The Molecular Basis of Friedreich Ataxia

  • Massimo Pandolfo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 516)


Friedreich ataxia (FRDA) is the most common of the early-onset hereditary ataxias in Indo-European and North African populations. The disease was first described in 1863 by Nicholaus Friedreich, Professor of Medicine in Heidelberg. Friedreich’s papers reported the essential clinical and pathological features of the disease, a “degenerative atrophy of the posterior columns of the spinal cord” leading to progressive ataxia, sensory loss and muscle weakness, often associated with scoliosis, foot deformity and heart disease. However, the subsequent description of atypical cases and of clinically similar diseases clouded classification for many years. Diagnostic criteria were established in the late 1970s, after a renewed interest in the disease prompted several rigorous clinical studies. The Quebec Collaborative Group described the typical features of the disease in well-established cases.1 Harding modified some of the Québec Collaborative Group diagnostic criteria to include cases at an early stage of the disease.2 According to Harding, essential clinical features include:
  1. i)

    autosomal recessive inheritance

  2. ii)

    onset before 25 years of age

  3. iii)

    progressive limb and gait ataxia

  4. iv)

    absent tendon reflexes in the legs

  5. v)

    electrophysiologic evidence of axonal sensory neuropathy, followed within five years of onset by: dysarrhria, areflexia at all four limbs, distal loss of position and vibration sense, extensor plantar responses and pyramidal weakness of the legs



Friedreich Ataxia Mitochondrial Iron Frataxin Gene Cytosolic Iron Frataxin Deficiency 
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  1. 1.
    Geoffroy G, Barbeau A, Breton, G et al. Clinical description and roentgenologic evaluation of patients with Friedreich ataxia. Can J Neurol Sci 1976; 3:279–286.PubMedGoogle Scholar
  2. 2.
    Harding AE. Friedreich ataxia: A clinical and genetic study of 90 families with an analysis of early diagnosis criteria and intrafamilial clustering of clinical features. Brain 1981; 104:589–620.PubMedCrossRefGoogle Scholar
  3. 3.
    Koeppen A. The neuropathology of inherited ataxias. In: Manto M, Pandolfo M, eds. The Cerebellum and its Disorders. Cambridge: Cambridge University Press, 2001: Part VII, Neuropathology: 25.Google Scholar
  4. 4.
    Campuzano V, Montermini L, Moho MD,Pianese L, Coss& M, Cavalcanti F et al. Friedreich ataxia: Autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 1996; 271:1423–1427.PubMedCrossRefGoogle Scholar
  5. 5.
    Montermini L, Richter A, Morgan K, Justice CM, Julien D, Castelloti B et al. Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion. Ann Neurol 1997; 41:675–682.PubMedCrossRefGoogle Scholar
  6. 6.
    Chamberlain S, Shaw J, Rowland A et al. Mapping of mutation causing Friedreich’ ataxia to human chromosome 9. Nature 1988; 334:248–250.PubMedCrossRefGoogle Scholar
  7. 7.
    Jiralerspong S, Liu Y, Montermini L, Stifani S, Pandolfo M. Frataxin shows developmentally regulated tissue-specific expression in the mouse embryo. Neurobiol Dis 1997; 4:103–113.PubMedCrossRefGoogle Scholar
  8. 8.
    Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini 0, Koenig M. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet 1997; 16:345–351.PubMedCrossRefGoogle Scholar
  9. 9.
    Coss& M, Schmitt M, Campuzano V et al. Evolution of the Friedreich ataxia trinucleotide repeat expansion: Founder effect and premutations. Proc Natl Acad Sci USA 1997; 94:7452–7457.CrossRefGoogle Scholar
  10. 10.
    Montermini L, Andermann E, Labuda M et al. The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. Hum Mol Genet 1997; 6:1261–1266.PubMedCrossRefGoogle Scholar
  11. 11.
    Cossee M, Diirr A, Schmitt M et al. Frataxin point mutations and clinical presentation of compound heterozygous Friedreich ataxia patients. Ann Neurol 1999; 45:200–206.PubMedCrossRefGoogle Scholar
  12. 12.
    Dun A, Coss& M, Agid Y et al. Clinical and genetic abnormalities in patients with Friedreich ataxia. N Engl J Med 1996; 335:1169–1175.CrossRefGoogle Scholar
  13. 13.
    Filla A, De Michele G, Cavalcanti F et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am J Hum Genet 1996; 59:554–560.PubMedGoogle Scholar
  14. 14.
    Pianese L, Cavalcanti F, De Michele G, Filla A, Campanella G, Calabrese et al. The effect of parental gender on the GAA dynamic mutation in the FRDA gene. Am J Hum Genet 1997; 60:463–466.Google Scholar
  15. 15.
    Monros E, Moho MD, Martinez F et al. Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Am J Hum Genet 1997; 61:101–110.PubMedCrossRefGoogle Scholar
  16. 16.
    Montermini L, Kish SJ, Jiralerspong S, Lamarche JB, Pandolfo M. Somatic mosaicism for the Friedreich’s ataxia GAA triplet repeat expansions in the central nervous system. Neurology 1997; 49:606–610.PubMedCrossRefGoogle Scholar
  17. 17.
    Kapitonov V, Jurka J. The age of Alu subfamilies. J Mol Evol 1996; 42:59–65.PubMedCrossRefGoogle Scholar
  18. 18.
    Arcot SS, Fontius JJ, Deininger PL and Batzer MA. Identification and analysis of a young polymorphic Alu element. Biochem et Biophys 1995; 1263:99–102.CrossRefGoogle Scholar
  19. 19.
    Richards RI, Sutherland GR. Simple repeat DNA is not replicated simply. Nature Genet 1994; 6:114–116.PubMedCrossRefGoogle Scholar
  20. 20.
    Wells RD. Molecular basis of genetic instability of triplet repeats. J Biol Chem 1996; 271:2875–2878.PubMedGoogle Scholar
  21. 21.
    Pluciennik A, lyer RR, Parniewski P, Wells RD. Tandem duplication. A novel type of triplet repeat instability. J Biol Chem 2000; 275:28386–28397.PubMedCrossRefGoogle Scholar
  22. 22.
    Jakupciak JP, Wells RD. Gene conversion (recombination) mediates expansions of CTG•CAG repeats. J Biol Chem 2000; 275:40003–40013.PubMedCrossRefGoogle Scholar
  23. 23.
    Labuda D, Labuda M, Zietkiewicz E. The genetic clock and the age of the founder effect in growing populations: a lesson from French Canadians and Ashkenazim. Am J Hum Genet 1997; 61:768–771.PubMedCrossRefGoogle Scholar
  24. 24.
    Harpending HC, Batzer MA, Gurven M et al. Genetic traces of ancient demography. Proc Natl Acad Sci 1998; 95:1961–1967.PubMedCrossRefGoogle Scholar
  25. 25.
    Labuda M, Labuda D, Miranda C, Poirier J, Soong B, Barucha NE et al. Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology 2000; 54:2322–2324.PubMedCrossRefGoogle Scholar
  26. 26.
    Geschwind DH, Perlman S, Grody W et al. The Friedreich’s Ataxia GAA repeat expansion in patients with recessive or sporadic ataxia. Neurology 1997; 49:1004–1009.PubMedCrossRefGoogle Scholar
  27. 27.
    Eichler EE, Holden JJA, Popovich BW, Reiss AL, Snow K, Thibodeau SN et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature Genet 1994; 8:88–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Gacy AM, Goellner G, Juranic N, Macura S, McMurray CT. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 1995; 81:533–540.PubMedCrossRefGoogle Scholar
  29. 29.
    Skelly JV, Edwards KJ, Jenkins TC, Neidle S. Crystal structure of an oligonucleotide duplex containing G•G base pairs: Influence of mispairing on DNA backbone conformation. Proc Natl Acad Sci USA 1993; 90:804–808.PubMedCrossRefGoogle Scholar
  30. 30.
    Wells RD, Collier DA, Hanvey JC, Shimizu M, Wohlrab F. The chemistry and biology of unusual DNA structures adopted by oligopurine-oligopyrimidine sequences. FASEB J 1988; 2:2939–2949.PubMedGoogle Scholar
  31. 31.
    LeProust EM, Pearso CE, Sinden RR, Gao X. Unexpected formation of parallel duplex in GAA and TTC trinucleotide repeats of Friedreich’s ataxia. J Mol Biol 2000; 302:1063–1080.PubMedCrossRefGoogle Scholar
  32. 32.
    Imbert G, Kretz C, Johnson K, Mandel J-L. Origin of the expansion mutation in myotonic dystrophy. Nature Genet 1993; 3:72–75.CrossRefGoogle Scholar
  33. 33.
    Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990; 215:403–410.PubMedGoogle Scholar
  34. 34.
    Ohshima K, Sakamoto N, Labuda M et al. A nonpathogenic GAAGGA repeat in the Friedreich gene: Implications for pathogenesis. Neurol 1999; 53:1854–1857CrossRefGoogle Scholar
  35. 35.
    Wells RD, Sinden RR. Defined ordered sequence DNA, DNA structure, and DNA-directed mutation. In: Davies K, Warren S, eds. Genome Analysis. Vol. 7. Genome Rearrangement and Stability. Cold Spring Harbor Press, 1993:107–138.Google Scholar
  36. 36.
    Frank-Kamenetskii MD, Mirkin SM. Triplex DNA Structures. Annu Rev Biochem 1995; 64:65–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Soyfer VN, Potaman VN. Triple-Helical Nucleic Acids. New York: Springer-Verlag Publishers, 1996.CrossRefGoogle Scholar
  38. 38.
    Sinden RR. DNA Structure and Function. San Diego: Academic Press, Inc., 1994.Google Scholar
  39. 39.
    Guieysse A-L, Praseuth D, Grigoriev M, Harel-Bellan A and Helene C. Detection of covalent triplex with human cells. Nucl Acids Res 1996; 24:4210–4216.PubMedCrossRefGoogle Scholar
  40. 40.
    Bacolla A, Ulrich MJ, Larson JE, Ley TJ, Wells RD. An intramolecular triplex in the human gamma-globin 5’-flanking region is altered by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem 1995; 270:24556–24563.PubMedCrossRefGoogle Scholar
  41. 41.
    Xu G, Goodridge AG. Characterization of a polypyrimidine/polypurine tract in the promoter of the gene for chicken malic enzyme. J Biol Chem 1996; 271:16008–16019.PubMedCrossRefGoogle Scholar
  42. 42.
    Hanvey JC, Klysik J, Wells RD. Influence of DNA sequence on the formation of non-B right-handed helices in oligopurine/oligopyrimidine inserts in plasmids. J Biol Chem 1988; 263:7386–7396.PubMedGoogle Scholar
  43. 43.
    Hanvey JC, Shimizu M, Wells RD. Intramolecular DNA triplexes in supercoiled plasmids. Proc Natl Acad Sci 1988; 85:6292–6296.PubMedCrossRefGoogle Scholar
  44. 44.
    Shimizu M, Hanvey JC, Wells RD. Intramolecular DNA triplexes in supercoiled plasmids: I. Effect of loop size on formation and stability. J Biol Chem 1989; 264:5944–5949.PubMedGoogle Scholar
  45. 45.
    Hanvey JC, Shimizu M, Wells RD. Intramolecular DNA triplexes in supercoiled plasmids: II. Effect of base composition and non-central interruptions on formation and stability. J Biol Chem 1989; 264:5950–5956.PubMedGoogle Scholar
  46. 46.
    Hanvey JC, Shimizu M. Wells RD. Site-specific inhibition of EcoRI restriction/modification enzymes via DNA triple helix. Nucl Acids Res 1989; 18:157–161.CrossRefGoogle Scholar
  47. 47.
    Shimizu M, Hanvey JC, Wells RD. Multiple Non-B-DNA Conformations of polypurine/ polypyrimidine sequences in plasmids. Biochemistry 1990; 29:4704–4713.PubMedCrossRefGoogle Scholar
  48. 48.
    Kang S, Wohlrab F, Wells RD. Metal ions cause the isomerization of certain intramolecular triplexes. J Biol Chem 1992; 267:1259–1264.PubMedGoogle Scholar
  49. 49.
    Kang S, Wohlrab F, Wells RD. GC rich flanking tracts decrease the kinetics of intramolecular DNA triplex formation. J Biol Chem 1992; 267:19435–19442.PubMedGoogle Scholar
  50. 50.
    Ohshima K, Kang S, Larson JE, Wells RD. Cloning, characterization, and properties of seven triplet repeat DNA sequences. J Biol Chem 1996; 271:16773–16783.PubMedCrossRefGoogle Scholar
  51. 51.
    Morgan AR, Wells RD. Specificity of the three-stranded complex formation between double-stranded DNA and single-stranded RNA containing repeating nucleotide sequences. J Mol Biol 1968; 37:63–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Postel EH, Flint SJ, Kessler DJ, Hogan ME. Evidence that a triplex-forming oligodeoxyribonucleotide binds to the c-myc promoter in HeLa cells, thereby reducing c-myc mRNA levels. Proc Natl Acad Sci USA 1991; 88:8227–8231.PubMedCrossRefGoogle Scholar
  53. 53.
    Pandolfo M, Koenig M. Friedreich’s ataxia. In: Wells RD, Warren ST, eds. Genetic Instabilities and Hereditary Neurological Diseases. San-Diego: Academic Press Inc., 1998:373–400.Google Scholar
  54. 54.
    Said G, Marion MH, Selva J, Jamet C. Hypotrophic and dying-back nerve fibers in Friedreich’s ataxia. Neurology 1986; 36:1292–1299.PubMedCrossRefGoogle Scholar
  55. 55.
    Junck L, Gilman S, Gebarski SS, Koeppe RA, Kluin KJ, Markel DS. Structural and functional brain imaging in Friedreich’s ataxia. Arch Neurol 1994; 51:349–355.PubMedCrossRefGoogle Scholar
  56. 56.
    Palau F, De Michele G, Vilchez JJ, Pandolfo M, Monros E, Cocozza S et al. Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to Friedreich’s ataxia locus on chromosome 9q. Ann Neurol 1997; 37:359–362.CrossRefGoogle Scholar
  57. 57.
    Finocchiaro G, Baio G, Micossi P, Pozza G, Di Donato S. Glucose metabolism alterations in Friedreich’s ataxia. Neurology 1998; 38:1292–1296.CrossRefGoogle Scholar
  58. 58.
    Schoenle EJ, Boltshauser EJ, Baekkeskov S, Landin Olsson M, Torresani T, von Felten A. Preclinical and manifest diabetes mellitus in young patients with Friedreich’s ataxia: No evidence of immune process behind the islet cell destruction. Diabetologia 1989; 32:378–381.PubMedCrossRefGoogle Scholar
  59. 59.
    Fantus IG, Seni MH, Andermann E. Evidence for abnormal regulation of insulin receptors in Friedreich’s ataxia. J Clin Endocrinol Metab 1993; 76:60–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Leone M, Rocca WA, Rosso MG, Mantel N, Schoenberg BS, Schiffer D. Friedreich’s disease: Survival analysis in an Italian population. Neurology 1988; 38:1433–1438.PubMedCrossRefGoogle Scholar
  61. 61.
    Bidichandani SI, Ashizawa T, Patel PI. The GAA triplet-repeat expansion in Friedreich’s ataxia interferes with transcription and may be associated with an unusual DNA structure. Am J Hum Genet 1998; 62:111–121.PubMedCrossRefGoogle Scholar
  62. 62.
    Filla A, De Michele G, Cavalcanti F, Pianese L, Monticelli A, Campanella G et al. The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.. Am J Hum Genet 1996; 59:554–560.PubMedGoogle Scholar
  63. 63.
    Ohshima K, Montermini L, Wells RD, Pandolfo M. Inhibitory effects of expanded GAA•TTC triplet repeats from intron I of Friedreich’s ataxia gene on transcription and replication in vivo. J Biol Chem 1998; 273:14588–14595.PubMedCrossRefGoogle Scholar
  64. 64.
    Grabczyk E, Usdin K. Length dependent transcription attenuation in the Friedreich’s ataxia triplet expansion mutation (GAA) via triple helix formation. Abstract presented at 17th International Congress of Biochemistry and Molecular Biology in conjunction with 1997 Annual Meeting of the American Society for Biochemistry and Molecular Biology, San Francisco, CA, August 24–29, 1997, Abstract No. 1998 (1997).Google Scholar
  65. 65.
    Gacy AM, Goeliner GM, Spiro C, Dyer R, Mikesell M, Yao JZ et al. DNA structures associated with class I expansion of GAA in Friedreich’s ataxia. Poster number CS3–103, presented at Santa Fe meeting on “Unstable Triplets, Microsatellites, and Human Disease,” April 1–6, 1997 (J. Griffith, R.D. Wells, and D. L. Nelson, organizers).Google Scholar
  66. 66.
    Reaban ME, Griffin JA. Induction of RNA-stabilized DNA conformers by transcription of an immunoglobulin switch region. Nature 1990; 348:342–344.PubMedCrossRefGoogle Scholar
  67. 67.
    Reaban ME, Griffin JA. Scientific correspondence. Nature 1991; 351:447–448.Google Scholar
  68. 68.
    Reaban ME, Lebowitz J, Griffin JA. Transcription induces the formation of a stable RNA.DNA hybrid in the immunoglobulin alpha switch region. J Biol Chem 1994; 269:21850–21857.PubMedGoogle Scholar
  69. 69.
    Grabczyk E, Fishman MC. A long purine-pyrimidine homopolymer acts as a transriptional diode. J Biol Chem 1995; 270:1791–1797.PubMedCrossRefGoogle Scholar
  70. 70.
    Campuzano V, Montermini L, Lutz Y et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondria! membranes. Hum Mol Genet 1997; 6:1771–1780.PubMedCrossRefGoogle Scholar
  71. 71.
    Cossee M, Campuzano V, Koutnikova H et al. Frataxin fracas. Nat Genet 1997; 15:337–338.PubMedCrossRefGoogle Scholar
  72. 72.
    Monros E, Moho MD, Martinez F et al. Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Am J Hum Genet 1997; 61:101–110.PubMedCrossRefGoogle Scholar
  73. 73.
    Lamont PJ, Davis MB, Wood NW. Identification and sizing of the GAA trinucleotide repeat expansion of Friedreich ataxia in 56 patients-Clinical and genetic correlates. Brain 1997; 120:673–680.PubMedCrossRefGoogle Scholar
  74. 74.
    Schols L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C. Friedreich ataxia. Revision of the phenotype according to molecular genetics. Brain 1997; 120:2131–2140.PubMedCrossRefGoogle Scholar
  75. 75.
    Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet 1997; 60:1251–1256.PubMedGoogle Scholar
  76. 76.
    Coss& M, Puccio H,Gansmuller A et al.Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 2000; 9:1219–1226.CrossRefGoogle Scholar
  77. 77.
    De Michele G, Filla A, Cavalcanti F et al. Atypical Friedreich ataxia phenotype associated with a novel missense mutation in the X25 gene. Neurology 2000; 54:496–499.PubMedCrossRefGoogle Scholar
  78. 78.
    Babcock M, de Silva D, Oaks R et al. Regulation of mitochondrial iron accumulation by YFHI, a putative homolog of frataxin. Science 1997; 276:1709–1712.PubMedCrossRefGoogle Scholar
  79. 79.
    Branda SS, Cavadini P, Adamec J, Kalousek F, Taroni F, Isaya,G. Yeast and human frataxin • are processed to mature form in two sequential steps by the mitochondrial processing peptidase. J Biol Chem 1999; 274:22763–22769.PubMedCrossRefGoogle Scholar
  80. 80.
    Priller J, Scherzer CR, Faber PW, MacDonald ME, Young AB. Frataxin gene of Friedreich’s ataxia is targeted to mitochondria. Ann Neurol 1997; 42:265–269.PubMedCrossRefGoogle Scholar
  81. 81.
    Gordon DM, Shi Q, Dancis A, Pain D. Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase. Hum Mol Genet 1999; 8:2255–2262.PubMedCrossRefGoogle Scholar
  82. 82.
    Knight SA, Sepuri NB, Pain D, Dancis A. Mt-Hsp70 homolog, Ssc2p, required for maturation of yeast frataxin and mitochondrial iron homeostasis. J Biol Chem 1998; 273:1838918393.Google Scholar
  83. 83.
    Wilson RB, Roof DM. Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nature Genet 1997; 16:352–357.PubMedCrossRefGoogle Scholar
  84. 84.
    Radisky DC, Babcock MC, Kaplan J. The yeast frataxin homologue mediates mitochondrial iron efflux. Evidence for a mitochondrial iron cycle. J Biol Chem 1999; 274:4497–4499.PubMedCrossRefGoogle Scholar
  85. 85.
    Riitig A, deLonlay P, Chretien D et al. Frataxin gene expansion causes aconitase and mitochondria] iron-sulfur protein deficiency in Friedreich ataxia. Nature Genet 1997; 17:215–217.CrossRefGoogle Scholar
  86. 86.
    Gardner PR, Rainieri I, Epstein LB, White CW. Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem 1995; 270:13399–13405.PubMedCrossRefGoogle Scholar
  87. 87.
    Lill R, Diekert K, Kaut A et al. The essential role of mitochondria in the biogenesis of cellular iron-sulfur proteins. Biol Chem 1999; 380:1157–1166.PubMedCrossRefGoogle Scholar
  88. 88.
    Foury F. Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain. FEBS Lett 1999; 456:281–284.PubMedCrossRefGoogle Scholar
  89. 89.
    Isaya G, Adamec J, Rusnak F et al. Frataxin is an iron-storage protein. Am J Hum Genet 1999; 65(suppl.):A33 (abstract).Google Scholar
  90. 90.
    Musco G, Stier G, Kolmerer B, Adinolfi S, Martin S, Frenkiel T et al. Towards a structural understanding of Friedreich’s ataxia: The solution structure of frataxin. Structure Fold Des 2000; 8:695–707.PubMedCrossRefGoogle Scholar
  91. 91.
    Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE. Crystal structure of human frataxin. J Biol Chem 2000 Jul 18 [epub ahead of print].Google Scholar
  92. 92.
    Cho SJ, Lee MG, Yang JK, Lee JY, Song HK, Suh SW. Crystal structure of Escherichia coli CyaY protein reveals a previously unidentified fold for the evolutionarily conserved frataxin family. Proc Nat! Acad Sci USA 2000; 97:8932–8937.CrossRefGoogle Scholar
  93. 93.
    Lamarche JB, Cate M, Lemieux B. The cardiomyopathy of Friedreich ataxia morphological observations in 3 cases. Can J Neurol Sci 1980; 7:389–396.PubMedGoogle Scholar
  94. 94.
    Waldvogel D, van Gelderen P, Hallett M. Increased iron in the dentate nucleus of patients with Friedreich ataxia. Ann Neurol 1999; 46:123–125.PubMedCrossRefGoogle Scholar
  95. 95.
    Delatycki MB, Camakaris J, Brooks H, Evans-Whipp T, Thorburn DR, Williamson R et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann Neurol 1999; 45:673–675.PubMedCrossRefGoogle Scholar
  96. 96.
    Emond M, Lepage G, Vanasse M, Pandolfo M. Increased levels of plasma malondialdehyde in Friedreich ataxia. Neurol 2000; 55:1752–1753.CrossRefGoogle Scholar
  97. 97.
    Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G. The Friedreich ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 1999; 8:425–430.PubMedCrossRefGoogle Scholar
  98. 98.
    Ben Hamida M, Belal S, Sirugo G et al. Friedreich ataxia phenotype not linked to chromosome 9 and associated with selective autosomal recessive vitamin E deficiency in two inbred Tunisian families. Neurology 1993; 43:2179–2183.Google Scholar
  99. 99.
    Di Mascio P, Murphy ME, Sies H. Antioxidant defense systems: The role of carotenoids, tocopherols, and thiols. Am J Clin Nutr 1991; 53:194S–200S.PubMedGoogle Scholar
  100. 100.
    Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ et al. Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci USA 1999; 96:11492–11495.PubMedCrossRefGoogle Scholar
  101. 101.
    Wilson RB, Lynch DR, Farmer JM, Brooks DG, Fischbeck KH. Increased serum transferrin receptor concentrations in Friedreich ataxia. Ann Neurol 2000; 47:659–661.PubMedCrossRefGoogle Scholar
  102. 102.
    Hentze MW, Kiihn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA 1996; 93:8175–8182.PubMedCrossRefGoogle Scholar
  103. 103.
    Santoro L, Perretti A, Lanzillo B et al. Influence of GAA expansion size and disease duration on central nervous system impairment in Friedreich’s ataxia: contribution to the understanding of the pathophysiology of the disease. Clin Neurophysiol 2000; 1 1:1023–1030.CrossRefGoogle Scholar
  104. 104.
    Puccio H, Simon D, Cossee M, Criqui-Filipe P, Tiziano F, Melki J et al. Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 2001; 27:181–618.PubMedCrossRefGoogle Scholar
  105. 105.
    Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A. Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: A preliminary study. Lancet 1999; 354:477–479.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Massimo Pandolfo
    • 1
  1. 1.Centre Hospitalier de lé Université de MontréalHopital Notre-Dame,MontréalCanada

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