Clinical Information

Friedreich ataxia (FA) is an autosomal recessive disease affecting approximately 1:50,000 individuals in the white population. The disease is clinically characterized by progressive spasticity, ataxia, dysarthria, absent lower limb reflexes, sensory loss, and scoliosis. Cardiac involvement occurs with the development of myocardial fibrosis due to mitochondrial proliferation and loss of contractile proteins. It tends to be correlated with the clinical neurologic age of onset and the GAA triplet repeat length, but not the duration of disease or the severity of neurologic symptoms. Although most individuals begin experiencing initial symptoms between 10 and 15 years of age, atypical late-onset forms with initial symptoms presenting after age 25 do occur.

FA is caused by variants in the FXN gene encoding a mitochondrial protein, frataxin. Variants in this gene lead to a reduced expression of frataxin, which causes the clinical manifestations of the disease. Approximately 96% of individuals with FA have a homozygous expansion of the GAA trinucleotide repeat in intron 1 of FXN. The remaining 4% of FA patients have the trinucleotide expansion on 1 allele and a point alteration or deletion on the second allele. Normal alleles contain between 5 to 33 GAA repeats. Disease-causing alleles typically range from 66 to 1700 repeats, although the majority of individuals with FA have repeats ranging from 600 to 1200.

Historically, FA has been diagnosed by use of a DNA-based molecular test to detect the presence of the GAA expansion. Unfortunately, testing for the triplet repeat expansion will miss those with point alterations or deletions. Moreover, a molecular-based analysis is not able to effectively monitor treatment. In contrast, this protein-based assay measuring concentration of frataxin is suitable for both diagnosis as well as treatment monitoring in individuals with FA.

For patients with a low frataxin level, molecular repeat expansion analysis of the FXN gene (AFXN / Friedreich Ataxia, Repeat Expansion Analysis, Varies) allows for detection of disease-causing expansion alleles.