Friedreich ataxia
Friedreich’s ataxia is a disorder where there is impaired mitochondrial function that results in damage to various organ systems.
In particular, the nervous system gets damaged which causes ataxia, where the muscles cannot be moved in a coordinated way.
The disorder also affects other organs like the heart and pancreas. The disease gets its name from the German physician Nikolaus Friedreich who first described the disease over 150 years ago.So, normally on chromosome 9, there’s a gene called the FXN gene that encodes a mitochondrial protein called frataxin.
The normal amount of frataxin varies by tissue, with some tissues like the nervous system, pancreas, and heart, containing lots of it.
Frataxin helps put together cofactors called iron-sulfur clusters. It is a combination of iron and sulfur that form part of enzymes with many functions such as electron transfer, a key part of mitochondrial ATP production.
Friedreich’s ataxia is caused by a mutation in the FXN gene where there is an abnormal repetition of a GAA sequence within that gene.
This is called a triplet repeat, or trinucleotide repeat, which means that a group of three DNA nucleotides is repeated multiple times in a row, in this case guanine, adenine, and adenine.
Normally, the GAA sequence is repeated 7 to 34 times within the FXN gene. But, in Friedreich’s ataxia there is repeat expansion where there are 100 to 1700 times as many copies, with most individuals having repeats ranging from 600 to 1200 times.
Now, Friedreich’s ataxia is inherited as an autosomal recessive condition. It’s passed on by parents who are “carriers” because they have one expanded FXN gene and one normal FXN gene, but don’t have any symptoms of Friedreich ataxia.
They end up passing on their expanded FXN genes to their kid. Inheriting both copies of the FXN gene with an expanded GAA repeat is the most common way to get Friedreich’s ataxia.
The repeat expansion causes gene silencing which is when the FXN gene is not transcribed normally and very little frataxin protein is made.
With low levels of frataxin, the mitochondria are unable to efficiently incorporate iron into iron-sulfur clusters and as a result, there is lower mitochondrial ATP production, so there’s less energy available for the cell.
Furthermore, iron accumulates inside the mitochondria which reacts with oxygen to create unstable oxygen radicals. Over time these free radicals damage DNA and proteins in the cells in a process called oxidative damage.
Then, this energy deficiency and oxidative damage result in dysfunction and death of cells that are highly dependent on mitochondrial function such as neurons, cardiomyocytes and pancreatic beta cells.
The loss of neurons leads to ataxia. In the heart, there is abnormal thickening of the ventricles, a condition called hypertrophic cardiomyopathy, which is the most common cause of death in people with Friedreich’s ataxia.
In the pancreas, beta cells die off leading to decreased insulin production and diabetes mellitus. In individuals with Friedreich ataxia, the ataxia usually begins in childhood, which causes them to have difficulty in walking.
They might have some muscle weakness, and loss of proprioception, which is the sense of your position in space relative to other objects.
Usually it affects the legs and then moves up into the torso. A generalized feeling of fatigue is also common.
Eventually, most people with Friedreich’s ataxia need a wheelchair to get around. In later stages they may develop complications of cardiomyopathy, such as heart failure, and some even end up losing their vision and hearing.The diagnosis of Friedreich ataxia is established by genetic testing.
This test is used to identify the expanded GAA repeat in both copies of the FXN gene, the most common cause of Friedreich’s ataxia.
Additional tests may be performed to help determine the extent of disease, such as an MRI of the brain and spinal cord, and echocardiography to measure the heart wall thickness.
There is no treatment that can slow or halt the progression of Friedreich ataxia, but symptoms can be managed. For example, physical therapy can help maintain muscle function.
All right, as a quick recap, Friedreich’s ataxia is caused by a repeat expansion in the FXN gene on chromosome 9. It is normal to have less than 34 GAA repeats, but it is pathogenic if there are over 100 repeats.
Friedreich's ataxia affects the nervous system, pancreas and heart due to defective mitochondrial function and oxidative damage.
No notes for this video yet
Try adding a note below