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Fragile X–Associated Tremor/Ataxia Syndrome (FXTAS)

by Hector A. Gonzalez-Usigli, MD, Alberto Espay, MD

Fragile X–associated tremor/ataxia syndrome (FXTAS) is a genetic disorder affecting mostly men and causing tremor, ataxia, and dementia.

FXTAS affects about 1/3000 men > 50. A premutation (50 to 200 CGG repeats) occurs 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

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. Patients develop ataxia (which progressively worsens), then parkinsonism, 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 yr.

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, grandparents of patients that have Fragile X syndrome should be asked whether they have symptoms suggesting FXTAS; if so, genetic counseling is recommended for their children and/or grandchildren, except for the patient known to have Fragile X syndrome.

MRI is done; it may identify the characteristic increased signal in the middle cerebellar peduncles. Diagnosis is confirmed by genetic testing.

Treatment

Tremor can often be relieved with primidone, propranolol, and/or antiparkinsonian drugs (see Cervical Dystonia : Treatment).

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