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 medications.
(See also Overview of Movement and Cerebellar Disorders.)
Fragile X–associated tremor/ataxia syndrome (FXTAS) 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).
Risk of developing FXTAS increases with age and the number or CGG repeats.
Symptoms and Signs of FXTAS
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.
Patients with other X chromosome disorders (eg, Klinefelter syndrome [XXY karyotype]) may have tremor that mimics essential tremor.
Цінні поради та підводні камені
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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 of FXTAS
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 of FXTAS
Primidone, propranolol, topiramate, gabapentin, pregabalin, benzodiazepines, and/or antiparkinsonian medications
The resting tremor in FXTAS can often be relieved with primidone, propranolol, topiramate, gabapentin, pregabalin, benzodiazepines, and/or antiparkinsonian medications; doses have not yet been standardized (1, 2).
Довідковий матеріал щодо лікування
1. Hall DA, Berry-Kravis E, Hagerman RJ, et al: Symptomatic treatment in the fragile X-associated tremor/ataxia syndrome. Mov Disord 21 (10):1741–1744, 2006.doi: 10.1002/mds.21001
2. Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ: Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathophysiology and clinical implications. Int J Mol Sci 21 (12): 4391, 2020. Published online 2020 Jun 20. doi: 10.3390/ijms21124391
Ключові моменти
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 when the gene mutation is full (more repeats).
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, topiramate, gabapentin, pregabalin, benzodiazepines, and/or antiparkinsonian medications.
