Interruptions of the FXN GAA repeat tract delay the age at onset of Friedreich's ataxia in a location dependent manner.

Background: Friedreich's ataxia is a rare autosomal recessive neurological disorder caused by the homozygous expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene and frataxin protein deficiency. It has previously been observed that large interruptions of the GAA repeat tract, determined by abnormal MboII digestion, are very rare. Methods and Results: Here we have used triplet repeat primed PCR (TP PCR) assays to identify small interruptions at the 5' and 3' ends of the GAA repeat tract through alterations in the electropherogram trace signal. We found that contrary to large interruptions, small interruptions are more common, with 3' interruptions being most frequent. The patient cohort (n=101) was stratified into groups: 5' interruption, 3' interruption, both 5' and 3' interruptions or lacking interruption. Those patients with a 3' interruptions were associated with shorter GAA1 repeat tracts and later ages at disease onset. The age at disease onset was modelled by a group-specific exponential decay model. Conclusions and Significance: Based on this modelling, a 3' interruption is predicted to delay disease onset by approximately 9 years relative to those lacking 5' and 3' interruptions, highlightening the key role of interruptions at the 3' end of the GAA repeat tract in modulating the disease phenotype and its impact on prognosis for the patient.