Expression of the frataxin gene appears to correlate with the main sites of pathology in the nervous system, heart and beta cells of the pancreas. Neurons and cardiocytes may be particularly sensitive to mitochondrion defects since they are totally reliant on aerobic respiration. The truncating mutations in clinically typical FRDA patients also show evidence for loss of function. Larger repeats on the smallest allele are also associated with additional clinical manifestations such as cardiomyopathy. However, since there is much variation, length of the smallest repeat is of little value for individual prognosis.
Maternal alleles appear to either increase or decrease in size.
The progression of FRDA and the association of hypertrophic cardiomyopathy, diabetes mellitus, blindness and deafness are consistent with a mitochondrial disorder. Initial computer models predicted a mitochondrial targeting signal in the yeast homologue. Although frataxin has no hydrophobic transmembrane segment it is associated with the mitochondrial membranes. Abnormal iron accumulation is observed in yeast cells deficient for a frataxin homologue. Mammalian cells may have developed numerous protective pathways against free radical toxicity eg the anti-oxidant molecule Vitamin E which may partially compensate for loss of frataxin function.