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.