Friedreich Ataxia (FA) is a rare, inherited disorder that progressively damages the nervous system and can affect heart function. It is the most common form of hereditary ataxia in the United States, impacting approximately 1 in every 50,000 people. The disease develops due to an abnormally repeated DNA sequence.
Understanding Friedreich Ataxia
Friedreich Ataxia is a neurodegenerative condition that primarily affects coordination, balance, and other bodily functions. It causes nerve fibers in the spinal cord and peripheral nerves to thin, impairing signal transmission between the brain and body. The cerebellum, which coordinates balance and movement, is also significantly impacted.
Beyond the nervous system, FA can lead to complications affecting the heart, spine, and pancreas. Symptoms often begin in childhood and gradually intensify. While there is currently no cure, various treatments and therapies aim to manage symptoms and enhance quality of life.
The Trinucleotide Repeat Expansion
A trinucleotide repeat is a specific sequence of three DNA building blocks that appears multiple times in a gene. In Friedreich Ataxia, the specific repeat is a “GAA” sequence, located within the first intron of the FXN gene on chromosome 9. Normally, the FXN gene contains fewer than 12 GAA repeats.
However, in individuals with FA, this segment is abnormally expanded, ranging from 66 to over 1,000 repeats. This expansion disrupts the normal production of frataxin, a protein coded by the FXN gene. The greater the number of GAA repeats, the lower the frataxin protein produced, with levels often decreased by 70-98% compared to healthy individuals.
Frataxin is a small protein found primarily within mitochondria, the cell’s energy-producing structures. Its function is not fully understood, but it helps assemble iron-sulfur clusters, necessary for energy production. Frataxin also regulates iron levels within mitochondria, preventing free iron buildup that can lead to oxidative stress and cellular damage. A frataxin deficiency therefore impairs mitochondrial function, reducing the cell’s ability to produce energy and increasing its susceptibility to damage from reactive molecules.
Consequences and Diagnosis
Reduced frataxin production leads to mitochondrial dysfunction, which in turn impacts various cells, particularly those highly dependent on energy, such as neurons, heart muscle cells, and pancreatic beta cells. This cellular damage results in characteristic Friedreich Ataxia symptoms. These include ataxia (a lack of coordination and balance) and dysarthria (slow or slurred speech).
Other common symptoms include scoliosis (a curvature of the spine) and foot deformities. Heart disease, specifically hypertrophic cardiomyopathy, is a frequent complication, often representing the most common cause of death in people with FA. Diabetes mellitus can also develop due to the impact on pancreatic beta cells. Symptoms typically begin between ages 5 and 15, though later onset can occur, with earlier onset often correlating with more severe disease progression.
Diagnosis of Friedreich Ataxia is primarily genetic. Genetic testing is the definitive method to identify the GAA trinucleotide repeat expansion in the FXN gene, confirming the disorder. It is highly reliable and can also determine carrier status or be used for prenatal screening. Diagnosis often begins with a physical and neurological examination, noting symptoms like gait unsteadiness, loss of reflexes, and sensory impairment, which then prompts genetic testing for confirmation.