FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy
Valérie Biancalana1, Mathias Toft, Isabelle Le Ber
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasburg, France.
Background:
Fragile X-associated tremor/ataxia syndrome (FXTAS), a novel disorder in male carriers of premutations of the fragile X mental retardation 1 gene (FMR1), was recently described. The clinical presentation of FXTAS most closely resembles multiple system atrophy (MSA) because both disorders manifest with cerebellar ataxia, intention tremor, autonomic dysfunction, and parkinsonism. It has been proposed that FXTAS might be a common neurodegenerative disorder.
Objective:
To determine whether FXTAS accounts for patients currently diagnosed as having MSA or a related clinical diagnosis.
Design:
Patients with MSA or related phenotypes were examined by experienced movement disorders neurologists, and DNA samples were obtained for genetic study.
Setting:
Salpêtrière Hospital.
Patients:
Seventy-seven patients clinically diagnosed as having MSA, 19 as having olivopontocerebellar atrophy, and 27 as having cerebellar ataxia.
Main Outcome Measure:
The number of FMR1 repeats was determined in all patients by polymerase chain reaction. Alleles above 40 CGG repeats were controlled by Southern blot analysis.
Results:
Two patients carried FMR1 premutations of 110 and 135 repeats: a man with a familial form of cerebellar ataxia and a woman diagnosed as having MSA-cerebellar type. In addition, 9 patients (7%) carried alleles in the intermediate size range, from 41 to 53 repeats.
Conclusions:
We confirm the recent initial description of FXTAS in women. Our data suggest that FXTAS is rare in MSA and indicate that FXTAS might be less prevalent than proposed.
Insights
Fragile X-associated tremor/ataxia syndrome (FXTAS) is rare in multiple system atrophy (MSA) patients. This study found FXTAS in only two individuals, suggesting it is less common than previously proposed.
Area of Science:
- Neurogenetics
- Neurology
- Genetics
Background:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is a novel neurodegenerative disorder affecting male carriers of fragile X mental retardation 1 (FMR1) gene premutations.
- FXTAS clinical presentation overlaps significantly with multiple system atrophy (MSA), including cerebellar ataxia, tremor, autonomic dysfunction, and parkinsonism.
- FXTAS has been hypothesized to be a common neurodegenerative disorder.
Observation:
- This study investigated the prevalence of FXTAS in patients diagnosed with MSA or related conditions.
- Seventy-seven patients with MSA, 19 with olivopontocerebellar atrophy, and 27 with cerebellar ataxia were evaluated.
- FMR1 gene CGG repeat analysis was performed using polymerase chain reaction and Southern blot.
Findings:
- Two patients (one man with familial cerebellar ataxia, one woman with MSA-cerebellar type) carried FMR1 premutations (110 and 135 repeats).
- Nine patients (7%) had intermediate-size FMR1 alleles (41-53 repeats).
- FXTAS was confirmed in a female patient, aligning with recent descriptions.
Implications:
- FXTAS appears to be rare among patients diagnosed with MSA.
- The prevalence of FXTAS may be lower than previously suggested.
- This research aids in differentiating FXTAS from MSA and refining diagnostic criteria for both conditions.
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