Premutations in the FMR1 gene are uncommon in men undergoing genetic testing for spinocerebellar ataxia
Sara A Adams1, Kelle J Steenblock, Stephen N Thibodeau
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
To determine the prevalence of Fragile X-associated Tremor Ataxia Syndrome (FXTAS) among men with undiagnosed ataxic disorders. PCR amplification of CGG repeats in the FMR1 gene and a chart review of clinical features were performed for 286 male subjects who had non diagnostic genetic testing for spinocerebellar ataxia between November 1998 and October 2002 prior to widespread clinical testing of FXTAS. Chart review showed that 55% of tested subjects manifested only one cardinal clinical feature of FXTAS (progressive intention tremor, ataxia, and cognitive decline), 20% had two of the three findings, and 4% had all three. Gait ataxia associated with clinical features not characteristic of FXTAS was reported in 47% of subjects. Molecular analysis yielded one FMR1 premutation (100 CGG repeats). Combining our data with that of comparable published studies shows 17/1,320 (1.3%) males tested for adult-onset ataxia had FMR1 premutations. FMR1 premutations are an uncommon cause of spinocerebellar ataxia. This study is in agreement with other similar studies and supports recommendations that testing be considered only if there are additional supporting clinical features indicating that a possible FMR1 premutation may be involved.
Insights
Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is uncommon in men with undiagnosed ataxia. Testing for FMR1 premutations should consider additional clinical features, as it
Area of Science:
- Neurogenetics
- Neurology
- Genetics
Background:
- Fragile X-associated Tremor Ataxia Syndrome (FXTAS) is a genetic disorder affecting older adults.
- Ataxic disorders can have various underlying causes, including genetic factors.
Purpose of the Study:
- To investigate the prevalence of FXTAS in males with undiagnosed ataxic disorders.
- To evaluate the utility of FMR1 gene testing in this patient population.
Main Methods:
- Retrospective chart review and molecular analysis (PCR amplification of CGG repeats in FMR1 gene).
- Study included 286 male subjects with undiagnosed ataxic disorders undergoing non-diagnostic genetic testing for spinocerebellar ataxia.
- Data collected between November 1998 and October 2002.
Main Results:
- 55% of subjects showed one cardinal clinical feature of FXTAS, 20% had two, and 4% had all three.
- Molecular analysis identified one FMR1 premutation (100 CGG repeats) among the 286 subjects.
- Combined data with published studies indicated a 1.3% prevalence of FMR1 premutations in males tested for adult-onset ataxia.
Conclusions:
- FMR1 premutations are an uncommon cause of adult-onset ataxia and spinocerebellar ataxia.
- Consider FMR1 premutation testing for FXTAS only when supporting clinical features are present.
- This study supports existing recommendations for targeted FXTAS genetic testing.
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