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Fragile X–Associated Tremor/Ataxia Syndrome (FXTAS)

By

Hector A. Gonzalez-Usigli

, MD, HE UMAE Centro Médico Nacional de Occidente

Last full review/revision May 2020| Content last modified May 2020
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Topic Resources

Fragile X–associated tremor/ataxia syndrome is a genetic disorder affecting mostly men and causing tremor, ataxia, and dementia. Tremor is a common early symptom that is followed by ataxia, parkinsonism, and eventually dementia. Diagnosis is confirmed by genetic testing. Tremor can often be relieved with primidone, propranolol, and/or antiparkinsonian drugs.

Fragile X–associated tremor/ataxia syndrome (FXTAS) affects about 1/3000 men > 50. It results from a premutation (50 to 200 CGG repeats) in the Fragile X mental retardation (FMR1) gene on the X chromosome. Fragile X syndrome, the most common form of intellectual disability in males, develops when the mutation is full (> 200 repeats).

People with the premutation are considered carriers. Daughters (but not sons) of men with the premutation inherit the premutation. These daughters' children (grandchildren of the men with the FXTAS premutation) have a 50% chance of inheriting the premutation, which can expand into a full mutation when passed from mother to child (and thus cause Fragile X syndrome).

FXTAS develops in about 30% of men with the premutation and in < 5% of women with the premutation.

Risk of developing FXTAS increases with age.

Symptoms and Signs

FXTAS symptoms become noticeable in late adulthood. The more CGG repeats, the more severe the symptoms and the earlier the onset.

Tremor, often misdiagnosed as essential tremor, is a common early symptom of FXTAS. Tremors are usually intention tremors. Patients develop ataxia (which progressively worsens), then parkinsonism (including a resting tremor), and eventually dementia.

Pearls & Pitfalls

  • Consider FXTAS in patients diagnosed with essential tremor if they develop ataxia or signs of parkinsonism.

Dementia begins with loss of short-term memory, slowed thought, and difficulty problem solving. Depression, anxiety, impatience, hostility, and mood lability may develop.

Peripheral neuropathy is often present, causing loss of sensation and reflexes in the feet. Dysautonomia (eg, orthostatic hypotension) may occur. In later stages, bladder and bowel control may be lost.

Life expectancy after motor symptoms develop ranges from about 5 to 25 years.

In women with the premutation, symptoms are usually less severe, possibly because the presence of another X chromosome is protective. These women have an increased risk of early menopause, infertility, and ovarian dysfunction.

Diagnosis

  • Genetic testing

If FXTAS is suspected, patients should be asked whether any of their grandchildren have intellectual disability and whether their daughters have had early menopause or infertility.

Also, if a patient has Fragile X syndrome, clinicians should determine whether the patient's grandparents have symptoms suggesting FXTAS; if so, genetic counseling is recommended for the grandparent's children and grandchildren.

MRI is done; it may identify the characteristic increased signal in the middle cerebellar peduncles.

Diagnosis of FXTAS is confirmed by genetic testing.

Treatment

  • Primidone, propranolol, and/or antiparkinsonian drugs

The resting tremor in FXTAS can often be relieved with primidone, propranolol, and/or antiparkinsonian drugs; doses have not yet been standardized (1).

Treatment reference

Key Points

  • Fragile X–associated tremor/ataxia syndrome (FXTAS) affects about 1/3000 men > 50; Fragile X syndrome, the most common cause of intellectual disability in males, develops from a related gene mutation.

  • Ask patients whether any of their grandchildren have intellectual disability and whether their daughters have had early menopause or infertility, and ask grandparents of patients with Fragile X syndrome whether they have symptoms suggesting FXTAS.

  • Do genetic testing to confirm the diagnosis.

  • Treat tremor with primidone, propranolol, and/or antiparkinsonian drugs.

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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