FXN

The FXN gene provides instructions for making a protein called frataxin. This protein is found in cells throughout the body, with the highest levels in the heart, spinal cord, liver, pancreas, and muscles used for voluntary movement (skeletal muscles). Within the cell, frataxin is found in specialized energy-producing centers called mitochondria. Although its function is not fully understood, frataxin appears to help assemble clusters of iron and sulfur that are critical for the function of many proteins, including those needed for energy production.

One region of the FXN gene contains a segment of DNA building blocks (nucleotides) known as a GAA triplet repeat, or GAA trinucleotide repeat. This particular segment of three nucleotides is repeated multiple times within the gene. Most commonly, the FXN gene contains fewer than 12 GAA repeats (referred to as short normal). Sometimes, however, the GAA segment is repeated 12 to 33 times (referred to as long normal).

Friedreich ataxia - caused by mutations in the FXN gene

Friedreich ataxia is an autosomal recessive disorder, which means that both copies of the FXN gene in each cell are altered. Most cases of Friedreich ataxia are caused by a mutation in which the GAA triplet repeat is abnormally expanded in both copies of the FXN gene. Instead of having 33 or fewer repeats, people with Friedreich ataxia have GAA segments that are repeated 66 to more than 1,000 times. About 4 percent of individuals with Friedreich ataxia, however, have an expanded GAA repeat in one copy of the FXN gene and a different kind of mutation in the other copy of the gene. The other mutation deletes part of the FXN gene or replaces a single nucleotide with an incorrect nucleotide.

The length of the GAA repeat appears to correlate with the onset of the disorder. GAA segments repeated fewer than 500 times tend to be associated with a late onset of symptoms (after age 25 years).

It is not fully understood how FXN mutations cause Friedreich ataxia. FXN mutations disrupt frataxin production, greatly reducing the amount of this protein in cells. A shortage of frataxin appears to decrease the activity of proteins that contain iron-sulfur clusters, which could impair the energy-producing activity in mitochondria. Cells with insufficient amounts of frataxin are also particularly sensitive to reactive molecules (free radicals) that can damage and destroy cells. Cells in the brain, spinal cord, and muscles that are damaged or have inadequate energy supplies may not function properly, leading to the signs and symptoms of Friedreich ataxia.