Friedreich’s ataxia (FA), a genetic condition that affects the nervous system and muscles, is caused by a mutation in a gene called frataxin (FXN). The FXN gene provides instructions for the frataxin protein, which is essential for the proper functioning of mitochondria, the energy-producing factories within the cell.
Genetic cause of FA
The genetic defect that causes Friedreich’s ataxia is an expansion of a GAA trinucleotide repeat. Each gene consists of a coding sequence made up of four chemical units called nucleotides – adenine (A), cytosine (C), guanine (G), and thymine (T).
In the FXN gene, there is a region where three nucleotides, GAA, are repeated several times (from 5 to 33 times). The number of repeats in people with FA is increased (ranging from 66 repeats to more than 1,000 repeats) in both copies of the FXN gene.
The length of the GAA trinucleotide repeat appears to be related to the age of onset, the degree of severity, and pace of progression of the symptom. People with GAA segments repeated fewer than 300 times tend to have a later onset of symptoms (after age 25) than those with larger GAA trinucleotide repeats.
Around 2 percent of people with FA have an expanded GAA trinucleotide repeat in one copy and a different type of mutation in the other copy of the FXN gene. In most of these cases, the other mutation changes a single coding nucleotide (called a point mutation), within the FXN gene.
Although it is not clear how these mutations cause Friedreich’s ataxia, scientists think the frataxin protein controls the production of energy in the mitochondria. Frataxin keeps iron in a bound form and provides it for the synthesis of mitochondrial enzymes used to produce energy. When there’s a lack of frataxin, all the iron is in free-form, which cannot be utilized for mitochondrial enzyme synthesis, resulting in a disruption in the production of energy. Free iron then accumulates, resulting in a buildup of harmful reactive molecules (called free radicals), damaging and destroying the cells.
Since mitochondria is an essential source of energy, cells in the brain, spinal cord, and muscles, which require a lot of energy, are particularly vulnerable to mitochondrial problems and become easily damaged by an insufficient energy supply. This leads to the signs and symptoms of Friedreich’s ataxia.
FA is inherited in an autosomal recessive manner, which means that an individual develops FA only when he or she carries genetic defects in both copies of the FXN gene: one copy inherited from each parent.
If an individual inherits one normal copy and one defective copy of the FXN gene, he or she shows no symptoms and is said to be a carrier. If both parents are carriers, the risk of a child developing FA is 25 percent.
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