Sorbi et al describe a patient with atypical very late-onset FRDA who was apparently homozygous for an expansion containing 90 GAA repeats as further confirmation of our observation that FRDA needs to be considered in patients with onset of ataxia in the sixth decade.1 While the patient described by Sorbi et al may indeed extend the clinical and molecular spectrum of FRDA, several questions pertaining to the molecular findings are important to consider before assigning a definitive diagnosis of FRDA to this patient. First, given the lack of consanguinity, it is unusual that the patient is homozygous for an expansion with 90 repeats. As well, it is unclear from the authors' description whether Southern blot analysis with the restriction enzyme Bsi KHA1 or a long polymerase chain reaction was used to detect the expansion. Findings from long-range polymerase chain reactions typically need to be confirmed by Southern blot analysis to accurately assess the GAA expansion. Second, the method used for determining the size of the expansion is an important variable, especially for expansions with fewer than 100 GAA repeats. Was the number of repeats verified by more than one method? Third, the authors state that point mutations in exons 1 to 5a of the frataxin gene were ruled out by single-strand conformational polymorphism analysis. However, this method is not the most robust mutation detection method and its sensitivity for detecting point mutations can range anywhere from 60% to 94%.2- 5 Given these caveats, detailed examination of cell lines from the patient for reduced frataxin messenger RNA or protein levels may lend better support to the argument that the frataxin locus is causatively related to the clinical phenotype in this patient.
Patel PI, Dimachkie MM. Atypical Friedreich Ataxia With a Very Late Onset and an Unusual Limited GAA Repeat—Reply. Arch Neurol. 2000;57(9):1380-1383. doi: