Sequence variation in GAA repeat expansions may cause differential penotype display in Friedreich's ataxia

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia i s known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabet es. Genetically, it is identified by the expression of an unstable trinucle otide GAA repeat expansion located in the first intron of the X25 gene on c hromosome 9. Two brothers with very late adult-onset ataxia, and their unaf fected sister, were examined for the clinical presentation of FA and for th e presence of the mutated FA gene. The relationship of the expanded gene se quence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and propriocept ive loss, with age of onset between 60 and 70 years of age. DNA from periph eral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The exp anded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequ ences. The unaffected sister carried a normal FA genotype with 8-uninterrup ted GAA repeat, observed by sequence analysis. In addition, the levels of F A gene transcript in both brothers were relatively lower than that in the u naffected sister. No detectable cardiomyopathy or diabetes was observed. Ph enotypic diversity of FA is increasingly expanding. The age of onset and th e structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmatio n of the FA gene mutation in the atypical case, broadens the clinical spect rum of FA, and supports the idea that patients with even a mild form of ata xia of late adult onset should be considered for molecular testing. (C) 200 1 Movement Disorder Society.