FMR1 premutations associated with fragile X-associated tremor/ataxia syndrome in multiple system atrophy

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: Salpetrire 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.