Friedreich Ataxia (FA)

Friedreich ataxia (FA), although rare, is the most common of the inherited, autosomal-recessive forms of neurodegenerative ataxia, especially among persons of European heritage. FA is characterized by progressive discoordination of the extremities and trunk, muscular weakness and spasticity, difficulty walking, cardiomyopathy, dysarthria, and the onset of disease-related diabetes mellitus in one-third of patients.1

Genetic Etiology of FA

More than 96% of cases of FA are caused by mutations in the FXN gene, which encodes the protein frataxin.1-3 The mutations result in a pathological repeat expansion of the GAA (guanine-adenine-adenine) trinucleotide within the first intron of the FXN gene. Between 1% and 4% of the remaining cases are caused by point mutations or deletions that result in compound heterozygous expansion.1,3 

In normal FXN genes, the GAA trinucleotide expansion has fewer than 40 repeats,1,3 whereas between 56 and more than 1000 repeats can occur in the FXN genes of patients with FA.1 The number of repeats in FA most frequently ranges between 600 and 900.3

Abnormal DNA methylation has been detected upstream of the trinucleotide expansion on the silenced FXN gene. DNA methylation mediates gene expression throughout the human genome, and abnormal DNA methylation in patients with FA may contribute to FXN gene silencing.3

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Frataxin Protein Deficiency

The GAA trinucleotide expansions in intron 1 silence the FXN gene and significantly suppress frataxin protein biosynthesis, resulting in frataxin deficiency.3,4 A complete absence of frataxin is incompatible with embryonic survival because of a lack of iron accumulation.4 

Normally, frataxin is encoded in cellular nuclei, expressed in cellular cytoplasm as a precursor polypeptide, and imported into the mitochondria.3 Frataxin deficiency has been linked to increased iron deposition in the mitochondria and decreased activity of iron-sulfur cluster (ISC)-containing subunits of mitochondrial respiratory chain complexes I through III. ISC subunits are involved in gene regulation, enzyme catalysis, and oxidative phosphorylation.3

Researchers conducting studies in yeast discovered a strong correlation between frataxin levels and mitochondrial iron. Decreased levels of frataxin were associated with iron overload and a tendency toward oxidative stress. The study suggested that frataxin plays a role in mitochondrial iron homeostasis by directly and indirectly regulating iron levels through iron export, storage, chaperoning, and interactions with other proteins that promote iron uptake.3,5

Although the exact nature of the role of frataxin has yet to be elucidated, studies have provided sufficient evidence that frataxin plays a critical role in ISC biogenesis. ​​Recombinant and immunoprecipitant protein studies have demonstrated a direct interaction between the ISC core assembly complex and human frataxin, in which frataxin plays a role as an allosteric modular by accelerating sulfur transfer on the ISC assembly protein, ISCU2.3,6,7 In FA, the disruption of ISC formation leads to the excess accumulation and oxidation of iron.3

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Role of Iron in Friedreich Ataxia

Studies have detected pathological levels of iron deposition within the mitochondria of patients with FA; however, the evidence indicating that iron deposition occurs throughout the nervous system in FA is less supportive.

Some studies have shown increased intracellular ferritin expression within the microglial cells supporting the dentate nucleus and dorsal root ganglia (DRG).3,8,9 Excess ferritin expression in the microglial cells may promote the inflammatory destruction of neurons and the dysfunction of satellite cells, resulting in impaired neuronal growth in the DRG as seen on imaging studies.3,9 

Primary sites of neuronal loss include the spinal cord and spinal nerve roots; neuronal loss particularly affects large myelinated axons in the peripheral nerves.10 Histopathological examination of nerve tissue samples from patients with FA reveals a loss of myelinated fibers in the dorsal columns and corticospinal tracts, and milder involvement of the spinocerebellar tracts is also seen.11

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Associated Inflammation and Oxidative Stress

Frataxin deficiency linked to excessive iron accumulation and deposition results in increased inflammation and oxidative tissue damage due to the production of reactive oxygen species by free iron. Free radicals produced by respiratory chain complexes I and II in the mitochondria contribute to glutathione depletion, lipid peroxidation, and cellular apoptosis. Oxidative consequences related to frataxin deficiency are linked to impaired cytoskeletal dynamics, increased mitophagy, altered lipid metabolism, altered mitochondrial transport, and abnormal calcium homeostasis.3,12 

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  1. Delatycki MB, Bidichandani SI. Friedreich ataxia-pathogenesis and implications for therapies. Neurobiol Dis. 2019;132:104606. doi:10.1016/j.nbd.2019.104606
  2. Friedreich ataxia fact sheet. NIH. National Institute of Neurological Disorders and Stroke. Accessed January 11, 2023.
  3. Cook A, Giunti P. Friedreich’s ataxia: clinical features, pathogenesis and management. Br Med Bull. 2017;124(1):19-30. doi:10.1093/bmb/ldx034
  4. Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011;303(1-2):1-12. doi:10.1016/j.jns.2011.01.010
  5. Branda SS, Yang Z, Chew A, Isaya G. Mitochondrial intermediate peptidase and the yeast frataxin homolog together maintain mitochondrial iron homeostasis in saccharomyces cerevisiae. Hum Mol Genet. 1999;8(6):1099-1110. doi:10.1093/hmg/8.6.1099
  6. Bridwell-Rabb J, Fox NG, Tsai CL, Winn AM, Barondeau DP. Human frataxin activates Fe–S cluster biosynthesis by facilitating sulfur transfer chemistry. Biochemistry. 2014;53(30):4904-4913. doi:10.1021/bi500532e
  7. Schmucker S, Martelli A, Colin F, et al. Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PLoS One. 2011;6(1):e16199. doi:10.1371/journal.pone.0016199
  8. Koeppen AH, Ramirez RL, Yu D, et al. Friedreich’s ataxia causes redistribution of iron, copper, and zinc in the dentate nucleus. Cerebellum. 2012;11(4):845-860. doi:10.1007/s12311-012-0383-5
  9. Koeppen AH, Ramirez RL, Becker AB, Mazurkiewicz JE. Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation. Acta Neuropathol Commun. 2016;4:46. doi:10.1186/s40478-016-0288-5
  10. Chawla J. Friedreich ataxia: pathophysiology. Medscape. Updated May 4, 2021. Accessed January 11, 2023.
  11. Chawla J. Friedreich ataxia: histologic findings. Medscape. Updated May 4, 2021. Accessed January 11, 2023.
  12. Abeti R, Parkinson MH, Hargreaves IP, et al. Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia. Cell Death Dis. 2016;7(5):e2237. doi:10.1038/cddis.2016.111

Reviewed by Debjyoti Talukdar, MD, on 1/23/2023.