of cerebral white matter.”
  5. MRI findings indicating “moderate to severe generalized brain atrophy.”

Other FXTAS Symptoms (not considered “official” diagnostic criteria)

  1. Neuropathy or numbness/tingling of the extremities.
  2. Mood instability, irritability, explosive outbursts, personality changes.
  3. Cognitive decline—loss of skills including math, reading, etc.
  4. Impotence, loss of bladder or bowel functions (called “autonomic functioning” problems).
  5. High blood pressure, thyroid disorders, fibromyalgia (more common in females and very common in the general population).

Definite vs. Probable vs. Possible FXTAS

Definite FXTAS

  • Individuals with one “major” clinical symptom (#1 or 2 under “major” symptoms) and one “major” radiological symptom (#3 or 4 under “major” symptoms).
  • Any individual with the presence of FXTAS inclusions based on neuropathology.

Probable FXTAS

  • Individuals with two major clinical symptoms (both #1 and 2 under “major” symptoms).
  • Individuals with one “minor” clinical symptom (#1, 2 or 3 under “minor symptoms) and one major radiological symptom (# 3 or 4 under “major” symptoms).

Possible FXTAS

  • Individuals with one major clinical symptom (#1 or 2 under “major” symptoms) and one minor radiological symptom (#4 or 5 under “minor” symptoms).

Any individual who may be a Fragile X carrier (with or without a family history of Fragile X) or who has symptoms in any of these three categories should be seen by a neurologist, movement disorders specialist or psychiatrist familiar with FXTAS or the other Fragile X conditions.

There are three purposes of therapy for FXTAS:

  • To reduce symptoms
  • To slow the progression of disease
  • To cure disease

While there are no known treatments to slow progression or cure FXTAS, intense research is being done in this regard. There are a number of treatments that many affected persons have found helpful in reducing symptoms and disability.

In general, therapy that is most likely to help in any disease has been tested in well designed and executed clinical trials. However, FXTAS was only first published in 2001, so there has not yet been any treatments studied well enough to know if they definitely help.

Until we have proven therapies for FXTAS, it is reasonable to consider treatments that have been shown to reduce the same symptoms when they occur in other diseases. For example, many persons with FXTAS and shaking in their hands (tremor) will find that taking a medication that reduces hand shaking in another disease, eg, essential tremor, is helpful.

Each person with FXTAS is unique; each will have their own set of problems.

  • While most will have hand shaking and balance problems, these will vary in severity and the need for treatment.
  • Further, each affected person has a unique medical history, biological make-up and personality.
  • The symptoms of FXTAS are known to vary from one person to another; so the best treatment options vary from person to person.

Useful treatments for FXTAS include:

  • Medications
  • Psychological and genetic counseling
  • Rehabilitative treatments such as speech, occupational and physical therapy
  • Gait training
  • Surgery
  • Family supportive services and counseling are also important

While many of the FXTAS symptoms are neurological, many other body systems are also affected. To receive optimal care it is best to have a medical care team that is knowledgeable about FXTAS. The team should include a neurologist and primary care physician at a minimum.

Other specialists, eg in the areas of psychiatry, psychology, rehabilitation, urology, cardiology, and movement disorders neurology, may also be needed. The following article describes the current knowledge of treatment of FXTAS.

Physicians, please visit our Professional Resources for FXTAS page for more information.

Fragile X syndrome (FXS) and Fragile X-associated tremor ataxia syndrome (FXTAS) are not the same condition. Both FXS and FXTAS are caused by mutations of the same gene, the FMR1 gene. But they are caused by different changes in this gene. FXS is caused by a full mutation of the FMR1 gene, FXTAS by a premutation of the FMR1 gene.

Even more important in distinguishing between FXS and FXTAS are the different features, age of onset, and diagnostic criteria of the two conditions.

Fragile X Syndrome (FXS)

FXS is present (though often not diagnosed) at birth. Children display features of the condition early in life, usually noticed by family members in infancy, toddlerhood or early childhood. These features include:

  • Delays in cognitive, language and social development.
  • Behavioral issues.
  • Physical characteristics such as large ears, large testes in males, flexible joints and a long face (more common as children get older).

Fragile X-associated Tremor Ataxia Syndrome (FXTAS)

FXTAS develops in adulthood—usually after age 50. The symptoms may appear slowly and develop over years or decades. Individuals with FXTAS usually are healthy, usually with normal cognitive skills prior to the onset of the condition. They have no unique physical characteristics and did not experience the developmental delays in childhood that are seen in FXS.

Other Differences

  • In FXS, the FMR1 gene is fully methylated.
  • In FXTAS, the FMR1 gene is in its normally unmethylated state.
  • FXS is diagnosed by molecular (DNA) testing of the FMR1 gene. Virtually all boys with a full mutation have FXS and about 50 percent of girls with a full mutation have features of FXS.
  • FXTAS is diagnosed by fulfilling certain criteria. These include being an FMR1 premutation carrier, the appearance of neurological features such as ataxia (balance problems), tremors, and other symptoms, and MRI findings.

FXTAS was first described in five grandfathers of children with Fragile X syndrome in 2001 by Dr. Randi Hagerman and her colleagues at the MIND Institute, University of California, Davis. These men were generally healthy until the onset of the FXTAS-related symptoms.

For a few years prior to the first report, Dr. Hagerman and other Fragile X experts had been noticing a pattern of grandfathers of children with Fragile X syndrome diagnosed with:

  • Parkinson’s disease
  • Alzheimer’s disease
  • Various “ataxias” (balance problems)
  • Tremors (shakiness of the hands)
  • Other neurological conditions

Sometimes these men accompanied their grandchildren to the clinic where their symptoms were noticed, or it was reported when the family was giving family health histories.

Eventually, magnetic resonance imaging (MRI) exams were obtained on these men, and similar findings were noted among them. This information linked together:

  • Their symptoms
  • Their genetic markers (the FMR1 premutation) and
  • The MRI changes in their brains.

Based on this data and a great deal of scientific consultation, Dr. Hagerman and her team introduced the term “FXTAS” in 2003. Though it initially included only male carriers over the age of 50, females were later also found to have features of FXTAS, though the symptoms are usually milder and the condition is not seen as often.

Within a short time, individuals with no family history of Fragile X were being diagnosed with FXTAS at various medical clinics. These were FMR1 premutation carriers who did not have known family members with Fragile X syndrome, and may not have known they carried the FMR1 premutation.