The current data confirm previous reports5,7,8
and find that male premutation carriers have markedly more tremor and ataxia, and moderately more parkinsonism, than age-matched, noncarrier controls. This study shows that in men, increasing CGG repeat length is a powerful risk factor for the motor signs common in FXTAS. In addition, increasing age correlates with the severity of motor features of FXTAS.
Women carriers, conversely, have relatively few motor signs compared with male carriers. However, when the percent of active mutant alleles is factored into the analysis, increasing CGG repeat length is a significant risk factor for ataxia in women. This intriguing observation suggests that a threshold number of neural cells with elevated mRNA levels—those in which the abnormal allele is active—may be sufficient to trigger the neurologic dysfunction underlying FXTAS. Previous work15–18
had shown clear cases of FXTAS in women, but a controlled study7
found that symptoms were generally milder in women carriers compared with men. Besides the activation ratio, there may be other sex-related effects on phenotype, including hormonal status. Although women have milder FXTAS motor signs than men, they are more common than in noncarriers, and their children are at high risk for fragile X syndrome. Because the classic syndrome was first described in men, the focus has been on tremor, ataxia, and parkinsonism. Further study of the clinical expression of the premutation in women may reveal other features of diagnostic importance specific to this sex.
mRNA levels did not correlate with motor symptoms in this study. At first glance, the finding seems surprising because FMR1
mRNA has been identified within the brain intranuclear inclusions,32
high levels of abnormal mRNA are postulated to play an important role in the pathophysiology of FXTAS,1,7
and one study found a correlation between leukocyte mRNA levels and psychological features in premutation carriers.33
However, other studies have not reported similar associations between phenotype and leukocyte mRNA level.10,34–36
These observations likely reflect the fact that although regional brain levels of mRNA are elevated in FXTAS,22
blood levels do not closely correlate with brain levels. More specifically, because brain levels of FMR1
mRNA vary widely across different brain regions,22
leukocyte values may not accurately reflect expression levels in the relevant brain regions. However, the significant associations between CGG repeat length and the severity of movement disorder likely reflect the overall trend in brain mRNA levels.
Correct diagnosis of FXTAS is vital because ensuing generations are at high risk for fragile X syndrome. However, the first clinical description of FXTAS was published only 6 years ago,1
and physicians are just gradually learning about the syndrome. A recent study37
showed that only 4% of persons diagnosed with FXTAS had been previously seen by a movement disorders neurologist; the majority had been followed by general neurologists or primary care physicians. Increasing knowledge of the disorder by the latter physicians would prompt them to ask appropriate patients ()20
about a family history of fragile X syndrome. Although it is important to obtain a family history, doing so may not be helpful in making the diagnosis, because the affected man may not have daughters or the daughters may not have children with a correct diagnosis of fragile X syndrome. Another obstacle to diagnosis of FXTAS is that the presentation may be nonspecific, e.g., progressive balance difficulty, cognitive dysfunction, and mild tremor in an aging male, and these findings are often ascribed to multiple strokes or simply aging. Our experience and studies suggest that typical FXTAS patients will not seek medical care; instead, they are brought into the clinic by a spouse frustrated by the patient’s change in behavior (e.g., agitation, poor insight) or cognitive decline. On examination, patients generally at least have impaired tandem gait. Many affected persons deny tremor and have minor tremor on examination.
Phenotypic groups recommended for FXTAS testing*
This study used a newly developed instrument, the FXTAS Rating Scale,25
to effectively discriminate between the type and severity of major motor signs in carriers vs controls. One advantage of the scale is its reliance on items of interest selected directly from scales that are already familiar to movement disorder neurologists. The scale is also easily applied with standard neurologic tests (quiet observation, eye movements, simple motor tasks, and walking) that are feasible to rate from a videotape or in person. In its current form, however, the scale has 44 items. Further clinimetric study may allow elimination of duplicative items. Our long-term goal is to provide a comprehensive, but practical, tool for conduct of therapeutic and longitudinal trials in FXTAS.
This report helps to further define the clinical features of FMR1
carriers, in particular, showing that motor signs are associated with increasing CGG repeat length in men and with increasing percentage of active mutant FMR1
alleles in women. Further research in defining the clinical manifestations of FMR1
carriers is needed, because FXTAS often goes unrecognized. The disorder is estimated to be similar in prevalence to atypical parkinsonian disorders such as progressive supranuclear palsy (6 per 100,000) and multiple system atrophy (2 to 5 per 100,000) and is a noteworthy cause of ataxia38
(1 to 2 per 6,000) in aging men.39