(See also Overview of Movement and Cerebellar Disorders Overview of Movement and Cerebellar Disorders Voluntary movement requires complex interaction of the corticospinal (pyramidal) tracts, basal ganglia, and cerebellum (the center for motor coordination) to ensure smooth, purposeful movement... read more .)
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 Fragile X Syndrome Fragile X syndrome is a genetic abnormality on the X chromosome that leads to intellectual disability and behavioral disorders. Diagnosis is with molecular DNA analysis. Treatment is supportive... read more , 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 of FXTAS
FXTAS symptoms become noticeable in late adulthood. The more CGG repeats, the more severe the symptoms and the earlier the onset.
Tremor Tremor Tremors are involuntary, rhythmic, oscillatory movements of reciprocal, antagonistic muscle groups, typically involving the hands, head, face, vocal cords, trunk, or legs. Diagnosis is clinical... read more , 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 Secondary and Atypical Parkinsonism Secondary parkinsonism refers to a group of disorders that have features similar to those of Parkinson disease but have a different etiology. Atypical parkinsonism refers to a group of neurodegenerative... read more (including a resting tremor), and eventually dementia.
Patients with other X chromosome disorders (eg, Klinefelter syndrome Klinefelter Syndrome (47,XXY) Klinefelter syndrome is the presence of two or more X chromosomes plus one Y, resulting in a phenotypic male. Diagnosis is based on clinical findings and is confirmed by cytogenetic analysis... read more [XXY karyotype]) may have tremor that mimics essential tremor.
Pearls & Pitfalls
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 Overview of Peripheral Nervous System Disorders The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. It includes the cranial nerves and spinal nerves from their origin to their end. The anterior... read more is often present, causing loss of sensation and reflexes in the feet. Dysautonomia (eg, orthostatic hypotension Orthostatic Hypotension Orthostatic (postural) hypotension is an excessive fall in blood pressure (BP) when an upright position is assumed. The consensus definition is a drop of > 20 mm Hg systolic, 10 mm Hg diastolic... read more ) 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
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 drugs
The resting tremor in FXTAS can often be relieved with primidone, propranolol, topiramate, gabapentin, pregabalin, benzodiazepines, and/or antiparkinsonian drugs Treatment Parkinson disease is a slowly progressive, degenerative disorder characterized by resting tremor, stiffness (rigidity), slow and decreased movement (bradykinesia), and eventually gait and/or... read more ; doses have not yet been standardized (1 Treatment reference 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,... read more , 2 Treatment reference 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,... read more ).
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
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, topiramate, gabapentin, pregabalin, benzodiazepines, and/or antiparkinsonian drugs.
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