Background and Prevalence
Male and female carriers of the fragile X premutation are at risk for developing a newly discovered movement disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). Although the prevalence of FXTAS in the general population is unknown, preliminary research suggests that a significant percentage of men with the fragile X premutation may be affected. Recent research suggests that the likelihood of being affected by FXTAS increases with age. In one study, 17% of men with the fragile X premutation developed FXTAS in their 50s. Three-quarters of male premutation carriers age 80 and older were affected. Although the prevalence of the disorder among women is not known, it is clear that women are significantly less likely than men to develop FXTAS. Women who do develop the disorder are less severely affected than men tend to be. Individuals with the full mutation (i.e., fragile X syndrome) are not at risk for developing FXTAS unless they have a "mosaic" pattern of gene inheritance, in which some X chromosomes contain a fragile X gene with the full mutation and others contain a gene with the premutation.
The fragile X premutation results from a mutation in the fragile X mental retardation 1 (FMR1) gene, which resides on the X chromosome. The mutation involves an expansion of a specific pattern of molecules that make up the gene (i.e., cytosine, guanine, and guanine, or "CGG"). The number of repetitions of the pattern is referred to as "CGG repeats." Individuals with between 6 and 40 CGG repeats have a normal gene. Those with 55 to 200 CGG repeats have the fragile X premutation. At this time, it is not known why some carriers of the fragile X premutation develop FXTAS and others do not.
Some carriers of the fragile X premutation begin to develop symptoms of FXTAS in their 50s and 60s. The disorder typically begins with a tremor in the hands and/or problems with balance and coordination. As FXTAS progresses, other common symptoms include weakness in the limbs, hypertension, and impotence, as well as symptoms that resemble Parkinson disease (e.g., resting tremor, muscular rigidity).
Individuals with FXTAS tend to experience specific cognitive impairments, including problems with their concentration, short-term memory, learning, and what are called executive cognitive abilities. The executive functions include such abilities as planning, organization, behavioral self-regulation, active problem solving, and the ability to critically monitor one's own behavior. Anxiety, depression, and irritability may be common in individuals with FXTAS. Although it is unclear how changes in brain structure may be related to these symptoms, research has shown that FXTAS is associated with a decrease in overall brain volume and the development of abnormal structures, known as inclusion bodies, in the nuclei of cells in the brain. The severity of symptoms of FXTAS tends to increase over time, although there appears to be a good deal of variability among individuals in the rate of progression.
Most physicians are not yet familiar with FXTAS, although geneticists and neurologists are becoming increasingly aware of the disorder. FXTAS was first reported in 2001 when researchers affiliated with the Consortium were conducting a family study and discovered that a number of the grandfathers of children with fragile X syndrome had developed an unusual pattern of movement, cognitive, and functional deficits. Because this disorder is newly discovered, FXTAS often is confused with other neurological diseases that share similar symptoms. Most commonly, FXTAS patients initially are diagnosed with atypical Parkinson disease, Alzheimer's disease, multiple system atrophy, olivopontocerebellar degeneration, or essential tremor. As knowledge of FXTAS increases, patients with the disorder will benefit from improved diagnosis and from treatment approaches tailored specifically to this condition.
Because FXTAS is a newly discovered disorder, there are as yet no guidelines for its treatment. Currently, treatment of FXTAS patients focuses on addressing the specific symptoms of the disorder, particularly tremor. Treatment approaches applied to disorders with similar symptomatology often are used in the treatment of FXTAS. For example, medications typically used to control tremor in patients with Parkinson disease often are used to treat similar symptoms in individuals with FXTAS.