Friedreich’s ataxia – causes, symptoms, diagnosis, treatment, pathology

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. To stabilize themselves, the oxygen radicals
try to steal electrons from nearby molecules like DNA or proteins. Unfortunately, if this
happens enough times, it can cause the cell to die. In the nervous system, the loss of
neurons leads to ataxia. In the heart, the death of myocytes leads to difficulty pumping
blood through the heart, which thickens the heart’s lower chambers or ventricles. This
leads to hypertrophic cardiomyopathy, the most common cause of death in these individuals.
In the pancreas, insulin production is impaired as beta cells are affected, leading to diabetes
mellitus. Because individuals can develop hypertrophic cardiomyopathy and diabetes mellitus
– a mnemonic to remember is “Friedreich is your falling frat brother, with a heart
big and sweet”. In other words, the main symptom includes falling which refers to ataxia,
and the sweet big heart refers to diabetes and hypertrophic cardiomyopathy. In individuals with Friedreich ataxia, the
ataxia usually begins in childhood, which children falling or staggering when they walk.
They might have muscle weakness and a loss of vibratory sense and proprioception which
is a sense of where they are relative to other objects. Usually it affects the legs and then
moves up into the torso. In addition, individuals might lose their deep tendon reflexes, develop
involuntary eye movements, and feel more and more fatigue – eventually becoming dependent
on a wheelchair to get around. Diagnosis of Friedreich ataxia can be done
with genetic testing to look for uninterrupted GAA repeats. Additional studies to help determine
the extent of disease, an electromyogram or EMG, which tests the electrical activity of
muscle cells during contraction, and nerve conduction velocity studies, which test nerve
responses to small shocks, and an MRI of the brain and spinal cord. There is no treatment for Friedreich ataxia,
but symptoms can be managed. For example, a brace can be used for scoliosis, and physical
therapy can help maintain muscle tone. All right, quick recap, Friedreich’s ataxia
is the repeat of the FXN gene on chromosome 9. It is a pre-mutation if there are uninterrupted
GAA repeats of 34-100 times, and it is pathogenic if it repeats over 100 times. The nervous
system, pancreas and heart are affected due to oxygen radical accumulation. Ataxia, diabetes
and hypertrophic cardiomyopathy result.

11 thoughts on “Friedreich’s ataxia – causes, symptoms, diagnosis, treatment, pathology”

  1. I was just looking at this diagnosis! So interesting. Happy to see your video. Thanks for all the quality content!

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