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A 12-year-old boy comes to the office with his parents because he has started stumbling and tripping lately. He is thinking about quitting his soccer team since he is embarrassed by his frequent falls when his legs sometimes “give out” under him. He was diagnosed with scoliosis by his school nurse last month. During his workup, an ECG shows hypertrophic cardiomyopathy and an ECHO is ordered. Which of the following is the most likely genetic abnormality underlying his condition?
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.