Fragile X premutation with atypical symptoms at onset

OBJECTIVE: To evaluate the presence of carriers of the fragile X premutation among male patients with sporadic ataxia without expansion into known spinocerebellar ataxia genes. DESIGN: Clinical and genetic examinations were performed on patients with sporadic pure ataxia and patients with ataxia associated with extracerebellar features such as pyramidal and extrapyramidal signs, dementia, or peripheral neuropathy. SETTING: University department of neurology. PATIENTS: One hundred forty-two Italian men with sporadic ataxia with onset at age 30 to 84 years. INTERVENTIONS: The CGG repeat size of the FMR1 gene was evaluated with fluorescent polymerase chain reaction. Premutated allele lengths were confirmed with Southern blot analysis. RESULTS: FMR1 premutation alleles with a repeat number greater than 55 were detected in 3 probands (2.1%) from a total of 142 male subjects initially referred to our university medical center for evaluation of sporadic ataxia. Two patients had typical fragile X syndrome with associated tremor or ataxia, and the third patient had spastic paraparesis without clear symptoms of cerebellar ataxia and without the common signs seen at magnetic resonance imaging. CONCLUSIONS: Genetic analysis of the FMR1 gene could provide a reliable diagnostic tool for the definitive diagnosis of late-onset ataxias. Additional studies are needed to clarify the importance of premutation screening in patients with movement disorders or other associated atypical features at onset, such as paraparesis.