fragile x associated tremors/ataxia syndrome

Age-standardised disability-adjusted life year...

Age-standardised disability-adjusted life year (DALY) rates from Parkinson disease by country (per 100,000 inhabitants). (Photo credit: Wikipedia)

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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. A premutation (an increased number of CGG repeats) occurs in the fragile X mental retardation (FMR1) gene on the X chromosome; if the mutation is full, > 200 repeats occur, causing fragile X syndrome. People with the premutation are considered carriers. Daughters (but not sons) of men with the premutation inherit the premutation. Their children (grandchildren of men with the gene) 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 usually develop in older age; average age of onset in 60 yr. The more CGG repeats, the more severe are the symptoms.

Tremor that resembles essential tremor is a common early symptom, usually followed by ataxia within 2 yr. Other symptoms may include slow movements, stiffness, and decreased facial expression, similar to Parkinson’s disease.

Cognitive impairment, including loss of short-term memory, slowed thought, and difficulty problem-solving, varies. These symptoms often progress to dementia. Depression, anxiety, impatience, hostility, and mood lability may develop.

Sensation and reflexes in the feet may be lost. Dysautonomia (eg, orthostatic hypotension) may occur. In later stages, bladder and bowel control may be lost. Life expectancy after motor symptoms is reported to range 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. Symptoms more often suggest multiple sclerosis or fibromyalgia than FXTAS. These women have an increased risk of early menopause, infertility, and ovarian dysfunction.

Diagnosis

Genetic testing

Grandfathers of children who have fragile X syndrome should be asked whether they have neurologic symptoms associated with FXTAS. MRI can detect the characteristic brightness in the middle cerebellar peduncles, which is not always present in FXTAS but is rarely caused by other disorders. Diagnosis is confirmed by genetic testing.

Treatment

Tremor can often be relieved with many of the drugs used to control tremors due to Parkinson’s disease (see Movement and Cerebellar Disorders: Treatment).

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