Review

Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

‡Authors contributed equally

Kellie McIntyre^‡

Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

‡Authors contributed equally

Search for more papers by this author

Layne N Rodden

Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

Search for more papers by this author

Kim Schadt

Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

Search for more papers by this author

David R Lynch

*Author for correspondence: Tel.: +1 215 590 2242;

E-mail Address: lynchd@pennmedicine.upenn.edu

https://orcid.org/0000-0001-7168-214X

Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

Search for more papers by this author

Published Online:29 Jun 2022https://doi.org/10.2217/nmt-2022-0011

View article

Abstract

Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000–100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.

Plain language summary

Friedreich's ataxia (FRDA), mainly referred to as a disorder of balance, is characterized by loss of coordination (ataxia) in the arms and legs and other neurological features, affecting about 1 in 50,000 people in the USA. FRDA also includes serious heart disease, aggressive scoliosis, diabetes and many other disease characteristics. Due to various clinical care needs, disease-specific clinical care guidelines have been created. New developments in FRDA include the advancement of clinical drug trials targeting cell signaling pathways and restoration of the deficient protein found in individuals with FRDA. Additionally, a new understanding of the role of the various genetic factors that contribute to the development of FRDA could affect current and future therapies. Finally, new perspectives on the early developmental features of FRDA will help refine the time course and accelerate new treatments.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Koeppen AH. Friedreich's ataxia: pathology, pathogenesis and molecular genetics. J. Neurol. Sci. 303(1-2), 1–12 (2011).
Medline CASGoogle Scholar
2. Pandolfo M. Friedreich ataxia: new pathways. J. Child Neurol. 27(9), 1204–1211 (2012).
MedlineGoogle Scholar
3. Pandolfo M. Friedreich ataxia. Handb. Clin. Neurol. 103, 275–294 (2012).
MedlineGoogle Scholar
4. Pandolfo M. Friedreich ataxia: the clinical picture. J. Neurol. 256(Suppl. 1), 3–8 (2009).
MedlineGoogle Scholar
5. Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich Ataxia: Multidisciplinary Clinical Care. J. Multidiscip. Healthcare. 14, 1645–1658 (2021).
MedlineGoogle Scholar
6. McDaniel DO, Keats B, Vedanarayanan VV, Subramony SH. Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. Mov. Disord. 16(6), 1153–1158 (2001).
Medline CASGoogle Scholar
7. Stolle CA, Frackelton EC, McCallum J et al. Novel, complex interruptions of the GAA repeat in small, expanded alleles of two affected siblings with late-onset Friedreich ataxia. Mov. Disord. 23(9), 1303–6 (2008).
MedlineGoogle Scholar
8. Lazaropoulos M, Dong Y, Clark E et al. Frataxin levels in peripheral tissue in Friedreich ataxia. Ann. Clin. Transl. Neurol. 2(8), 831–842 (2015).
Medline CASGoogle Scholar
9. Dürr A, Cossee M, Agid Y et al. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N. Engl. J. Med. 335(16), 1169–1175 (1996). • The original article linking clinical phenomena and GAA repeat length in Friedreich ataxia (FRDA).
Medline CASGoogle Scholar
10. Patel M, Isaacs CJ, Seyer L et al. Progression of Friedreich ataxia: quantitative characterization over 5 years. Ann. Clin. Transl. Neurol. 3(9), 684–694 (2016).
MedlineGoogle Scholar
11. Martelli A, Puccio H. Dysregulation of cellular iron metabolism in Friedreich ataxia: from primary iron-sulfur cluster deficit to mitochondrial iron accumulation. Front. Pharmacol. 5, 130 (2014).
MedlineGoogle Scholar
12. Rötig A, de Lonlay P, Chretien D et al. Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17(2), 215–217 (1997).
Medline CASGoogle Scholar
13. Musco G, Stier G, Kolmerer B et al. Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin. Structure 8(7), 695–707 (2000).
Medline CASGoogle Scholar
14. Delatycki MB, Camakaris J, Brooks H et al. Direct evidence that mitochondrial iron accumulation occurs in Friedreich ataxia. Ann. Neurol. 45(5), 673–675 (1999).
Medline CASGoogle Scholar
15. Harding IH, Lynch DR, Koeppen AH, Pandolfo M. Central nervous system therapeutic targets in Friedreich ataxia. Hum. Gene Ther. 31(23-24), 1226–1236 (2020). • Collaborative expert review identifying present thoughts on neuroanatomy of FRDA.
Medline CASGoogle Scholar
16. Reetz K, Dogan I, Costa AS et al. Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data. Lancet Neurol. 14(2), 174–182 (2015).
MedlineGoogle Scholar
17. Corben LA, Tai G, Wilson C, Collins V, Churchyard AJ, Delatycki MB. A comparison of three measures of upper limb function in Friedreich ataxia. J. Neurol. 257(4), 518–523 (2010).
Medline CASGoogle Scholar
18. Seyer LA, Galetta K, Wilson J et al. Analysis of the visual system in Friedreich ataxia. J. Neurol. 260(9), 2362–2369 (2013).
MedlineGoogle Scholar
19. Fortuna F, Barboni P, Liguori R et al. Visual system involvement in patients with Friedreich's ataxia. Brain 132(Pt 1), 116–123 (2009).
MedlineGoogle Scholar
20. Givre SJ, Wall M, Kardon RH. Visual loss and recovery in a patient with Friedreich ataxia. J. Neuroophthalmol. 20(4), 229–233 (2000).
Medline CASGoogle Scholar
21. Pinto F, Amantini A, de Scisciolo G, Scaioli V, Guidi L, Frosini R. Visual involvement in Friedreich's ataxia: PERG and VEP study. Eur. Neurol. 28(5), 246–251 (1988).
Medline CASGoogle Scholar
22. Carroll WM, Kriss A, Baraitser M, Barrett G, Halliday AM. The incidence and nature of visual pathway involvement in Friedreich's ataxia. A clinical and visual evoked potential study of 22 patients. Brain 103(2), 413–434 (1980).
Medline CASGoogle Scholar
23. Bogdanova-Mihaylova P, Plapp HM, Chen H et al. Longitudinal assessment using optical coherence tomography in patients with Friedreich's ataxia. Tomography. 7(4), 915–931 (2021).
MedlineGoogle Scholar
24. Noval S, Contreras I, Sanz-Gallego I, Manrique RK, Arpa J. Ophthalmic features of Friedreich ataxia. Eye (Lond.). 26(2), 315–320 (2012).
Medline CASGoogle Scholar
25. Hamedani AG, Hauser LA, Perlman S et al. Longitudinal analysis of contrast acuity in Friedreich ataxia. Neurol. Genet. 4(4), e250 (2018).
MedlineGoogle Scholar
26. Afsharian P, Nolan-Kenney R, Lynch AE, Balcer LJ, Lynch DR. Correlation of visual quality of life with clinical and visual status in Friedreich ataxia. J. Neuroophthalmol. 40(2), 213–217 (2020).
MedlineGoogle Scholar
27. Rance G, Corben L, Barker E et al. Auditory perception in individuals with Friedreich's ataxia. Audiol Neurootol. 15(4), 229–40 (2010).
MedlineGoogle Scholar
28. Koohi N, Thomas-Black G, Giunti P, Bamiou DE. Auditory phenotypic variability in Friedreich's ataxia patients. Cerebellum 20, 497–508 (2021).
MedlineGoogle Scholar
29. Rance G, Starr A. Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain 138(11), 3141–3158 (2015).
MedlineGoogle Scholar
30. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. Auditory neuropathy. Brain (Pt 3), 741–53 (1996).
MedlineGoogle Scholar
31. Knezevic W, Stewart-Wynne EG. Brainstem auditory evoked responses in hereditary spinocerebellar ataxias. Clin. Exp. Neurol. 21, 149–155 (1985).
Medline CASGoogle Scholar
32. Rance G, Corben LA, Du Bourg E, King A, Delatycki MB. Successful treatment of auditory perceptual disorder in individuals with Friedreich ataxia. Neuroscience. 171(2), 552 –5 (2010).
Medline CASGoogle Scholar
33. Tsou AY, Paulsen EK, Lagedrost SJ et al. Cross-sectional analysis of electrocardiograms in a large heterogeneous cohort of Friedreich ataxia subjects. J. Child Neurol. 27(9), 1187–1192 (2012).
MedlineGoogle Scholar
34. Legrand L, Weinsaft JW, Pousset F et al. Characterizing cardiac phenotype in Friedreich's ataxia: The CARFA study. Arch. Cardiovasc. Dis. 115(1), 17–28 (2022).
MedlineGoogle Scholar
35. Pousset F, Legrand L, Monin ML et al. A 22-year follow-up study of long-term cardiac outcome and predictors of survival in Friedreich ataxia. JAMA Neurol. 72(11), 1334–1341 (2015).
MedlineGoogle Scholar
36. Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V. Heart disease in Friedreich's ataxia. World J. Cardiol. 11(1), 1–12 (2019).
MedlineGoogle Scholar
37. Payne RM. The heart in Friedreich's ataxia: basic findings and clinical implications. Prog Pediatr Cardiol. 31(2), 103–109 (2011).
MedlineGoogle Scholar
38. Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, St John Sutton MG. Management and therapy for cardiomyopathy in Friedreich's ataxia. Expert Rev. Cardiovasc. Ther. 10(6), 767–777 (2012).
Medline CASGoogle Scholar
39. Koeppen AH, Ramirez RL, Becker AB et al. The pathogenesis of cardiomyopathy in Friedreich ataxia. PLoS ONE 10(3), e0116396 (2015).
MedlineGoogle Scholar
40. Dedobbeleer C, Rai M, Donal E, Pandolfo M, Unger P. Normal left ventricular ejection fraction and mass but subclinical myocardial dysfunction in patients with Friedreich's ataxia. Eur Heart J Cardiovasc. Imaging. 13(4), 346–352 (2012).
MedlineGoogle Scholar
41. St John Sutton M, Ky B, Regner SR et al. Longitudinal strain in Friedreich ataxia: a potential marker for early left ventricular dysfunction. Echocardiography 31(1), 50–57 (2014).
MedlineGoogle Scholar
42. Legrand L, Heuze C, Diallo A et al. Prognostic value of longitudinal strain and ejection fraction in Friedreich's ataxia. Int. J. Cardiol. 330, 259–265 (2021).
Medline CASGoogle Scholar
43. Friedman LS, Schadt KA, Regner SR et al. Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia. Int. J. Cardiol. 167(4), 1622–1624 (2013).
MedlineGoogle Scholar
44. Legrand L, Maupain C, Monin ML et al. Significance of NT-proBNP and high-sensitivity troponin in Friedreich ataxia. J. Clin. Med. 9(6), 1630 (2020).
CASGoogle Scholar
45. Rummey C, Flynn JM, Corben LA et al. Scoliosis in Friedreich's ataxia: longitudinal characterization in a large heterogeneous cohort. Ann. Clin. Transl. Neurol. 8(6), 1239–1250 (2021).
MedlineGoogle Scholar
46. Tsirikos AI, Smith G. Scoliosis in patients with Friedreich's ataxia. J. Bone Joint Surg. Br. 94(5), 684–689 (2012).
Medline CASGoogle Scholar
47. Simon AL, Meyblum J, Roche B et al. Scoliosis in patients with friedreich ataxia: results of a consecutive prospective series. Spine Deform. 7(5), 812–821 (2019).
MedlineGoogle Scholar
48. Reetz K, Dogan I, Hohenfeld C et al. Nonataxia symptoms in Friedreich Ataxia: report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS). Neurology 91(10), e917–e930 (2018).
MedlineGoogle Scholar
49. Milbrandt TA, Kunes JR, Karol LA. Friedreich's ataxia and scoliosis: the experience at two institutions. J. Pediatr. Orthop. 28(2), 234–238 (2008).
MedlineGoogle Scholar
50. Tamaroff J, DeDio A, Wade K et al. Friedreich's Ataxia related Diabetes: epidemiology and management practices. Diabetes Res. Clin. Pract. 186, 109828 (2022).
MedlineGoogle Scholar
51. Azzi AS, Cosentino C, Kibanda J, Féry F, Cnop M. OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia. Ann. Clin. Transl. Neurol. 6(1), 161–166 (2018).
MedlineGoogle Scholar
52. McCormick A, Farmer J, Perlman S et al. Impact of diabetes in the Friedreich ataxia clinical outcome measures study. Ann. Clin. Transl. Neurol. 4(9), 622–631 (2017).
Medline CASGoogle Scholar
53. Isaacs CJ, Brigatti KW, Kucheruk O et al. Effects of genetic severity on glucose homeostasis in Friedreich ataxia. Muscle Nerve 54(5), 887–894 (2016).
Medline CASGoogle Scholar
54. Chakraborty PP, Ray S, Bhattacharjee R et al. First presentation of diabetes as diabetic ketoacidosis in a case of Friedreich's ataxia. Clin. Diabetes. 33(2), 84–86 (2015).
MedlineGoogle Scholar
55. Greeley NR, Regner S, Willi S, Lynch DR. Cross-sectional analysis of glucose metabolism in Friedreich ataxia. J. Neurol. Sci. 342(1-2), 29–35 (2014).
Medline CASGoogle Scholar
56. Pappa A, Häusler MG, Veigel A et al. Diabetes mellitus in Friedreich Ataxia: a case series of 19 patients from the German-Austrian diabetes mellitus registry. Diabetes Res. Clin. Pract. 141, 229–236 (2018).
MedlineGoogle Scholar
57. Corben LA, Ho M, Copland J, Tai G, Delatycki MB. Increased prevalence of sleep-disordered breathing in Friedreich ataxia. Neurology 81(1), 46–51- (2013).
Medline CASGoogle Scholar
58. Reddy PL, Grewal RP. Friedreich's ataxia: a clinical and genetic analysis. Clin. Neurol. Neurosurg. 109(2), 200–202 (2007).
MedlineGoogle Scholar
59. Eigentler A, Nachbauer W, Donnemiller E, Poewe W, Gasser RW, Boesch S. Low bone mineral density in Friedreich ataxia. Cerebellum. 13(5), 549–557 (2014).
MedlineGoogle Scholar
60. Weber DR. Bone health in childhood chronic disease. Endocrinol. Metab. Clin. North Am. 49(4), 637–650 (2020).
MedlineGoogle Scholar
61. Dunn J, Tamaroff J, DeDio A et al. Bone mineral density and current bone health screening practices in Friedreich's ataxia. Front. Neurosci. 16, 818750 (2022).
MedlineGoogle Scholar
62. Han EY, Choi JH, Kim SH, Im SH. The effect of weight bearing on bone mineral density and bone growth in children with cerebral palsy: a randomized controlled preliminary trial. Medicine 96(10), e5896 (2017).
MedlineGoogle Scholar
63. Ward LM, Hadjiyannakis S, McMillan HJ, Noritz G, Weber DR. Bone health and osteoporosis management of the patient with duchenne muscular dystrophy. Pediatrics 142, S34–S42 (2018).
MedlineGoogle Scholar
64. Musegante AF, Almeida PN, Monteiro RT, Barroso U Jr. Urinary symptoms and urodynamics findings in patients with Friedreich's ataxia. Int. Braz. J. Urol. 39(6), 867–874 (2013).
MedlineGoogle Scholar
65. Nieto A, Hernández-Torres A, Pérez-Flores J, Montón F. Depressive symptoms in Friedreich ataxia. Int. J. Clin. Health Psychol. 18(1), 18–26 (2018)
MedlineGoogle Scholar
66. Pérez-Flores J, Hernández-Torres A, Montón F, Nieto A. Health-related quality of life and depressive symptoms in Friedreich ataxia. Qual. Life Res. 29(2), 413–420 (2020).
MedlineGoogle Scholar
67. Costabile T, Capretti V, Abate F et al. Emotion recognition and psychological comorbidity in Friedreich's ataxia. Cerebellum. 17(3), 336–345 (2018).
MedlineGoogle Scholar
68. Sayah S, Rotgé JY, Francisque H et al. Personality and neuropsychological profiles in Friedreich ataxia. Cerebellum. 17(2), 204–212 (2018).
MedlineGoogle Scholar
69. Flood MK, Perlman SL. The mental status of patients with Friedreich's ataxia. J. Neurosci. Nurs. 19(5), 251–255 (1987).
Medline CASGoogle Scholar
70. Xiong E, Lynch AE, Corben LA et al. Health related quality of life in Friedreich Ataxia in a large heterogeneous cohort. J. Neurol. Sci. 410, 116642 (2020).
MedlineGoogle Scholar
71. Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB. Clinical Management Guidelines Writing Group. Consensus clinical management guidelines for Friedreich ataxia. Orphanet. J. Rare Dis. 9, 184 (2014).
MedlineGoogle Scholar
72. Deutsch EC, Seyer LA, Perlman SL, Yu J, Lynch DR. Clinical monitoring in a patient with Friedreich ataxia and osteogenic sarcoma. J. Child Neurol. 27(9), 1159–1163 (2012).
MedlineGoogle Scholar
73. Griffiths JD, Stark RJ, Ding JC, Cooper IA. Vincristine neurotoxicity in Charcot-Marie-Tooth syndrome. Med. J. Aust. 143(7), 305–306 (1985).
Medline CASGoogle Scholar
74. Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 77(7), 1356–1362 (1996).
Medline CASGoogle Scholar
75. Kearney M, Orrell RW, Fahey M, Pandolfo M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database Syst. Rev. 4, CD007791 (2012).
Google Scholar
76. Myers L, Farmer JM, Wilson RB et al. Antioxidant use in Friedreich ataxia. J. Neurol. Sci. 267(1-2), 174–176 (2008).
Medline CASGoogle Scholar
77. Meier T, Perlman SL, Rummey C, Coppard NJ, Lynch DR. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J. Neurol. 259(2), 284–291 (2012).
Medline CASGoogle Scholar
78. Lagedrost SJ, Sutton MS, Cohen MS et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am. Heart J. 161(3), 639–645.e1 (2011).
Medline CASGoogle Scholar
79. Lynch DR, Perlman SL, Meier T. A Phase III, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch. Neurol. 67(8), 941–947 (2010).
MedlineGoogle Scholar
80. Rinaldi C, Tucci T, Maione S, Giunta A, De Michele G, Filla A. Low-dose idebenone treatment in Friedreich's ataxia with and without cardiac hypertrophy. J. Neurol. 256(9), 1434–1437 (2009).
Medline CASGoogle Scholar
81. Schulz JB, Di Prospero NA, Fischbeck K. Clinical experience with high dose idebenone in Friedreich ataxia. J. Neurol. 256(Suppl. 1), 42–5 (2009).
Medline CASGoogle Scholar
82. Meier T, Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J. Neurol. 256(Suppl. 1), 25–30 (2009).
Medline CASGoogle Scholar
83. Pineda M, Arpa J, Montero R et al. Idebenone treatment in paediatric and adult patients with Friedreich ataxia: long-term follow-up. Eur. J. Paediatr. Neurol. 12(6), 470–475 (2008).
MedlineGoogle Scholar
84. 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. 6(10), 878–886 (2007).
MedlineGoogle Scholar
85. Di Prospero NA, Sumner CJ, Penzak SR, Ravina B, Fischbeck KH, Taylor JP. Safety, tolerability, and pharmacokinetics of high dose idebenone in patients with Friedreich ataxia. Arch. Neurol. 64(6), 803–808 (2007).
MedlineGoogle Scholar
86. Zesiewicz T, Heerinckx F, De Jager R et al. Randomized, clinical trial of RT001: early signals of efficacy in Friedreich's ataxia. Mov. Disord. 33(6), 1000–1005 (2018).
Medline CASGoogle Scholar
87. Brenna JT, James G, Midei M et al. J. Pharm. Sci. 109(11), 3496–3503 (2020).
Medline CASGoogle Scholar
88. Mariotti C, Fancellu R, Caldarazzo S et al. Erythropoietin in Friedreich ataxia: no effect on frataxin in a randomized controlled trial. Mov. Disord. 27(3), 446–449 (2012).
Medline CASGoogle Scholar
89. Saccà F, Puorro G, Marsili A et al. Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia. Mov. Disord. 31(5), 734–741 (2016).
Medline CASGoogle Scholar
90. Boesch S, Nachbauer W, Mariotti C et al. Safety and tolerability of carbamylated erythropoietin in Friedreich's ataxia. Mov. Disord. 29(7), 935–939 (2014).
Medline CASGoogle Scholar
91. Nachbauer W, Boesch S, Schneider R 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 8(7), e69229 (2013).
Medline CASGoogle Scholar
92. Nachbauer W, Hering S, Seifert M et al. Effects of erythropoietin on frataxin levels and mitochondrial function in Friedreich ataxia–a dose-response trial. Cerebellum. 10(4), 763–769 (2011).
Medline CASGoogle Scholar
93. Saccà F, Piro R, De Michele G et al. Epoetin alfa increases frataxin production in Friedreich's ataxia without affecting hematocrit. Mov. Disord. 26(4), 739–742 (2011).
MedlineGoogle Scholar
94. Boesch S, Sturm B, Hering S et al. Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial. Mov. Disord. 23(13), 1940–1944 (2008).
MedlineGoogle Scholar
95. 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. 62(5), 521–524 (2007).
Medline CASGoogle Scholar
96. Britti E, Delaspre F, Sanz-Alcázar A et al. Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich ataxia. Biochem. J. 478(1), 1–20 (2021).
Medline CASGoogle Scholar
97. Alfedi G, Luffarelli R, Condò I et al. Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia. Mov. Disord. 34(3), 323–334 (2019).
Medline CASGoogle Scholar
98. Vavla M, Arrigoni F, Toschi N et al. Sensitivity of neuroimaging indicators in monitoring the effects of interferon gamma treatment in Friedreich's ataxia. Front. Neurosci. 14, 872 (2020).
MedlineGoogle Scholar
99. Vavla M, D'Angelo MG, Arrigoni F. Safety and efficacy of interferon γ in friedreich's ataxia. Mov. Disord. 35(2), 370–371 (2020).
MedlineGoogle Scholar
100. Lynch DR, Hauser L, McCormick A et al. Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich ataxia. Ann. Clin. Transl. Neurol. 6(3), 546–553 (2019).
Medline CASGoogle Scholar
101. Wyller VB, Jacobsen K, Dahl MB et al. Interferon gamma may improve cardiac function in Friedreich's ataxia cardiomyopathy. Int. J. Cardiol. 221, 376–378 (2016).
MedlineGoogle Scholar
102. Marcotulli C, Fortuni S, Arcuri G et al. GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients. Neurol. Sci. 37(3), 361–364 (2016).
MedlineGoogle Scholar
103. Seyer L, Greeley N, Foerster D et al. Open-label pilot study of interferon gamma-1b in Friedreich ataxia. Acta Neurol. Scand. 132(1), 7–15 (2015).
Medline CASGoogle Scholar
104. Pandolfo M, Arpa J, Delatycki MB et al. Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann. Neurol. 76(4), 509–521 (2014).
Medline CASGoogle Scholar
105. Arpa J, Sanz-Gallego I, Rodríguez-de-Rivera FJ et al. Triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia - open-label trial. Acta Neurol. Scand. 129(1), 32–40 (2014).
Medline CASGoogle Scholar
106. Arpa J, Sanz-Gallego I, Rodríguez-de-Rivera FJ et al. Triple therapy with darbepoetin alfa, idebenone, and riboflavin in Friedreich's ataxia: an open-label trial. Cerebellum. 12(5), 713–720 (2013).
Medline CASGoogle Scholar
107. Patel M, Schadt K, McCormick A, Isaacs C, Dong YN, Lynch DR. Open-label pilot study of oral methylprednisolone for the treatment of patients with friedreich ataxia. Muscle Nerve 60(5), 571–575 (2019).
Medline CASGoogle Scholar
108. Qureshi MY, Patterson MC, Clark V et al. Safety and efficacy of (+)-epicatechin in subjects with Friedreich's ataxia: a phase II, open-label, prospective study. J. Inherit. Metab. Dis. 44(2), 502–514 (2021).
Medline CASGoogle Scholar
109. Yiu EM, Tai G, Peverill RE et al. An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels. J. Neurol. 262(5), 1344–1353 (2015).
Medline CASGoogle Scholar
110. Lynch DR, Willi SM, Wilson RB et al. A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial. Mov. Disord. 27(8), 1026–1033 (2012).
Medline CASGoogle Scholar
111. Zesiewicz T, Salemi JL, Perlman S et al. Double-blind, randomized, and controlled trial of EPI-743 in Friedreich's ataxia. Neurodegener. Dis. Manag. 8(4), 233–242 (2018).
Google Scholar
112. Enns GM, Kinsman SL, Perlman SL et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol. Genet. Metab. 105(1), 91–102 (2012).
Medline CASGoogle Scholar
113. Rodríguez-Pascau L, Britti E, Calap-Quintana P et al. PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia. Neurobiol. Dis. 148, 105162 (2021).
Medline CASGoogle Scholar
114. García-Giménez JL, Sanchis-Gomar F, Pallardó FV. Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients? Mov. Disord. 26(5), 769–771 (2011).
MedlineGoogle Scholar
115. Marmolino D, Acquaviva F, Pinelli M et al. PPAR-gamma agonist Azelaoyl PAF increases frataxin protein and mRNA expression: new implications for the Friedreich's ataxia therapy. Cerebellum. 8(2), 98–103 (2009).
Medline CASGoogle Scholar
116. D'Oria V, Petrini S, Travaglini L et al. Frataxin deficiency leads to reduced expression and impaired translocation of NF-E2-related factor (Nrf2) in cultured motor neurons. Int. J. Mol. Sci. 14(4), 7853–7865 (2013).
MedlineGoogle Scholar
117. Shan Y, Schoenfeld RA, Hayashi G et al. Frataxin deficiency leads to defects in expression of antioxidants and Nrf2 expression in dorsal root ganglia of the Friedreich's ataxia YG8R mouse model. Antioxid. Redox Signal. 19(13), 1481–1493 (2013).
Medline CASGoogle Scholar
118. Paupe V, Dassa EP, Goncalves S et al. Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS ONE 4(1), e4253 (2009).
MedlineGoogle Scholar
119. La Rosa P, Russo M, D'Amico J et al. Nrf2 induction re-establishes a proper neuronal differentiation program in Friedreich's ataxia neural stem cells. Front. Cell. Neurosci. 13, 356 (2019).
MedlineGoogle Scholar
120. Abeti R, Baccaro A, Esteras N, Giunti P. Novel Nrf2-inducer prevents mitochondrial defects and oxidative stress in Friedreich's ataxia models. Front. Cell. Neurosci. 12, 188 (2018).
MedlineGoogle Scholar
121. Petrillo S, Piermarini E, Pastore A et al. Nrf2-inducers counteract neurodegeneration in frataxin-silenced motor neurons: disclosing new therapeutic targets for Friedreich's ataxia. Int. J. Mol. Sci. 18(10), 2173 (2017).
Google Scholar
122. Anzovino A, Chiang S, Brown BE, Hawkins CL, Richardson DR, Huang ML. Molecular alterations in a mouse cardiac model of Friedreich ataxia: an impaired Nrf2 response mediated via upregulation of Keap1 and activation of the Gsk3β Axis. Am. J. Pathol. 187(12), 2858–2875 (2017).
Medline CASGoogle Scholar
123. Abeti R, Uzun E, Renganathan I, Honda T, Pook MA, Giunti P. Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia. Pharmacol. Res. 99, 344–350 (2015).
Medline CASGoogle Scholar
124. La Rosa P, Petrillo S, Turchi R et al. The Nrf2 induction prevents ferroptosis in Friedreich's ataxia. Redox Biol. 38, 101791 (2021).
MedlineGoogle Scholar
125. Lynch DR, Chin MP, Delatycki MB et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe Study). Ann. Neurol. 89(2), 212–225 (2021). •• Along with reference 127, one of two double blind trials showing benefits of omaveloxolone.
Medline CASGoogle Scholar
126. Petrillo S, D'Amico J, La Rosa P, Bertini ES, Piemonte F. Targeting NRF2 for the treatment of Friedreich's ataxia: a comparison among drugs. Int. J. Mol. Sci. 20(20), 5211 (2019).
CASGoogle Scholar
127. Lynch DR, Farmer J, Hauser L et al. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann. Clin. Transl. Neurol. 6(1), 15–26 (2018). •• Along with reference 125, one of two double blind trials showing benefits of omaveloxolone.
MedlineGoogle Scholar
128. Sahdeo S, Scott BD, McMackin MZ et al. Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia. Hum. Mol. Genet. 23(25), 6848–6862 (2014).
Medline CASGoogle Scholar
129. Li Y, Polak U, Bhalla AD et al. Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich's ataxia. Mol. Ther. 23(6), 1055–1065 (2015).
Medline CASGoogle Scholar
130. Codazzi F, Hu A, Rai M et al. Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor. Hum. Mol. Genet. 25(22), 4847–4855 (2016).
Medline CASGoogle Scholar
131. Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat. Chem. Biol. 2(10), 551–8 (2006).
Medline CASGoogle Scholar
132. Rai M, Soragni E, Jenssen K et al. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model. PLoS ONE 3(4), e1958 (2008).
MedlineGoogle Scholar
133. Chutake YK, Lam CC, Costello WN, Anderson MP, Bidichandani SI. Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor. Nucleic Acids Res. 44(11), 5095–5104 (2016).
Medline CASGoogle Scholar
134. Soragni E, Miao W, Iudicello M et al. Epigenetic therapy for Friedreich ataxia. Ann. Neurol. 76(4), 489–508 (2014).
Medline CASGoogle Scholar
135. Vyas PM, Tomamichel WJ, Pride PM et al. A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model. Hum. Mol. Genet. 21(6), 1230–1247 (2012).
Medline CASGoogle Scholar
136. Britti E, Delaspre F, Feldman A et al. Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment. J. Cell Mol. Med. 22(2), 834–848 (2018).
Medline CASGoogle Scholar
137. Mincheva-Tasheva S, Obis E, Tamarit J, Ros J. Apoptotic cell death and altered calcium homeostasis caused by frataxin depletion in dorsal root ganglia neurons can be prevented by BH4 domain of Bcl-xL protein. Hum. Mol. Genet. 23(7), 1829–1841 (2014).
Medline CASGoogle Scholar
138. Perdomini M, Belbellaa B, Monassier L et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nat. Med. 20(5), 542–547 (2014).
Medline CASGoogle Scholar
139. Piguet F, de Montigny C, Vaucamps N, Reutenauer L, Eisenmann A, Puccio H. Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia. Mol. Ther. 26(8), 1940–1952 (2018).
Medline CASGoogle Scholar
140. Belbellaa B, Reutenauer L, Monassier L, Puccio H. Correction of half the cardiomyocytes fully rescue Friedreich ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms. Hum. Mol. Genet. 28(8), 1274–1285 (2019).
Medline CASGoogle Scholar
141. Cherif K, Gérard C, Rousseau J, Ouellet DL, Chapdelaine P, Tremblay JP. Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE SunTag. Mol. Ther. Nucleic Acids. 12, 19–32 (2018).
Medline CASGoogle Scholar
142. ClinicalTrials.gov. Single Ascending Dose Study of CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia (2020). https://clinicaltrials.gov/ct2/show/NCT04176991
Google Scholar
143. Fischell JM, Fishman PS. A multifaceted approach to optimizing AAV delivery to the brain for the treatment of neurodegenerative diseases. Front Neurosci. 15, 747726 (2021).
MedlineGoogle Scholar
144. Hinderer C, Bell P, Katz N et al. Evaluation of intrathecal routes of administration for adeno-associated viral vectors in large animals. Hum. Gene Ther. 29(1), 15–24 (2018).
Medline CASGoogle Scholar
145. Taymans JM, Vandenberghe LH, Haute CV et al. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 18(3), 195–206 (2007).
Medline CASGoogle Scholar
146. Belbellaa B, Reutenauer L, Messaddeq N, Monassier L, Puccio H. High levels of Frataxin overexpression lead to mitochondrial and cardiac toxicity in mouse models. Mol. Ther. Methods Clin. Dev. 19, 120–138 (2020).
Medline CASGoogle Scholar
147. Erwin GS, Grieshop MP, Ali A et al. Synthetic transcription elongation factors license transcription across repressive chromatin. Science 358(6370), 1617–1622 (2017). •• Article showing the elegant approach to the Gene TAC drug design.
Medline CASGoogle Scholar
148. Rodden LN, Chutake YK, Gilliam K et al. Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia. Hum. Mol. Genet. 29(23), 3818–3829 (2021). •• Initial article on variegated silencing, a mechanism that may revolutionize thought process in FRDA.
MedlineGoogle Scholar
149. Rodden LN, Gilliam KM, Lam C et al. DNA methylation in Friedreich ataxia silences expression of frataxin isoform E. Sci. Rep. 12(1), 5031 (2022).
Medline CASGoogle Scholar
150. Rodden LN, Gilliam KM, Lam C, Lynch DR, Bidichandani SI. Epigenetic heterogeneity in Friedreich ataxia underlies variable FXN reactivation. Front. Neurosci. 15, 752921 (2021).
MedlineGoogle Scholar
151. Saveliev A, Everett C, Sharpe T, Webster Z, Festenstein R. DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing. Nature 422(6934), 909–913 (2003).
Medline CASGoogle Scholar
152. Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM. Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia. Nat. Chem. Biol. 2(10), 551–558 (2006).
Medline CASGoogle Scholar
153. Greene E, Mahishi L, Entezam A, Kumari D, Usdin K. Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia. Nucleic Acids Res. 35(10), 3383–3390 (2007).
Medline CASGoogle Scholar
154. Soragni E, Herman D, Dent SY, Gottesfeld JM, Wells RD, Napierala M. Long intronic GAA*TTC repeats induce epigenetic changes and reporter gene silencing in a molecular model of Friedreich ataxia. Nucleic Acids Res. 36(19), 6056–6065 (2008).
Medline CASGoogle Scholar
155. Castaldo I, Pinelli M, Monticelli A et al. DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients. J. Med. Genet. 45(12), 808–812 (2008).
Medline CASGoogle Scholar
156. Al-Mahdawi S, Pinto RM, Ismail O 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. 17(5), 735–746 (2008).
Medline CASGoogle Scholar
157. De Biase I, Chutake YK, Rindler PM, Bidichandani SI. Epigenetic silencing in Friedreich ataxia is associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription. PLoS ONE 4(11), e7914 (2009).
MedlineGoogle Scholar
158. Evans-Galea MV, Carrodus N, Rowley SM et al. FXN methylation predicts expression and clinical outcome in Friedreich ataxia. Ann. Neurol. 71(4), 487–497 (2012).
Medline CASGoogle Scholar
159. Chan PK, Torres R, Yandim C et al. Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by vitamin B3. Hum. Mol. Genet. 22(13), 2662–2675 (2013).
Medline CASGoogle Scholar
160. Muller HJ. Types of visible variations induced by x-rays in drosophila. J. Genet. 1930 XXII, 22, 299–333 (1930).
Google Scholar
161. Rodden L, Rummey C, Dong YN, Lynch DR. Clinical evidence for variegated silencing in Friedreich ataxia patients. Neurology Genet. 8(3), e683 (2022).
MedlineGoogle Scholar
162. Lynch DR, Deutsch EC, Wilson RB, Tennekoon G. answered questions in Friedreich ataxia. J. Child Neurol. 27(9), 1223–1229 (2012).
MedlineGoogle Scholar
163. Koeppen AH, Becker AB, Qian J, Gelman BB, Mazurkiewicz JE. Friedreich ataxia: developmental failure of the dorsal root entry zone. J. Neuropathol. Exp. Neurol. 76(11), 969–977 (2017).
Medline CASGoogle Scholar
164. 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. 111(6), 1023–1030 (2000).
Medline CASGoogle Scholar
165. Coppola G, De Michele G, Cavalcanti F et al. Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study. J. Neurol. 246(5), 353–357 (1999).
Medline CASGoogle Scholar
166. Santoro L, De Michele G, Perretti A et al. Relation between trinucleotide GAA repeat length and sensory neuropathy in Friedreich's ataxia. J. Neurol. Neurosurg. Psychiatry 66(1), 93–96 (1999).
Medline CASGoogle Scholar
167. Naeije G, Coquelet N, Wens V, Goldman S, Pandolfo M, De Tiège X. Age of onset modulates resting-state brain network dynamics in Friedreich Ataxia. Hum. Brain. Mapp. 42(16), 5334–5344 (2021).
MedlineGoogle Scholar
168. Naeije G, Wens V, Coquelet N et al. Age of onset determines intrinsic functional brain architecture in Friedreich ataxia. Ann. Clin. Transl. Neurol. 7(1), 94–104 (2020).
Medline CASGoogle Scholar
169. Naeije G, Bourguignon M, Wens V et al. Electrophysiological evidence for limited progression of the proprioceptive impairment in Friedreich ataxia. Clin. Neurophysiol. 131(2), 574–576 (2020).
Medline CASGoogle Scholar
170. Marty B, Naeije G, Bourguignon M et al. Evidence for genetically determined degeneration of proprioceptive tracts in Friedreich ataxia. Neurology 93(2), e116–e124 (2019).
MedlineGoogle Scholar
171. Kemp KC, Cook AJ, Redondo J, Kurian KM, Scolding NJ, Wilkins A. Purkinje cell injury, structural plasticity and fusion in patients with Friedreich's ataxia. Acta Neuropathol. Commun. 4(1), 53 (2016).
MedlineGoogle Scholar
172. Quercia N, Somers GR, Halliday W, Kantor PF, Banwell B, Yoon G. Friedreich ataxia presenting as sudden cardiac death in childhood: clinical, genetic and pathological correlation, with implications for genetic testing and counselling. Neuromuscul. Disord. 20(5), 340–342 (2010).
MedlineGoogle Scholar

Vol. 12, No. 5

Supplemental Materials

Metrics

Downloaded 493 times

History

Received 18 April 2022

Accepted 15 June 2022

Published online 29 June 2022

Published in print October 2022

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nmt-2022-0011

Author contributions

M Keita, K McIntyre, LN Rodden and DR Lynch wrote the first draft. M Keita, K McIntyre, LN Rodden, K Schadt and DR Lynch provided critical revisions.

Financial & competing interests disclosure

DR Lynch receives grant money from the NIH, FDA, FARA, Reata, Retrotope, Design and PTC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download

Friedreich ataxia: clinical features and new developments

Abstract

Plain language summary

References