Definition
Fragile-X-Associated Tremor-Ataxia Syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansions in the 5’UTR fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of the disease is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes.
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Epidemiology
Premutation alleles of the FMR1 gene are relatively common in the general population, carried by 1 in 130-250 females and 1 in 500-800 males. FXTAS occurs in older carriers (50 years old), is more common in male and has age-dependent penetrance.
Recent study in female carriers suggests that 6% over 50 years old, develop FXTAS; perhaps this is related to a protective effect of the second normal X chromosome.
Symptoms
Fragile-X-Associated Tremor-Ataxia Syndrome consists of progressive intention tremor, gait ataxia, parkinsonism and autonomic dysfunction. Associated features include peripheral neuropathy with decreased sensation and vibration sense in the distal lower extremities, as well as cognitive deficits involving loss of memory, executive function and dementia. Neuropsychological problems, as anxiety and depression, are commonly seen in FXTAS patiens. Decline in mobility generally progresses through the use of cane, walker, and wheelchair, with eventual inability to ambulate. Additional features including autonomic dysfunction are impotentence, hypertension, orthostatic hypotension, urinary frequency and urinary and bowel incontinence in the later stages.
A subgroup of premutation carriers may have psychiatric problems even in childhood or adolescence, with features that can include obsessive/compulsive thinking, anxiety disorders or social difficulties.
Diagnosis
Molecular
- Analysis of the number of CGG repeats (55-200)
Clinical
- Major: Intention tremor, Gait ataxia
- Minor: Parkinsonism, Moderate to sever short term memory deficiency, Executive function deficit
Radiological
- Major: MRI white matter lesions involving middle cerebral peduncles
- Minor: MRI white matter lesions involving cerebral white matter, Moderate to severe generalized brain athrophy
Definitive diagnosis is in only with one major clinical and either one major radiological or presence of intranuclear inclusions.
Pathogenesis
The presence of elevated levels of abnormal (expanded CGG repeats) FMR1 mRNA led to propose an “RNA toxic gain of function” model for FXTAS in which the FMR1 mRNA itself is causative of neurological disorder.
The pathogenic mechanism in FXTAS condition might be an excess binding of premutate FMR1 mRNA with neuronal proteins; this sequestration process might deplete the proteins from the cellular pool, resulting in the loss of their normal functions in the other regulatory function. The sequestration process would also trigger the accumulation or abnormal processing of protein by the proteasomal degradation pathway, leading to inclusion formation with associated ubiquitinated proteins, proteasomal subunits, and stress response protein (HSP).
The Fragile-X-Premutation: A Maturing Perspective
Etiology
Its aetiology is still unknown, but molecular investigation in patient affect have led to the identification of a number of candidate genes, the most significant single gene associated with FXTAS is FMR1 at Xq27.3. FXTAS is caused by the expansion of a polymorphic CGG repeat in the 5’untraslated region of this gene. Repeat length in general population range from 5 to 55, while full mutations with repeat length above 200 result in hypermethylation of FMR1, transcriptional silencing, and the clinical syndrome fragile X mental retardation.
Intermediate length CGG expansions between 55 and 200, referred to the fragile X premutation, have been associated with FXTAS and FXPOF (premature ovarian failure associated with fragile X premutation).
The distribution of premutation alleles among transmitting male is likely to be biased toward larger CGG repeat length, since larger alleles, when transmitted through daughters, are more likely to give rise to full-mutation alleles and an effected proband.
Therapy
Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there are great deal of evidences regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS.
Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems
