Background

Friedreich ataxia (FA, FRDA, FRIEDREICH ATAXIA 1, OMIM# *229300) is an autosomal recessive ataxia resulting from a mutation of a gene locus on chromosome 9. The entity was first described in 1863 by Nikolaus Friedreich, a professor of medicine in Heidelberg, Germany.

FA was the earliest of the inherited ataxias to be distinguished from other locomotor ataxias and is the most common of the autosomal recessive ataxias. It accounts for at least 50% of cases of hereditary ataxias in most large series. Cardinal features include progressive limb and gait ataxia, dysarthria, loss of joint position and vibration senses, absent tendon reflexes in the legs, and extensor plantar responses.

Pathophysiology

The major pathophysiologic finding in Friedreich ataxia is a "dying back phenomena" of axons, beginning in the periphery with ultimate loss of neurons and a secondary gliosis. The primary sites of these changes are the spinal cord and spinal roots. This results in loss of large myelinated axons in peripheral nerves, which increases with age and disease duration. Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared.

The posterior columns and corticospinal, ventral, and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents.

Harding AE, Zilkha KJ. Pseudo-dominant' inheritance in Friedreich's ataxia. J Med Genet. 1981 Aug. 18(4):285-7. [QxMD MEDLINE Link].
Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich's ataxia: classical and atypical phenotypes. J Neurochem. 2013 Aug. 126 Suppl 1:103-17. [QxMD MEDLINE Link].
Nieto A, Correia R, de Nóbrega E, Montón F, Hess S, Barroso J. Cognition in Friedreich Ataxia. Cerebellum. 2012 Feb 16. [QxMD MEDLINE Link].
Noval S, Contreras I, Sanz-Gallego I, Manrique RK, Arpa J. Ophthalmic features of Friedreich ataxia. Eye (Lond). 2012 Feb. 26(2):315-20. [QxMD MEDLINE Link]. [Full Text].
Stolle CA, Frackelton EC, McCallum J, Farmer JM, Tsou A, Wilson RB, et al. Novel, complex interruptions of the GAA repeat in small, expanded alleles of two affected siblings with late-onset Friedreich ataxia. Mov Disord. 2008 Jul 15. 23(9):1303-6. [QxMD MEDLINE Link].
Dürr A, Cossee M, Agid Y, Campuzano V, Mignard C, Penet C, et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl J Med. 1996 Oct 17. 335(16):1169-75. [QxMD MEDLINE Link].
Marmolino D. Friedreich's ataxia: past, present and future. Brain Res Rev. 2011 Jun 24. 67(1-2):311-30. [QxMD MEDLINE Link].
Synofzik M, Godau J, Lindig T, Schöls L, Berg D. Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich's ataxia. Neurodegener Dis. 2011. 8(6):470-5. [QxMD MEDLINE Link].
Blair IA, Farmer J, Hersch S, Larkindale J, Lynch DR, Napierala J, et al. The current state of biomarker research for Friedreich's ataxia: a report from the 2018 FARA biomarker meeting. Future Sci OA. 2019 Jun 28. 5 (6):FSO398. [QxMD MEDLINE Link].
Creigh PD, Mountain J, Sowden JE, Eichinger K, Ravina B, Larkindale J, et al. Measuring peripheral nerve involvement in Friedreich's ataxia. Ann Clin Transl Neurol. 2019 Sep. 6 (9):1718-1727. [QxMD MEDLINE Link].
Borchers S, Synofzik M, Kiely E, Himmelbach M. Routine clinical testing underestimates proprioceptive deficits in Friedreich's ataxia. Cerebellum. 2013 Dec. 12(6):916-22. [QxMD MEDLINE Link].
Bürk K, Schulz SR, Schulz JB. Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales. J Neurochem. 2013 Aug. 126 Suppl 1:118-24. [QxMD MEDLINE Link].
Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, et al. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb. 89 (2):212-225. [QxMD MEDLINE Link]. [Full Text].
Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, et al. Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension. Mov Disord. 2023 Feb. 38 (2):313-320. [QxMD MEDLINE Link]. [Full Text].
Kosutic J, Zamurovic D. High-dose beta-blocker hypertrophic cardiomyopathy therapy in a patient with Friedreich ataxia. Pediatr Cardiol. 2005 Sep-Oct. 26(5):727-30. [QxMD MEDLINE Link].
Li K, Besse EK, Ha D, Kovtunovych G, Rouault TA. Iron-dependent regulation of frataxin expression: implications for treatment of Friedreich ataxia. Hum Mol Genet. 2008 Aug 1. 17(15):2265-73. [QxMD MEDLINE Link].
Trouillas P, Serratrice G, Laplane D, Rascol A, Augustin P, Barroche G, et al. Levorotatory form of 5-hydroxytryptophan in Friedreich's ataxia. Results of a double-blind drug-placebo cooperative study. Arch Neurol. 1995 May. 52(5):456-60. [QxMD MEDLINE Link].
Brandsema JF, Stephens D, Hartley J, Yoon G. Intermediate-dose idebenone and quality of life in Friedreich ataxia. Pediatr Neurol. 2010 May. 42(5):338-42. [QxMD MEDLINE Link].
Parkinson MH, Schulz JB, Giunti P. Co-enzyme Q10 and idebenone use in Friedreich's ataxia. J Neurochem. 2013 Aug. 126 Suppl 1:125-41. [QxMD MEDLINE Link].
Lynch DR, Perlman SL, Meier T. A Phase 3, Double-blind, Placebo-Controlled Trial of Idebenone in Friedreich Ataxia. Arch Neurol. 2010 Aug. 67(8):941-7. [QxMD MEDLINE Link].
Tomassini B, Arcuri G, Fortuni S, Sandi C, Ezzatizadeh V, Casali C, et al. Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model. Hum Mol Genet. 2012 Mar 23. [QxMD MEDLINE Link].
Pandolfo M, Hausmann L. Deferiprone for the treatment of Friedreich's ataxia. J Neurochem. 2013 Aug. 126 Suppl 1:142-6. [QxMD MEDLINE Link].
Elincx-Benizri S, Glik A, Merkel D, Arad M, Freimark D, Kozlova E, et al. Clinical Experience With Deferiprone Treatment for Friedreich Ataxia. J Child Neurol. 2016 Mar 29. [QxMD MEDLINE Link].
Milbrandt TA, Kunes JR, Karol LA. Friedreich's ataxia and scoliosis: the experience at two institutions. J Pediatr Orthop. 2008 Mar. 28(2):234-8. [QxMD MEDLINE Link].
Goulipian C, Bensoussan L, Viton JM, Milhe-De Bovis V, Ramon J, Delarque A. Orthopedic shoes improve gait in Friedreich's ataxia: a clinical and quantified case study. Eur J Phys Rehabil Med. 2008 Mar. 44(1):93-8. [QxMD MEDLINE Link].
Milne SC, Corben LA, Yiu E, Delatycki MB, Georgiou-Karistianis N. Gastrocnemius and soleus spasticity and muscle length in Friedreich's ataxia. J Clin Neurosci. 2016 Mar 25. [QxMD MEDLINE Link].
Tsou AY, Paulsen EK, Lagedrost SJ, Perlman SL, Mathews KD, Wilmot GR, et al. Mortality in Friedreich ataxia. J Neurol Sci. 2011 Aug 15. 307(1-2):46-9. [QxMD MEDLINE Link].
Weidemann F, Rummey C, Bijnens B, Störk S, Jasaityte R, Dhooge J, et al. The Heart in Friedreich Ataxia: Definition of Cardiomyopathy, Disease Severity, and Correlation with Neurological Symptoms. Circulation. 2012 Feb 29. [QxMD MEDLINE Link].
Wilson CL, Fahey MC, Corben LA, Collins VR, Churchyard AJ, Lamont PJ, et al. Quality of life in Friedreich ataxia: what clinical, social and demographic factors are important?. Eur J Neurol. 2007 Sep. 14(9):1040-7. [QxMD MEDLINE Link].
Paulsen EK, Friedman LS, Myers LM, Lynch DR. Health-related quality of life in children with Friedreich ataxia. Pediatr Neurol. 2010 May. 42(5):335-7. [QxMD MEDLINE Link].
Beltinger A, Riffel B, Stöhr M. Somatosensory evoked potentials following median and tibial nerve stimulation in patients with Friedreich's ataxia. Eur Arch Psychiatry Neurol Sci. 1987. 236(6):358-63. [QxMD MEDLINE Link].
Chamberlain S, Koenig M, Richter A, Palau F, Pandolfo M. Molecular analysis of the Friedreich's ataxia locus. Adv Neurol. 1993. 61:193-204. [QxMD MEDLINE Link].
Collins A. Clinical neurogenetics: friedreich ataxia. Neurol Clin. 2013 Nov. 31(4):1095-120. [QxMD MEDLINE Link].
Currier RD. A treatment for ataxia [editorial]. Arch Neurol. 1995 May. 52(5):449. [QxMD MEDLINE Link].
Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000 Jan. 37(1):1-8. [QxMD MEDLINE Link].
Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007 Oct. 6(10):878-86. [QxMD MEDLINE Link].
Epstein E, Farmer JM, Tsou A, Perlman S, Subramony SH, Gomez CM, et al. Health related quality of life measures in Friedreich Ataxia. J Neurol Sci. 2008 Sep 15. 272(1-2):123-8. [QxMD MEDLINE Link].
Forrest SM, Knight M, Delatycki MB, et al. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998 Aug. 1(4):253-7. [QxMD MEDLINE Link].
Friedman JH. Machado-Joseph disease/spinocerebellar ataxia 3 responsive to buspirone. Mov Disord. 1997 Jul. 12(4):613-4. [QxMD MEDLINE Link].
Friedman LS, Farmer JM, Perlman S, Wilmot G, Gomez CM, Bushara KO, et al. Measuring the rate of progression in Friedreich ataxia: implications for clinical trial design. Mov Disord. 2010 Mar 15. 25(4):426-32. [QxMD MEDLINE Link].
Hart PE, Lodi R, Rajagopalan B. Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol. 2005 Apr. 62(4):621-6. [QxMD MEDLINE Link].
Jitpimolmard S, Small J, King RH, Geddes J, Misra P, McLaughlin J, et al. The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival. Acta Neuropathol. 1993. 86(1):29-35. [QxMD MEDLINE Link].
Johnson WG. Friedreich ataxia. Clin Neurosci. 1995. 3(1):33-8. [QxMD MEDLINE Link].
Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol. 1998 Jun. 57(6):531-43. [QxMD MEDLINE Link].
Lane DJ, Richardson DR. Frataxin, a molecule of mystery: trading stability for function in its iron-binding site. Biochem J. 2010 Feb 9. 426(2):e1-3. [QxMD MEDLINE Link].
Lynch DR, Lech G, Farmer JM, Balcer LJ, Bank W, Chance B, et al. Near infrared muscle spectroscopy in patients with Friedreich's ataxia. Muscle Nerve. 2002 May. 25(5):664-73. [QxMD MEDLINE Link].
Mello KA, Abbott BP. Effect of sulfamethoxazole and trimethoprim on neurologic dysfunction in a patient with Joseph's disease. Arch Neurol. 1988 Feb. 45(2):210-3. [QxMD MEDLINE Link].
Pandolfo M. Friedreich ataxia. Handb Clin Neurol. 2012. 103:275-94. [QxMD MEDLINE Link].
Pandolfo M. Friedreich's ataxia: new development and perspectives. Generations: The Official Publication of the National Ataxia Foundation. 1999. 27(1):6-9.
Schipper HM. Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging. Biochim Biophys Acta. 2012 Mar. 1822(3):350-60. [QxMD MEDLINE Link].
Schmucker S, Puccio H. Understanding the molecular mechanisms of Friedreich Ataxia to develop therapeutic approaches. Hum Mol Genet. 2010 Apr 22. [QxMD MEDLINE Link].
Schulz JB, Pandolfo M. 150 years of Friedreich ataxia: from its discovery to therapy. J Neurochem. 2013 Aug. 126 Suppl 1:1-3. [QxMD MEDLINE Link].
Sedlak TL, Chandavimol M, Straatman L. Cardiac transplantation: a temporary solution for Friedreich's ataxia-induced dilated cardiomyopathy. J Heart Lung Transplant. 2004 Nov. 23(11):1304-6. [QxMD MEDLINE Link].
Stockner H, Sojer M, Hering S, Nachbauer W, Seppi K, Schmidauer C, et al. Substantia nigra hypoechogenicity in Friedreich ataxia. Mov Disord. 2012 Feb. 27(2):332-3. [QxMD MEDLINE Link].
Subramony SH, McDaniel O, Vedanarayanan VV. Very late-onset Friedreich's ataxia. Mov Disord. 1999. 14(5):904.
Trouillas P, Takayanagi T, Hallett M. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997 Feb 12. 145(2):205-11. [QxMD MEDLINE Link].
Voncken M, Ioannou P, Delatycki MB. Friedreich ataxia-update on pathogenesis and possible therapies. Neurogenetics. 2004 Feb. 5(1):1-8. [QxMD MEDLINE Link].
Wills AJ, Marsden CD. Fifty Neurologic Cases from the National Hospital. 1999.
Zouari M, Feki M, Ben Hamida C, Larnaout A, Turki I, Belal S, et al. Electrophysiology and nerve biopsy: comparative study in Friedreich's ataxia and Friedreich's ataxia phenotype with vitamin E deficiency. Neuromuscul Disord. 1998 Aug. 8(6):416-25. [QxMD MEDLINE Link].
Aranca TV, Jones TM, Shaw JD, Staffetti JS, Ashizawa T, Kuo SH, et al. Emerging therapies in Friedreich's ataxia. Neurodegener Dis Manag. 2016 Feb. 6 (1):49-65. [QxMD MEDLINE Link].
Rezende TJ, Silva CB, Yassuda CL, Campos BM, D'Abreu A, Cendes F, et al. Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia. Mov Disord. 2016 Jan. 31 (1):70-8. [QxMD MEDLINE Link].

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Author

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Hereditary Neuropathy Center, Co-Director, Center for Memory Loss and Brain Health, Co-Director, ALS Center, Hackensack University Medical Center; Associate Dean of Faculty, Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB Serve(d) as a speaker or a member of a speakers bureau for: Catalyst; Jazz; LivaNova; Neurelis; SK Life Science; Stratus; Synergy; UCB Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard, Xenon Received income in an amount equal to or greater than $250 from: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB.

Additional Contributors

Dianna Quan, MD Professor of Neurology, Director of Electromyography Laboratory, University of Colorado School of Medicine

Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Association of Neuromuscular and Electrodiagnostic Medicine; American Neuromuscular Foundation Serve(d) as a speaker or a member of a speakers bureau for: Alnylam Received research grant from: Alnylam; Momenta/Janssen; Avidity bioscience.

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