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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’s a buildup of iron that damages various organ systems - in particular, the nervous system gets damaged which causes ataxia, which is when the muscles don’t move in a coordinated way.
The disorder also affects some internal organs like the heart and pancreas.
The disease gets its name from the German physician Nikolaus Friedreich who first described the disease over a hundred years ago.
So, normally, there’s a gene called the FXN gene on chromosome 9 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 helps enzymes with many functions such as gene expression and electron transfer.
In a normal FXN gene, the expected DNA sequence is GAA, which means there’s one guanine followed by two adenine nucleic acids.
Friedreich’s ataxia is an autosomal recessive disorder 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 way more copies of the repeat.
This is caused by slipped mispairing, that’s where the enzyme DNA polymerase gets confused when copying a repetitive sequence.
DNA polymerase loses its place among the FXN triplet repeats and goes back to recopy what it already just copied. This is like getting lost in a video and watching the same part over and over.
This is like getting lost in a video and watching the same part over and over.
But since DNA polymerase is making copies, the effect is an increase, or expansion, of the number of repeats.
If the sequence is repeated between 34 to 100 times, Friedreich’s ataxia might manifest if the GAA sequences are uninterrupted, meaning there are no other nucleotides between the repeats.
Even in people who do not manifest the disease, this is considered a premutation, meaning that number of repeats could expand in the next generation and cause the disease to manifest.
Friedreich’s ataxia typically always develops when GAA is repeated uninterrupted from 100 to 1700 times, with most individuals having repeats ranging from 600 to 1200 times.
The repeat expansion causes gene silencing which is when the FXN gene does not get transcribed and no frataxin protein is made.
Without frataxin, the mitochondria is unable to turn iron into iron-sulfur clusters and as a result, iron accumulates inside the cell and reacts with oxygen to create unstable oxygen radicals.