Journal of Neurology

, Volume 256, Supplement 1, pp 3–8 | Cite as

Friedreich ataxia: The clinical picture



Friedreich ataxia (FRDA) is a rare autosomal recessive hereditary disorder that affects approximately 1 in 50,000 Caucasians. It is caused by hyperexpansion of GAA repeats in the first intron of the frataxin gene. Initial symptoms of FRDA usually appear around the beginning of the second decade of life. In addition to neuropathological disabilities such as ataxia, sensory loss, and muscle weakness, common signs are scoliosis, foot deformity, and hypertrophic cardiomyopathy. Approximately 10 % of patients with FRDA develop diabetes. The neuronopathy in the dorsal root ganglia, accompanied by the loss of peripheral sensory nerve fibres and the degeneration of posterior columns of the spinal cord, is a hallmark of the disease and is responsible for the typical combination of signs and symptoms specific to FRDA. Variation in neurophysiological abnormalities is correlated with the size of the GAA repeat expansion and likely accounts for individual variation in the progression of FRDA. Despite a range of disease severity, most patients will lose their ability to walk, stand, or sit without support within 10 to 15 years of disease onset. In addition to a review of the clinicopathological features of FRDA, a discussion of recent advances in our understanding of the underlying molecular mechanisms is provided.

Key words

inherited ataxia sensory loss muscle weakness gait instability hypertrophic cardiomyopathy dysarthria pyramidal tract degeneration frataxin gene mutation gene silencing 


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  1. 1.
    Friedreich N (1863) Über degenerativeAtrophie der spinalen Hinterstränge.Virchows Arch Pathol Anat 26:391–419CrossRefGoogle Scholar
  2. 2.
    Pandolfo M (2006) Friedreich’s ataxia(chapter 17). In Wells RD, Ashizawa(eds) Genetic Instabilities and NeurologicalDiseases, Burlington, Massachusetts,Academic Press, pp 277–296Google Scholar
  3. 3.
    Harding AE (1981) Friedreich’s ataxia:a clinical and genetic study of 90 familieswith an analysis of early diagnosticcriteria and intrafamilial clustering ofclinical features. Brain 104:589–620PubMedCrossRefGoogle Scholar
  4. 4.
    Campuzano V, Montermini L, MoltòMD, Pianese L, Cossée M, Cavalcanti F,et al. (1996) Friedreich’s ataxia: autosomalrecessive disease caused by anintronic GAA triplet repeat expansion.Science 271:1423–1427PubMedCrossRefGoogle Scholar
  5. 5.
    Corben LA, Georgiou-Karistianis N,Fahey MC, Storey E, Churchyard A,Horne M, Bradshaw JL, Delatycki MB(2006) Towards an understanding ofcognitive function in Friedreich ataxia.Brain Res Bull 70:197–202PubMedCrossRefGoogle Scholar
  6. 6.
    Koeppen AH (2002) Neuropathologyof the inherited ataxias (chapter 25). InManto M, Pandolfo M, editors. TheCerebellum and Its Disorders, NewYork, Cambridge University Press,pp 387–405Google Scholar
  7. 7.
    Santoro L, De Michele G, Perretti A,Crisci C, Cocozza S, Cavalcanti F,Ragno M, Monticelli A, Filla A, CarusoG (1999) Relation between trinucleotideGAA repeat length and sensoryneuropathy in Friedreich’s ataxia. JNeurol Neurosurg Psychiatry 66:93–96CrossRefGoogle Scholar
  8. 8.
    Santoro L, Perretti A, Lanzillo B,Coppola G, De Joanna G, Manganelli F,Cocozza S, De Michele G, Filla A,Caruso G (2000) Influence of GAA expansionsize and disease duration oncentral nervous system impairment inFriedreich’s ataxia: contribution to theunderstanding of the pathophysiologyof the disease. Clin Neurophysiol 111:1023–1030PubMedCrossRefGoogle Scholar
  9. 9.
    Della Nave R, Ginestroni A, GiannelliM, Tessa C, Salvatore E, Salvi F, DottiMT, De Michele G, Piacentini S,Mascalchi M (2008) Brain structuraldamage in Friedreich’s ataxia. J NeurolNeurosurg Psychiatry 79:82–85CrossRefGoogle Scholar
  10. 10.
    Della Nave R, Ginestroni A, Tessa C,Salvatore E, Bartolomei I, Salvi F, DottiMT, De Michele G, Piacentini S,Mascalchi M (2008) Brain white mattertracts degeneration in Friedreichataxia: an in vivo MRI study usingtract-based spatial statistics and voxel-basedmorphometry. Neuroimage 40:19–25PubMedCrossRefGoogle Scholar
  11. 11.
    Schapira A, Lodi R (2004) Assessmentof in vitro and in vivo mitochondrialfunction in Friedreich’s ataxia andHuntington’s disease. Methods MolBiol 277:293–307Google Scholar
  12. 12.
    Gilman S, Junck L, Markel DS, KoeppeRA, Kluin KJ (1990) Cerebral glucosehypermetabolism in Friedreich’s ataxiadetected with positron emission tomography.Ann Neurol 28:750–757PubMedCrossRefGoogle Scholar
  13. 13.
    Casazza F, Morpurgo M (1996) Thevarying evolution of Friedreich’s ataxiacardiomyopathy. Am J Cardiol 77:895–898PubMedCrossRefGoogle Scholar
  14. 14.
    Chamberlain S, Shaw J, Rowland A,et al. (1988) Mapping of mutation causingFriedreich’s ataxia to human chromosome9. Nature 334:248–250PubMedCrossRefGoogle Scholar
  15. 15.
    Jiralerspong S, Liu Y, Montermini L,Stifani S, Pandolfo M (1997) Frataxinshows developmentally regulatedtissue-specific expression in the mouseembryo. Neurobiol Dis 4:103–113PubMedCrossRefGoogle Scholar
  16. 16.
    Koutnikova H, Campuzano V, Foury F,Dollé P, Cazzalini O, Koenig M (1997)Studies of human, mouse and yeasthomologues indicate a mitochondrialfunction for frataxin. Nat Genet 16:345–351PubMedCrossRefGoogle Scholar
  17. 17.
    Cossée M, Schmitt M, Campuzano V,Reutenauer L, Moutou C, Mandel J-L,Koenig M (1997) Evolution of theFriedreich’s ataxia trinucleotide repeatexpansion: founder effect and premutations.Proc Natl Acad Sci USA 94:7452–7457PubMedCrossRefGoogle Scholar
  18. 18.
    Cossée M, Dürr A, Schmitt M, et al.(1999) Frataxin point mutations andclinical presentation of compoundheterozygous Friedreich ataxiapatients. Ann Neurol 45:200–206PubMedCrossRefGoogle Scholar
  19. 19.
    Beauchamp M, Labelle H, Duhaime M,Joncas J (1995) Natural history ofmuscle weakness in Friedreich’s ataxiaand its relation to loss of ambulation.Clin Orthop 311:270–275PubMedGoogle Scholar
  20. 20.
    Montermini L, Richter A, Morgan K,Justice CM, Julien D, Castellotti B,Mercier J, Poirier J, Capozzoli F,Bouchard JP, Lemieux B, Mathieu J,Vanasse M, Seni MH, Graham G,Andermann F, Andermann E, MelançonSB, Keats BJ, Di Donato S, PandolfoM (1997) Phenotypic variability inFriedreich ataxia: role of the associatedGAA triplet repeat expansion. AnnNeurol 41:675–682Google Scholar
  21. 21.
    Filla A, De Michele G, Cavalcanti F,Pianese L, Monticelli A, Campanella G,Cocozza S (1996) The relationshipbetween trinucleotide (GAA) repeatlength and clinical features in Friedreichataxia. Am J Hum Genet 59:554–560PubMedGoogle Scholar
  22. 22.
    Giacchetti M, Monticelli A, De Biase I,Pianese L, Turano M, Filla A, DeMichele G, Cocozza S (2004) MitochondrialDNA haplogroups influencethe Friedreich’s ataxia phenotype.J Med Genet 41:293–295PubMedCrossRefGoogle Scholar
  23. 23.
    Labuda M, Labuda D, Miranda C,Poirier J, Soong B-W, Barucha NE,Pandolfo M (2000) Unique origin andspecific ethnic distribution of theFriedreich ataxia GAA expansion.Neurology 54:2322–2324PubMedGoogle Scholar
  24. 24.
    Pianese L, Cavalcanti F, De Michele G,et al. (1997) The effect of parentalgender on the GAA dynamic mutationin the FRDA gene. Am J Hum Genet60:460–463PubMedGoogle Scholar
  25. 25.
    Montermini L, Kish SJ, Jiralerspong S,Lamarche JB, Pandolfo M (1997)Somatic mosaicism for the Friedreich’sataxia GAA triplet repeat expansionsin the central nervous system. Neurology49:606–610PubMedGoogle Scholar
  26. 26.
    De Biase I, Rasmussen A, Endres D,Al-Mahdawi S, Monticelli A, Cocozza S,Pook M, Bidichandani SI (2007) ProgressiveGAA expansions in dorsalroot ganglia of Friedreich’s ataxiapatients. Ann Neurol 61:55–60PubMedCrossRefGoogle Scholar
  27. 27.
    Zühlke CH, Dalski A, Habeck M,Straube K, Hedrich K, Hoeltzenbein M,Konstanzer A, Hellenbroich Y,Schwinger E (2004) Extension of themutation spectrum in Friedreich’sataxia: detection of an exon deletionand novel missense mutations. Eur JHum Genet 12:979–982CrossRefGoogle Scholar
  28. 28.
    Cavadini P, Gellera C, Patel PI, Isaya G(2000) Human frataxin maintainsmitochondrial iron homeostasis inSaccharomyces cerevisiae. Hum MolGenet 9:2523–2530Google Scholar
  29. 29.
    Wells RD (1996) Molecular basis ofgenetic instability of triplet repeats.J Biol Chem 271:2875–2878PubMedGoogle Scholar
  30. 30.
    Ohshima K, Kang S, Larson JE, WellsRD (1996) Cloning, characterization,and properties of seven triplet repeatDNA sequences. J Biol Chem 271:16773–16783PubMedCrossRefGoogle Scholar
  31. 31.
    Bidichandani SI, Ashizawa T, Patel PI(1998) The GAA triplet-repeat expansionin Friedreich ataxia interfereswith transcription and may be associatedwith an unusual DNA structure.Am J Hum Genet 62:111–121PubMedCrossRefGoogle Scholar
  32. 32.
    Jain A, Rajeswari MR, Ahmed F (2002)Formation and thermodynamic stabilityof intermolecular (R·R·Y) DNAtriplex in GAA/TTC repeats associatedwith Friedreich’s ataxia. J BiomolStruct Dyn 19:691–699Google Scholar
  33. 33.
    Ohshima K, Montermini L, Wells RD,Pandolfo M (1998) Inhibitory effects ofexpanded GAA·TTC triplet repeatsfrom intron I of the Friedreich’s ataxiagene on transcription and replicationin vivo. J Biol Chem 273:14588–14595PubMedCrossRefGoogle Scholar
  34. 34.
    Grabczyk E, Usdin K (2000) TheGAA·TTC triplet repeat expanded inFriedreich’s ataxia impedes transcriptionelongation by T7 RNA polymerasein a length and supercoil dependentmanner. Nucleic Acids Res 28:2815–2822PubMedCrossRefGoogle Scholar
  35. 35.
    Gacy AM, Goellner GM, Spiro C, ChenX, Gupta G, Bradbury EM, Dyer RB,Mikesell MJ, Yao JZ, Johnson AJ,Richter A, Melançon SB, McMurray CT(1998) GAA instability in Friedreich’sataxia shares a common, DNA-directedand intraallelic mechanism with othertrinucleotide diseases. Mol Cell 1:583–593PubMedCrossRefGoogle Scholar
  36. 36.
    Potaman VN, Oussatcheva EA,Lyubchenko YL, Shlyakhtenko LS,Bidichandani SI, Ashizawa T, SindenRR (2004) Length-dependent structureformation in Friedreich ataxia (GAA)n·(TTC)n repeats at neutral pH. NucleicAcids Res 32:1224–1231CrossRefGoogle Scholar
  37. 37.
    Janssen S, Cuvier O, Müller M,Laemmli UK (2000) Specific gain- andloss-of-function phenotypes inducedby satellite-specific DNA-bindingdrugs fed to Drosophila melanogaster.Mol Cell 6:1013–1024PubMedCrossRefGoogle Scholar
  38. 38.
    Saveliev A, Everett C, Sharpe T, WebsterZ, Festenstein R (2003) DNA tripletrepeats mediate heterochromatinprotein-1-sensitive variegated genesilencing. Nature 422:909–913PubMedCrossRefGoogle Scholar
  39. 39.
    Herman D, Jenssen K, Burnett R,Soragni E, Perlman SL, Gottesfeld JM(2006) Histone deacetylase inhibitorsreverse gene silencing in Friedreich’sataxia. Nat Chem Biol 2:551–558PubMedCrossRefGoogle Scholar
  40. 40.
    Rai M, Soragni E, Jenssen K, Burnett R,Herman D, Coppola G, Geschwind DH,Gottesfeld JM, Pandolfo M (2008)HDAC inhibitors correct frataxin deficiencyin a Friedreich ataxia mousemodel. PLoS ONE 3:e1958PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff-Verlag 2009

Authors and Affiliations

  1. 1.Service de NeurologieUniversité Libre de Bruxelles-Hôpital ErasmeBruxellesBelgium

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