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Fragile X syndrome is the most common inherited form of learning disability, caused by mutation of the FMR1 gene on the X-chromosome. Within the FMR1 gene is a region comprising a variable number of repeats of the sequence CGG. The normal number of CGG repeats is between 5 and about 50, whereas the mutated form of the gene has more than 200 repeats; this is referred to as a full mutation (FM). However, some individuals have between 55 and 200 CGG repeats in the FMR1 gene, and this is termed a premutation expansion (PM). Premutations can increase into the FM range when passed from mothers to their children. The frequency of FMR-1 premutations in the general population is estimated to be around 1in 250 for women and 1 in 800 for men; they are not associated with mental retardation, but around 20% of women who carry premutations experience premature ovarian failure. A recent paper [Jacquemont S et al. (2004) JAMA 291, 460-469] in the Journal of the American Medical Association reports on the prevalence of a newly identified neurodegenerative disorder affecting older male carriers of the fragile X premutation, fragile X–associated tremor/ataxia syndrome (FXTAS). This disorder involves progressive movement, cognitive and behavioural difficulties and is observed in some male PM carriers in their 50s or older.

In this Californian study of 192 individuals (PM carriers aged 50 or over and controls) from families affected by Fragile X syndrome, each participant was checked for their FMR1 genotype and completed questionnaires that were used to assess movement (tremor and gait problems), cognitive and emotional aspects of their health, as well as other medical issues and family history of neurological disease. Male premutation carriers were found to have a significantly higher incidence of tremor (involuntary shaking) and gait difficulties than the male control group, whilst no difference was observed between the female carrier and control groups. The penetrance of FXTAS in male carriers was estimated at an average of 39%, although incidence increased with age. Male PM carriers were calculated to have a 13-fold increased risk of tremor and ataxia (loss of muscle co-ordination) relative to the male control group.

Half of the study participants were also given a detailed neurological examination, to determine how reliable the self-reported symptoms from the surveys were. A high degree of concordance between the results of the surveys and clinical examinations were taken as evidence that the survey method was reasonably robust. Data from the clinical examinations showed that both male and female carriers showed significantly greater neurological impairment than the corresponding control groups, although the incidence of tremor and ataxia in female carriers was not significantly different from the male controls. There have been rare occurrences of FXTAS symptoms in women reported in the past, but the syndrome is apparently much more common in men.

The researchers conclude that, given a prevalence of 1 in 813 of male PM carriers in the general population and their FXTAS risk calculations, the prevalence of FXTAS in men aged 50 and above could approach 1 in 3000, which would make FXTAS one of the most common causes of late onset tremor and ataxia. They suggest that patients with these symptoms should be screened for permutation expansions of the FMR1 gene.

Comment: The authors of the study themselves observe that larger sample sizes will be required to accurately determine the true prevalence of FXTAS, and also concede that because study participants were all identified via their relationship to a child with fragile X syndrome, they are a biased sample, likely to have longer CGG repeat regions than PM carriers from the general population. However, their results are nonetheless suggestive that FXTAS may account for a significant proportion of cases of tremor and balance problems in ageing men, and could allow more accurate diagnosis of patients previously assumed to have other common neurodegenerative disorders such as Parkinson’s disease. Assuming these findings can be confirmed in larger studies, the next challenge will be to determine how the permutation expansion in the FMR1 gene causes disease, and to seek therapies for FXTAS.

For more information on Fragile X Syndrome and the FMR-1 gene, see the disease profile section.