FA Medical
Friedreich Ataxia (FA) was first described by German physician Nikolaus Friedreich in 1863. Friedreich’s ataxia (FA) is a neuromuscular disease that mainly affects the nervous system and the heart.
FA affects about one in 40,000 people worldwide, making it the most common in a group of related disorders called hereditary ataxias.
Friedreich Ataxia is also described in detail in the National Institutes of Health (NIH) US National Library of Medicine.
What are the symptoms of FA?
FA's major neurological symptoms include muscle weakness (ataxia) and sensory loss including loss of balance and coordination. FA mostly affects the spinal cord and the peripheral nerves that connect the spinal cord to the body’s muscles and sensory organs.
FA also affects the function of the cerebellum, a structure at the back of the brain that helps plan and coordinate movements. FA doesn’t typically affect the parts of the brain involved in cognitive function.
FA can cause hypertrophic cardiomyopathy - thickening and enlargement of ventricular walls, or cardiac muscles. This can also cause the heart’s blood-filled chambers to shrink, decreasing the organ’s pumping capacity, which can lead to arrhythmias,
What causes FA?
FA is a hereditary disease, caused by a mutation in a gene that can be passed down through a family in an autosomal recessive pattern. The gene that causes Friedreich Ataxia is called FXN and carries instructions for a protein called frataxin. The instruction results in lack of frataxin produced and diminished energy production in cells, including those of the nervous system and heart. On a cellular level, FA is linked to iron accumulation in the mitochondria and increased oxidant sensitivity. This primarily affects the tissue of the dorsal root ganglia, cerebellum, and heart muscle.
Frataxin
Frataxin is a protein that is encoded by the FXN gene. It is located in the mitochondrion and Frataxin mRNA is mostly expressed in tissues with a high metabolic rate. The function of frataxin is involved in assembly of iron-sulfur clusters. Reduced expression of frataxin is the cause of Friedreich's ataxia.
Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, and heart). Friedreich's ataxia is often considered a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin).
The reduction in frataxin gene expression may be attributable from either the silencing of transcription of the frataxin gene because of epigenetic modifications in the chromosomal entity or from the inability of splicing the expanded GAA repeats in the first intron of the pre-mRNA as seen in bacteria and Human cells or both. The expansion of intronic trinucleotide repeat GAA results in Friedreich's ataxia. This expanded repeat causes R-loop formation, and using a repeat-targeted oligonucleotide to disrupt the R-loop can reactivate frataxin expression.
96% of people with FA have a GAA trinucleotide repeat expansion in intron 1 of both alleles of their FXN gene. Overall, this leads to a decrease in frataxin mRNA synthesis and a decrease (but not absence) in frataxin protein in people with FA. A subset of FA patients have GAA expansion in one chromosome and a point mutation in the FXN exon in the other chromosome. In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels. FA patients’ peripheral tissues typically have less than 10% of the frataxin levels exhibited by unaffected people. Lower levels of frataxin result in earlier disease onset and faster progression.
What is the progression of FA?
FA has been diagnosed in people from ages 2 to 50. With the ease and cost effective expense of genetic testing, children are being diagnosed earlier and faster. In each individual, the sequence and severity of its progression is highly variable. Although there's no cure for FA, treatments exist for cardiac symptoms, and there are ways to manage ataxia and muscle weakness. Many people with FA lead active lives, going to university, holding careers, getting married and starting families.
How is FA diagnosed?
A genetic test for the FXN gene and number of repeats. Parents will usually be tested. Parents can chose to genetically test their other children to determine if they have FA or they are a carrier or non-carrier of FA.
