The Friedreichs Ataxia causes explained
Friedreich’s ataxia is a rare inherited neurodegenerative disorder that primarily affects the nervous system and the muscles used for movement. It typically manifests in childhood or adolescence and progresses over time, leading to significant disabilities. Understanding the causes of Friedreich’s ataxia involves exploring its genetic basis, molecular mechanisms, and the way these contribute to the disease’s development.
The root cause of Friedreich’s ataxia is a mutation in the FXN gene, which is responsible for producing a protein called frataxin. Frataxin plays a critical role in mitochondrial function, particularly in the formation of iron-sulfur clusters necessary for cellular energy production. When this gene is mutated, the production of frataxin is significantly reduced, leading to a deficiency of the protein. This deficiency disrupts mitochondrial function, resulting in impaired energy generation within cells, especially in nerve and heart tissues that have high energy demands.
The most common genetic mutation associated with Friedreich’s ataxia involves the expansion of a GAA trinucleotide repeat within the FXN gene. Normally, this sequence is repeated fewer than 40 times, but in affected individuals, it can be expanded to hundreds or even over a thousand repeats. This abnormal expansion causes the gene to become less active or silenced altogether, leading to decreased frataxin levels. The severity of the disease often correlates with the length of this GAA repeat expansion—the longer the repeat, the more severe the symptoms tend to be.
At a molecular level, the GAA expansion leads to the formation of abnormal DNA structures called triplexes or sticky DNA, which hinder the process of transcription—the way our cells read and produce proteins from genes. As a result, the production of frataxin diminishes, impairing mitochondrial function. The energy deficiency primarily affects neurons in the spinal cord and peripheral nerves, causing ataxia, muscle weakness, and loss of coordination. Additionally, the heart muscle can be affected, leading to cardiomyopathy, and the pancreas may also experience dysfunction, contributing to diabetes in some cases.
The cellular consequences of frataxin deficiency extend beyond energy production. It causes abnormal iron accumulation within mitochondria, which can generate harmful free radicals—unstable molecules that can damage cellular components like DNA, proteins, and lipids. This oxidative stress contributes further to neuronal degeneration and tissue damage observed in Friedreich’s ataxia.
In summary, Friedreich’s ataxia is caused by a genetic mutation leading to reduced frataxin levels, which impairs mitochondrial function and causes oxidative stress. The predominant GAA trinucleotide repeat expansion within the FXN gene is the hallmark of this disorder, with longer repeats correlating with more severe disease manifestations. While there is currently no cure, understanding the genetic and molecular causes of Friedreich’s ataxia is essential for developing targeted therapies to slow or halt its progression.
