Which are the causes of Friedreich Ataxia?

Friedreich Ataxia (FA) is a rare genetic disorder that primarily affects the nervous system. It is named after the German physician Nikolaus Friedreich, who first described the condition in the 1860s. FA is characterized by progressive damage to the nervous system, leading to various symptoms such as difficulty with coordination, muscle weakness, and impaired speech.

Causes:

FA is caused by mutations in the frataxin (FXN) gene, which is responsible for producing a protein called frataxin. Frataxin plays a crucial role in the mitochondria, the energy-producing structures within cells. The FXN gene mutation leads to a deficiency of frataxin, resulting in impaired mitochondrial function.

Genetic Inheritance:

FA is an autosomal recessive disorder, meaning that an individual must inherit two copies of the mutated FXN gene (one from each parent) to develop the condition. If a person inherits only one mutated gene, they are considered a carrier and do not typically show symptoms of FA. When two carriers have a child, there is a 25% chance that the child will inherit two mutated genes and develop FA.

Expansion of GAA Repeats:

The specific mutation in the FXN gene that causes FA involves the expansion of a repetitive DNA sequence known as GAA repeats. In unaffected individuals, this sequence is repeated a relatively small number of times. However, in individuals with FA, the GAA repeats are expanded, leading to the production of an abnormal form of frataxin.

Effects on Mitochondrial Function:

Frataxin is essential for the proper functioning of mitochondria, particularly in the cells of the nervous system, heart, and pancreas. Mitochondria are responsible for generating energy in the form of adenosine triphosphate (ATP), which is required for various cellular processes. In FA, the deficiency of frataxin disrupts the normal energy production within mitochondria, leading to a decrease in ATP levels.

Accumulation of Iron:

Another consequence of frataxin deficiency is the abnormal accumulation of iron within the mitochondria. Iron is an essential element for many cellular processes, but when it accumulates in excessive amounts, it can lead to oxidative stress and damage to cells. The iron buildup in FA is thought to contribute to the progressive degeneration of nerve tissue.

Cellular Dysfunction and Degeneration:

The impaired mitochondrial function, decreased ATP production, and iron accumulation in FA result in cellular dysfunction and degeneration, particularly in the peripheral nerves, spinal cord, and cerebellum. These areas of the nervous system are responsible for coordinating movement and maintaining balance. As the disease progresses, the damage to these regions leads to the characteristic symptoms of FA, including ataxia (loss of coordination), muscle weakness, and speech difficulties.

Other Factors:

While the primary cause of FA is the genetic mutation in the FXN gene, other factors may influence the severity and progression of the disease. These factors include the length of the GAA repeat expansion, the presence of other genetic modifiers, and environmental factors. However, the exact interplay between these factors and the development of FA is still not fully understood and is an active area of research.

In conclusion, Friedreich Ataxia is caused by mutations in the frataxin gene, leading to a deficiency of frataxin protein and impaired mitochondrial function. The expansion of GAA repeats in the FXN gene is a key genetic abnormality associated with FA. The resulting mitochondrial dysfunction, decreased ATP production, and iron accumulation contribute to the progressive degeneration of nerve tissue, leading to the characteristic symptoms of FA. While the genetic mutation is the primary cause, other factors may influence the disease's severity and progression.