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The deadly combination of tremors and ataxia: Do you know how FXTAS changes the brain?
Fragile X-associated tremor/taxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that primarily affects Fragile X syndrome (FXS) premutation carriers aged 50 years and older. The main clinical features of this disease include cerebellar gait disturbances and action tremors. Additionally, the syndrome may be accompanied by Parkinson's disease symptoms, cognitive decline, and dysfunction of the autonomic nervous system. Notably, FXTAS is present only in carriers of the fragile X premutation, a trinucleotide repeat expansion in the FMR1 gene that ranges from 55 to 200 CGG repeats. People with more than 200 repeats are diagnosed with full fragile X syndrome.
In FXTAS, FMR1 mRNA is expressed at higher levels, unlike in FXS, where it is transcriptionally silenced by DNA methylation.
While the full mutation of FXS is diagnosed in early childhood, symptoms of FXTAS usually appear after age 50. Due to the X-linked inheritance pattern of the mutation, FXTAS is most prevalent and severe in males, with an incidence of approximately 30-40% in male premutation carriers over the age of 50 and 8-15% in females.
Symptoms and signs of FXTASThe main physical symptoms of FXTAS include intention tremor, cerebellar dysregulation, and parkinsonian symptoms, which may manifest as a neurotic gait (short steps, dragging steps), muscle rigidity, and speech delay. Additionally, as the disease progresses, patients may be at risk for developing autonomic dysfunction, examples of which include high blood pressure, bowel and bladder dysfunction, and sexual impotence.
As the disease progresses, patients often experience a decline in cognitive abilities, including reductions in short-term memory and executive function.
Emotionally, FXTAS patients may show personality changes such as irritability, emotional outbursts, and impulsive behavior, which are often related to changes in the brain's limbic system.
Diagnostic Methods
The diagnosis of FXTAS requires a combination of molecular, physiological, and imaging findings. Patients must be premutation carriers to be at risk of developing FXTAS. Based on the combined clinical and imaging findings, a definite, possible, or probabilistic diagnosis of FXTAS can be made. Clinical findings are divided into major and minor symptoms, with major symptoms including intention tremor and gait disturbance, while additional minor symptoms, such as short-term memory deficits and decreased executive function, can further contribute to the diagnosis of FXTAS.
The main imaging finding is white matter lesions in the cerebellar peduncles, which are characteristic of FXTAS.
For a definitive diagnosis, both one major imaging finding and one major clinical finding must be present. Probabilistic diagnoses are based on one major imaging finding and one minor clinical finding or two major clinical findings alone. The presence of only one minor imaging finding and one major clinical finding may also provide a possible diagnosis.
Management Strategy
The goal of medical management of FXTAS is to reduce disability and minimize symptoms. To date, there are still many gaps in the management of FXTAS, a condition that was first described in the literature in 2001. Although there is currently no treatment that can reverse the pathology of FXTAS, a variety of pharmacological therapies are available to alleviate FXTAS symptoms. In the absence of randomized controlled trials to evaluate the effectiveness of these therapies, many current treatment options rely on experience with similar clinical presentations.
Current treatments include medications for tremors, ataxia, mood changes, anxiety, cognitive decline, and neuropathic pain.
Although there is currently no cure for FXTAS, neurological rehabilitation, occupational therapy, and physical therapy are also considered to potentially help improve function.
Prognosis
The progression of FXTAS symptoms varies greatly from patient to patient. For some people, symptoms may develop gradually, with the condition gradually getting worse over years or decades; others may experience rapidly progressive symptoms. FXTAS is strongly age-dependent, with a higher incidence affecting older premutation carriers. Male carriers over 50 have approximately a 30% chance of developing FXTAS, while male carriers over 75 have a 75% chance of being affected.
Although FXTAS was originally described to affect male carriers, female carriers have also been found to develop FXTAS.
However, due to the inactivation of the X gene, female carriers are less likely to develop dementia or classic disorders and tremors, and often display symptoms such as fibromyalgia, thyroid disease, high blood pressure and epilepsy. What kind of deeper genetic mechanism does this reflect, which deserves further study and reflection?
