Friedreich’s ataxia (FA), a genetic condition that affects the nervous system and muscles, is caused by a mutation in a gene called FXN. This gene provides instructions for the frataxin protein, which is essential for the proper functioning of mitochondria, the energy-producing factories within a cell.
Genetic cause of FA
The most common disease-causing genetic mutation is an expansion of a GAA trinucleotide repeat. Within a person’s DNA, each gene consists of a specific sequence of building blocks called nucleotides. In DNA, there are four nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T).
The FXN gene contains a region where the GAA sequence is repeated several times, normally from 5 to 33 times. In about 96% of FA cases, however, the number of GAA repeats is much higher — ranging from 66 to over 1,000 repeats — in both copies of the FXN gene.
The number of GAA triplets in FA patients is associated with the age of symptom onset, as well as with their severity and how quickly symptoms progress. Generally, more GAA segments correspond to a younger age at onset, with more severe and rapidly progressing symptoms, whereas fewer GAA segments correspond to an older age at onset and less severe symptoms.
Rarely, some people with Friedreich’s ataxia have an expanded GAA trinucleotide repeat in one FXN gene copy and a different type of mutation in the other copy. In most of these cases, the other mutation is a change in a single coding nucleotide within the FXN gene, which is called a point mutation.
Regardless of the mutation, the overall effect is a severe reduction in frataxin levels, typically to less than 10% of the levels seen in healthy people. While it is generally accepted that frataxin is required for the proper working of mitochondria, the exact function of this protein — and the biological consequences of its loss — are not completely understood.
Frataxin helps to regulate iron metabolism in cells, and is important for the production of certain iron-containing compounds. The enzymes that mitochondria use to produce energy require these iron-containing compounds to work properly, and frataxin’s lack affects these enzymes. Ultimately, the result is a disruption in energy production within cells, which is thought to be one of the main biological mechanisms that drives FA.
Neurons (nerve cells) and muscle cells are particularly susceptible to poor energy production, because electrical signaling and muscle movements are energy-intensive processes. Damage to these cell types is primarily what leads to the signs and symptoms of Friedreich’s ataxia.
The lack of frataxin, and the resulting disruption of iron metabolism, also are linked to increased levels of toxic reactive oxygen molecules that damage cellular structures, and promote cell death through multiple biological mechanisms.
FA is inherited in an autosomal recessive manner, which means that a person develops FA if they inherit mutated versions of both copies of the FXN gene (one copy comes from each biological parent).
If an individual inherits one normal copy and one mutated copy of the FXN gene, that person will not develop symptoms but will be a disease carrier.
If two carriers have a biological child, there is a 25% chance that the child will have FA, a 50% chance that the child will be a carrier, and a 25% chance that the child will neither have the disease nor be a carrier.
Last updated: April 6, 2021
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