friedreich ataxia

Summary

Summary: An autosomal recessive disease, usually of childhood onset, characterized pathologically by degeneration of the spinocerebellar tracts, posterior columns, and to a lesser extent the corticospinal tracts. Clinical manifestations include GAIT ATAXIA, pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy), and lower extremity weakness. Most forms of this condition are associated with a mutation in a gene on chromosome 9, at band q13, which codes for the mitochondrial protein frataxin. (From Adams et al., Principles of Neurology, 6th ed, p1081; N Engl J Med 1996 Oct 17;335(16):1169-75) The severity of Friedreich ataxia associated with expansion of GAA repeats in the first intron of the frataxin gene correlates with the number of trinucleotide repeats. (From Durr et al, N Engl J Med 1996 Oct 17;335(16):1169-75)

Top Publications

  1. Jauslin M, Vertuani S, Durini E, Buzzoni L, Ciliberti N, Verdecchia S, et al. Protective effects of Fe-Aox29, a novel antioxidant derived from a molecular combination of Idebenone and vitamin E, in immortalized fibroblasts and fibroblasts from patients with Friedreich Ataxia. Mol Cell Biochem. 2007;302:79-85 pubmed
    b>Friedreich Ataxia (FRDA), the most frequent inherited ataxia, is not only characterized by progressive gait and limb ataxia, but in most cases is also accompanied by a severe hypertrophic cardiomyopathy...
  2. Kumari D, Lokanga R, Yudkin D, Zhao X, Usdin K. Chromatin changes in the development and pathology of the Fragile X-associated disorders and Friedreich ataxia. Biochim Biophys Acta. 2012;1819:802-10 pubmed publisher
    The Fragile X-associated disorders (FXDs) and Friedreich ataxia (FRDA) are genetic conditions resulting from expansion of a trinucleotide repeat in a region of the affected gene that is transcribed but not translated...
  3. Puccio H. Multicellular models of Friedreich ataxia. J Neurol. 2009;256 Suppl 1:18-24 pubmed publisher
    Patients with Friedreich ataxia (FRDA) have severely reduced levels of the mitochondrial protein frataxin, which results from a large GAA triplet-repeat expansion within the frataxin gene (FXN)...
  4. Delatycki M. Evaluating the progression of Friedreich ataxia and its treatment. J Neurol. 2009;256 Suppl 1:36-41 pubmed publisher
    b>Friedreich ataxia is characterised by slowly progressive neurodegeneration and cardiomyopathy...
  5. Richardson D, Huang M, Whitnall M, Becker E, Ponka P, Suryo Rahmanto Y. The ins and outs of mitochondrial iron-loading: the metabolic defect in Friedreich's ataxia. J Mol Med (Berl). 2010;88:323-9 pubmed publisher
    ..More generally, disturbance of mitochondrial iron utilization in other diseases probably also results in similar compensatory alterations...
  6. Gregory S, Macrae C, Aziz K, Sims K, Schmahmann J, Kardan A, et al. Myocardial blood flow and oxygen consumption in patients with Friedreich's ataxia prior to the onset of cardiomyopathy. Coron Artery Dis. 2007;18:15-22 pubmed
  7. Al Mahdawi S, Pinto R, Ismail O, Varshney D, Lymperi S, Sandi C, et al. The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet. 2008;17:735-46 pubmed
    b>Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, leading to reduced expression of frataxin protein...
  8. Marmolino D, Acquaviva F, Pinelli M, Monticelli A, Castaldo I, Filla A, et al. PPAR-gamma agonist Azelaoyl PAF increases frataxin protein and mRNA expression: new implications for the Friedreich's ataxia therapy. Cerebellum. 2009;8:98-103 pubmed publisher
    ..We hypothesize that PPAR-gamma agonists could play a role in the treatment of FRDA, and our results offer the logical bases to further investigate the usefulness of this group of agents for the treatment of the FRDA...
  9. Fahey M, Corben L, Collins V, Churchyard A, Delatycki M. The 25-foot walk velocity accurately measures real world ambulation in Friedreich ataxia. Neurology. 2007;68:705-6 pubmed

More Information

Publications62

  1. Clark R, De Biase I, Malykhina A, Al Mahdawi S, Pook M, Bidichandani S. The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model. Hum Genet. 2007;120:633-40 pubmed
    b>Friedreich ataxia (FRDA) is caused by homozygosity for FXN alleles containing an expanded GAA triplet-repeat (GAA-TR) sequence...
  2. Steinkellner H, Scheiber Mojdehkar B, Goldenberg H, Sturm B. A high throughput electrochemiluminescence assay for the quantification of frataxin protein levels. Anal Chim Acta. 2010;659:129-32 pubmed publisher
    ..The assay has an excellent precision and provides a new tool for the set up of high-throughput screening for basic research and for clinical studies with FRDA patients...
  3. Gonzalez Cabo P, Llorens J, Palau F, Molto M. Friedreich ataxia: an update on animal models, frataxin function and therapies. Adv Exp Med Biol. 2009;652:247-61 pubmed publisher
    b>Friedreich ataxia (FRDA) is an autosomal recessive progressively debilitating degenerative disease that principally affects the nervous system and the heart. Although FRDA is considered a rare disease, is the most common inherited ataxia...
  4. Richardson T, Yang S, Wen Y, Simpkins J. Estrogen protection in Friedreich's ataxia skin fibroblasts. Endocrinology. 2011;152:2742-9 pubmed publisher
    ..These data show for the first time that phenolic E2-like compounds are potent protectors against oxidative stress-induced cell death in FRDA fibroblasts and are possible candidate drugs for the treatment and prevention of FRDA symptoms...
  5. Boesch S, Sturm B, Hering S, Scheiber Mojdehkar B, Steinkellner H, Goldenberg H, et al. Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial. Mov Disord. 2008;23:1940-4 pubmed publisher
    ..Safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach...
  6. Morral J, Davis A, Qian J, Gelman B, Koeppen A. Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia. Acta Neuropathol. 2010;120:97-108 pubmed publisher
    ..Sural nerves in FRDA showed no convincing change in ferritin and ferroportin, militating against local iron dysmetabolism. The result stands out in contrast to the previously reported changes in dorsal spinal roots of patients with FRDA...
  7. Acquaviva F, Castaldo I, Filla A, Giacchetti M, Marmolino D, Monticelli A, et al. Recombinant human erythropoietin increases frataxin protein expression without increasing mRNA expression. Cerebellum. 2008;7:360-5 pubmed publisher
    ..These findings could help the evaluation of the treatment with erythropoietin as a potential therapeutic agent for Friedreich's ataxia...
  8. Lynch D, Perlman S, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol. 2010;67:941-7 pubmed publisher
    To assess the efficacy of idebenone on neurological function in patients with Friedreich ataxia.
  9. Willis J, Isaya G, Gakh O, Capaldi R, Marusich M. Lateral-flow immunoassay for the frataxin protein in Friedreich's ataxia patients and carriers. Mol Genet Metab. 2008;94:491-7 pubmed publisher
  10. Clark R, Bhaskar S, Miyahara M, Dalgliesh G, Bidichandani S. Expansion of GAA trinucleotide repeats in mammals. Genomics. 2006;87:57-67 pubmed
    ..nine loci showed expanded alleles containing >65 triplets, analogous to disease-causing expansions in Friedreich ataxia, including two that are in introns of genes of unknown function...
  11. Koeppen A, Mazurkiewicz J. Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol. 2013;72:78-90 pubmed publisher
    b>Friedreich ataxia is an autosomal recessive disorder that affects children and young adults...
  12. Nachbauer W, Boesch S, Reindl M, Eigentler A, Hufler K, Poewe W, et al. Skeletal muscle involvement in friedreich ataxia and potential effects of recombinant human erythropoietin administration on muscle regeneration and neovascularization. J Neuropathol Exp Neurol. 2012;71:708-15 pubmed publisher
    b>Friedreich ataxia (FRDA) is caused by reduced expression of the mitochondrial protein frataxin...
  13. Anheim M, Mariani L, Calvas P, Cheuret E, Zagnoli F, Odent S, et al. Exonic deletions of FXN and early-onset Friedreich ataxia. Arch Neurol. 2012;69:912-6 pubmed
    b>Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene...
  14. Marmolino D. Friedreich's ataxia: past, present and future. Brain Res Rev. 2011;67:311-30 pubmed publisher
    ..This review will discuss recent findings on FRDA pathogenesis, frataxin function, new treatments, as well as recent animal and cellular models. Controversial aspects are also discussed...
  15. Liu J, Verma P, Evans Galea M, Delatycki M, Michalska A, Leung J, et al. Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem Cell Rev. 2011;7:703-13 pubmed publisher
    b>Friedreich ataxia (FRDA) is an autosomal recessive disorder characterised by neurodegeneration and cardiomyopathy...
  16. Lodi R, Tonon C, Calabrese V, Schapira A. Friedreich's ataxia: from disease mechanisms to therapeutic interventions. Antioxid Redox Signal. 2006;8:438-43 pubmed
    ..Pilot studies have shown the potential effect of antioxidant therapy in this condition and provide a strong rationale for designing larger clinical randomized trials...
  17. Lynch D, Farmer J, Tsou A, Perlman S, Subramony S, Gomez C, et al. Measuring Friedreich ataxia: complementary features of examination and performance measures. Neurology. 2006;66:1711-6 pubmed
    To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics.
  18. Lufino M, Silva A, Nemeth A, Alegre Abarrategui J, Russell A, Wade Martins R. A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds. Hum Mol Genet. 2013;22:5173-87 pubmed publisher
  19. Friedman L, Farmer J, Perlman S, Wilmot G, Gomez C, Bushara K, et al. Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. Mov Disord. 2010;25:426-32 pubmed publisher
    b>Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, and arreflexia...
  20. Di Prospero N, Sumner C, Penzak S, Ravina B, Fischbeck K, Taylor J. Safety, tolerability, and pharmacokinetics of high-dose idebenone in patients with Friedreich ataxia. Arch Neurol. 2007;64:803-8 pubmed
    b>Friedreich ataxia (FA) is a progressive, multisystem degenerative disorder in which oxidative stress is believed to have a role...
  21. Goncalves S, Paupe V, Dassa E, Rustin P. Deferiprone targets aconitase: implication for Friedreich's ataxia treatment. BMC Neurol. 2008;8:20 pubmed publisher
    b>Friedreich ataxia is a neurological disease originating from an iron-sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected...
  22. Koeppen A, Michael S, Knutson M, Haile D, Qian J, Levi S, et al. The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins. Acta Neuropathol. 2007;114:163-73 pubmed
    ..Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration...
  23. Boddaert N, Le Quan Sang K, Rotig A, Leroy Willig A, Gallet S, Brunelle F, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007;110:401-8 pubmed
    Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative ..
  24. Soragni E, Xu C, Cooper A, Plasterer H, Rusche J, Gottesfeld J. Evaluation of histone deacetylase inhibitors as therapeutics for neurodegenerative diseases. Methods Mol Biol. 2011;793:495-508 pubmed publisher
    ..Here, we describe the various techniques used in our laboratories to dissect mechanisms of gene silencing in FRDA and HD, and to test our HDAC inhibitors for their ability to reverse changes in gene expression in cellular models...
  25. Lim C, Kalinowski D, Richardson D. Protection against hydrogen peroxide-mediated cytotoxicity in Friedreich's ataxia fibroblasts using novel iron chelators of the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone class. Mol Pharmacol. 2008;74:225-35 pubmed publisher
    ..These findings further indicate the potential of PCTH for treatment of iron overload...
  26. Condo I, Ventura N, Malisan F, Tomassini B, Testi R. A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem. 2006;281:16750-6 pubmed
    Frataxin is a mitochondrial protein involved in iron metabolism. Defective expression of frataxin causes Friedreich ataxia (FA), an inherited degenerative syndrome characterized by ataxia, cardiomyopathy, and high incidence of diabetes...
  27. Du J, Campau E, Soragni E, Ku S, Puckett J, Dervan P, et al. Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J Biol Chem. 2012;287:29861-72 pubmed publisher
    The genetic mutation in Friedreich ataxia (FRDA) is a hyperexpansion of the triplet-repeat sequence GAA·TTC within the first intron of the FXN gene...
  28. Nachbauer W, Boesch S, Schneider R, Eigentler A, Wanschitz J, Poewe W, et al. Bioenergetics of the calf muscle in Friedreich ataxia patients measured by 31P-MRS before and after treatment with recombinant human erythropoietin. PLoS ONE. 2013;8:e69229 pubmed publisher
    b>Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in the FXN gene leading to reduced expression of the mitochondrial protein frataxin...
  29. Heidari M, Houshmand M, Hosseinkhani S, Nafissi S, Scheiber Mojdehkar B, Khatami M. A novel mitochondrial heteroplasmic C13806A point mutation associated with Iranian Friedreich's ataxia. Cell Mol Neurobiol. 2009;29:225-33 pubmed publisher
    ..It is possible that mutations in ND genes could constitute a predisposing factor which in combination with environmental risk factors affects age of onset and disease progression...
  30. Meier T, Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009;256 Suppl 1:25-30 pubmed publisher
    ..of clinical studies, published from 1999 to 2008, on the use of idebenone in the treatment of patients with Friedreich ataxia (FRDA)...
  31. Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich's ataxia to develop therapeutic approaches. Hum Mol Genet. 2010;19:R103-10 pubmed publisher
    ..and Pastore, A. (2009) The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J. Neurol., 256 (Suppl. 1), 9-17; Gottesfeld, J.M...
  32. Kearney M, Orrell R, Fahey M, Pandolfo M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev. 2009;:CD007791 pubmed publisher
    b>Friedreich ataxia is a rare inherited, autosomal recessive, neurological disorder characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties...
  33. Irazusta V, Cabiscol E, Reverter Branchat G, Ros J, Tamarit J. Manganese is the link between frataxin and iron-sulfur deficiency in the yeast model of Friedreich ataxia. J Biol Chem. 2006;281:12227-32 pubmed
    b>Friedreich ataxia is a human neurodegenerative and myocardial disease caused by decreased expression of the mitochondrial protein frataxin...
  34. Rance G, Corben L, Du Bourg E, King A, Delatycki M. Successful treatment of auditory perceptual disorder in individuals with Friedreich ataxia. Neuroscience. 2010;171:552-5 pubmed publisher
    b>Friedreich ataxia (FRDA) is a neurodegenerative disease affecting motor and sensory systems...
  35. Gakh O, Bedekovics T, Duncan S, Smith D, Berkholz D, Isaya G. Normal and Friedreich ataxia cells express different isoforms of frataxin with complementary roles in iron-sulfur cluster assembly. J Biol Chem. 2010;285:38486-501 pubmed publisher
    b>Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by insufficient expression of frataxin (FXN), a mitochondrial iron-binding protein required for Fe-S cluster assembly...
  36. Rufini A, Fortuni S, Arcuri G, Condo I, Serio D, Incani O, et al. Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia. Hum Mol Genet. 2011;20:1253-61 pubmed publisher
    ..Thus, we provide evidence for the therapeutic potential of directly interfering with the frataxin degradation pathway...
  37. Saccà F, Puorro G, Antenora A, Marsili A, Denaro A, Piro R, et al. A combined nucleic acid and protein analysis in Friedreich ataxia: implications for diagnosis, pathogenesis and clinical trial design. PLoS ONE. 2011;6:e17627 pubmed publisher
    ..No studies have yet reported frataxin protein and mRNA levels in a large cohort of FRDA patients, carriers and controls...
  38. Soragni E, Herman D, Dent S, Gottesfeld J, Wells R, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. 2008;36:6056-65 pubmed publisher
    b>Friedreich ataxia (FRDA) is caused by hyperexpansion of GAA*TTC repeats located in the first intron of the FXN gene, which inhibits transcription leading to the deficiency of frataxin...
  39. Coppola G, Choi S, Santos M, Miranda C, Tentler D, Wexler E, et al. Gene expression profiling in frataxin deficient mice: microarray evidence for significant expression changes without detectable neurodegeneration. Neurobiol Dis. 2006;22:302-11 pubmed
    ..The identification of a core set of genes changing early in the FRDA pathogenesis can be a useful tool in both clarifying the disease process and in evaluating new therapeutic strategies...
  40. Jones J, Estirado A, Redondo C, Bueno C, Martinez S. Human adipose stem cell-conditioned medium increases survival of Friedreich's ataxia cells submitted to oxidative stress. Stem Cells Dev. 2012;21:2817-26 pubmed publisher
    ..Also, this work shows how neurotrophic factors, particularly BDNF, are capable of increasing cell survival in response to oxidative stress, which occurs in many neurodegenerative diseases...
  41. Mariotti C, Fancellu R, Caldarazzo S, Nanetti L, Di Bella D, Plumari M, et al. Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov Disord. 2012;27:446-9 pubmed publisher
    b>Friedreich ataxia is a rare disease caused by GAA-trinucleotide-repeat expansions in the frataxin gene, leading to marked reduction of qualitatively normal frataxin protein...
  42. Koeppen A. Friedreich's ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011;303:1-12 pubmed publisher
  43. Stemmler T, Lesuisse E, Pain D, Dancis A. Frataxin and mitochondrial FeS cluster biogenesis. J Biol Chem. 2010;285:26737-43 pubmed publisher
    b>Friedreich ataxia is an inherited neurodegenerative disease caused by frataxin deficiency. Frataxin is a conserved mitochondrial protein that plays a role in FeS cluster assembly in mitochondria...
  44. Correia A, Wang T, Craig E, Gomes C. Iron-binding activity in yeast frataxin entails a trade off with stability in the alpha1/beta1 acidic ridge region. Biochem J. 2010;426:197-203 pubmed publisher
    ..Alterations on the conserved beta-sheet residues have only a modest impact on the protein stability, highlighting the functional importance of residues 122-124...
  45. Wang T, Craig E. Binding of yeast frataxin to the scaffold for Fe-S cluster biogenesis, Isu. J Biol Chem. 2008;283:12674-9 pubmed publisher
    b>Friedreich ataxia is caused by reduced activity of frataxin, a conserved iron-binding protein of the mitochondrial matrix, thought to supply iron for formation of Fe-S clusters on the scaffold protein Isu...
  46. Boesch S, Sturm B, Hering S, Goldenberg H, Poewe W, Scheiber Mojdehkar B. Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin. Ann Neurol. 2007;62:521-4 pubmed
    ..Treatment with recombinant human erythropoietin showed a persistent and significant increase in frataxin levels after 8 weeks (p < 0.01). All patients showed a reduction of oxidative stress markers...
  47. Meyer C, Schmid G, Görlitz S, Ernst M, Wilkens C, Wilhelms I, et al. Cardiomyopathy in Friedreich's ataxia-assessment by cardiac MRI. Mov Disord. 2007;22:1615-22 pubmed
    ..If despite this limitation intervention studies use left ventricular mass as outcome measure, MRI is recommended as the most accurate assessment of cardiac anatomy in vivo...
  48. Herman D, Jenssen K, Burnett R, Soragni E, Perlman S, Gottesfeld J. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat Chem Biol. 2006;2:551-8 pubmed
    ..This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia...
  49. Palomo G, Cerrato T, Gargini R, Diaz Nido J. Silencing of frataxin gene expression triggers p53-dependent apoptosis in human neuron-like cells. Hum Mol Genet. 2011;20:2807-22 pubmed publisher
  50. Ribai P, Pousset F, Tanguy M, Rivaud Pechoux S, Le Ber I, Gasparini F, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol. 2007;64:558-64 pubmed
    b>Friedreich ataxia (FA) is the most frequent autosomal recessive cerebellar ataxia. Although the phenotype is well known, disease progression has not been evaluated in a prospective manner.
  51. Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007;16:929-41 pubmed
    ..These data suggest that frataxin binds the iron-sulfur biogenesis Nfs1/ISCU complex through ISD11, that the interaction is nickel-dependent, and that multiple consequences of frataxin deficiency are duplicated by ISD11 deficiency...
  52. Michael S, Petrocine S, Qian J, Lamarche J, Knutson M, Garrick M, et al. Iron and iron-responsive proteins in the cardiomyopathy of Friedreich's ataxia. Cerebellum. 2006;5:257-67 pubmed
    ..Progressive cardiomyopathy in FRDA is the likely result of iron-catalyzed mitochondrial damage followed by muscle fiber necrosis and a chronic reactive myocarditis...
  53. Al Mahdawi S, Sandi C, Mouro Pinto R, Pook M. Friedreich ataxia patient tissues exhibit increased 5-hydroxymethylcytosine modification and decreased CTCF binding at the FXN locus. PLoS ONE. 2013;8:e74956 pubmed publisher
    b>Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, which induces epigenetic changes and FXN gene silencing...