Male and female carriers of the fragile X premutation are at risk for developing an adult onset (>50 years old most commonly) progressive neurodegenerative disorder called Fragile X Tremor Ataxia Syndrome (FXTAS). Male premutation carriers have an age-related risk for developing symptoms of FXTAS (tremors and difficulties with walking and balance), ranging from 17% risk at age 50-59 years old, 38% risk at age 60-69 years old, 47% risk at age 70-79, and up to a 75% risk over the age of 80. Female premutation carriers have an 8-16% lifetime risk for developing FXTAS and may present with milder symptoms.
Individuals who are premutation carriers of the FMR1 (Fragile X) gene (CGG repeats 55-200) are at risk of developing FXTAS. Research demonstrates that having the premutation leads to the overproduction of FMR1 mRNA (which contains the expanded repeats) and that these high levels of mRNA lead to signs and symptoms of FXTAS in some individuals, but not all, who carry the premutation.
The symptoms of FXTAS are characterized by minor and major clinical and MRI findings, with classification into definite, probable, or possible FXTAS, based primarily on presenting symptoms in men, as diagnostic criteria may differ for females, since they usually have milder symptoms. Type, severity, and progression rates of FXTAS symptoms vary among affected individuals.
Symptoms classified as major clinical symptoms of FXTAS include intention hand tremors (no tremor at rest), gait ataxia (balance problems when walking or navigating steps), MRI findings of white matter lesions involving middle cerebellar peduncles (MCP) signs, and neuropathology findings of inclusions within brain cells. Minor clinical symptoms of FXTAS include resting tremors, problems with short-term memory, difficulty with executive functioning and decision making, more general MRI findings than the MCP signs. Additional symptoms of FXTAS may include neuropathy (numbness/tingling in extremities), mood instability, cognitive decline, high blood pressure, thyroid disorders, fibromyalgia, and loss of bladder/bowl or impotence. Individuals are classified as definite, probable, or possible FXTAS based on diagnostic criteria with presenting symptoms and family history.
Individuals affected by FXTAS can receive optimal care with a medical team which includes a neurologist as well as primary care provider that is knowledgeable about FXTAS. Additional specialists who can provide associated care may include a psychiatrist, psychologist, counseling, rehab specialist, urology, cardiology, and movement disorders neurologist.
Currently there is no cure for FXTAS and treatments serve to reduce symptoms. As FXTAS was only first described in 2001, research is ongoing to study effective treatments. At this time, treatments may include medications, psychological and family counseling, gait training, surgery and rehabilitative treatments such as speech, occupational and physical therapy.
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