Current Treatment Options in Neurology

, Volume 13, Issue 1, pp 109–117 | Cite as

Leber’s Hereditary Optic Neuropathy

  • Alfredo A. Sadun
  • Chiara La MorgiaEmail author
  • Valerio Carelli
Neurologic Ophthalmology and Otology

Opinion statement

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disease with variable penetrance. Three primary mitochondrial DNA mutations, affecting the respiratory complex I, are necessary but not sufficient to cause blindness. Reduced efficiency of ATP synthesis and increased oxidative stress are believed to sensitize the retinal ganglion cells to apoptosis. Different therapeutic strategies are considered to counteract this pathogenic mechanism. However, potential treatments for the visual loss are complicated by the fact that patients are unlikely to benefit after optic atrophy occurs. There is no proven therapy to prevent or reverse the optic neuropathy in LHON. Results from a recent trial with idebenone hold promise to limit neurodegeneration and improve final outcome, promoting recovery of visual acuity. Other therapeutic options are under scrutiny, including gene therapy, agents increasing mitochondrial biogenesis, and anti-apoptotic drugs.


Optical Coherence Tomography Retinal Nerve Fiber Layer Optic Neuropathy Mitochondrial Permeability Transition Pore Mitochondrial Permeability Transition Pore 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading

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  1. 1.
    Carelli V, Ross-Cisneros FN, Sadun AA: Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004, 23:53–89.CrossRefPubMedGoogle Scholar
  2. 2.••
    Fraser JA, Biousse V, Newman NJ: The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol 2010, 55(4):299–334.CrossRefPubMedGoogle Scholar
  3. 3.
    Wallace DC, Singh G, Lott MT, et al.: Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988, 242:1427–1430.CrossRefPubMedGoogle Scholar
  4. 4.
    Sadun AA, Carelli V, Salomao SR, et al.: A very large Brazilian pedigree with 11778 Leber’s hereditary optic neuropathy. Trans Am Ophthalmol Soc 2002, 100:169–178. discussion 178–179.PubMedGoogle Scholar
  5. 5.
    Sadun AA, Carelli V, Salomao SR, et al.: Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 2003, 136:231–238.CrossRefPubMedGoogle Scholar
  6. 6.
    Carelli V, Achilli A, Valentino ML, et al.: Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet 2006, 78:564–574.CrossRefPubMedGoogle Scholar
  7. 7.
    Hudson G, Carelli V, Spruijt L, et al.: Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet 2007, 81:228–233.CrossRefPubMedGoogle Scholar
  8. 8.
    Shankar SP, Fingert JH, Carelli V, et al.: Evidence for a novel x-linked modifier locus for Leber hereditary optic neuropathy. Ophthalmic Genet 2008, 29:17–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Savini G, Barboni P, Valentino ML, et al.: Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations. Ophthalmology 2005, 112:127–131.CrossRefPubMedGoogle Scholar
  10. 10.
    Ventura DF, Quiros P, Carelli V, et al.: Chromatic and luminance contrast sensitivities in asymptomatic carriers from a large Brazilian pedigree of 11778 Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2005, 46:4809–4814.CrossRefPubMedGoogle Scholar
  11. 11.
    Ventura DF, Gualtieri M, Oliveira AG, et al.: Male prevalence of acquired color vision defects in asymptomatic carriers of Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2007, 48:2362–2370.CrossRefPubMedGoogle Scholar
  12. 12.
    Gualtieri M, Bandeira M, Hamer RD, et al.: Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber’s hereditary optic neuropathy. Vis Neurosci 2008, 25:469–474.PubMedGoogle Scholar
  13. 13.
    Sadun AA, Win PH, Ross-Cisneros FN, et al.: Leber’s hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc 2000, 98:223–232. discussion 232–235.PubMedGoogle Scholar
  14. 14.••
    Barboni P, Carbonelli M, Savini G, et al.: Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology 2010, 117(3):623–627.CrossRefPubMedGoogle Scholar
  15. 15.
    Sadun AA, Salomao SR, Berezovsky A, et al.: Subclinical carriers and conversions in Leber hereditary optic neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc 2006, 104:51–61.PubMedGoogle Scholar
  16. 16.
    Barboni P, Savini G, Valentino ML, et al.: Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy. Ophthalmology 2005, 112:120–126.CrossRefPubMedGoogle Scholar
  17. 17.
    Sadun F, De Negri AM, Carelli V, et al.: Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 2004, 137:271–277.CrossRefPubMedGoogle Scholar
  18. 18.•
    Kirkman MA, Yu-Wai-Man P, Korsten A, et al.: Gene-environment interactions in Leber hereditary optic neuropathy. Brain 2009, 132:2317–2326.CrossRefPubMedGoogle Scholar
  19. 19.•
    Ramos C, Bellusci C, Savini G, et al.: Association of optic disc size with development and prognosis of Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2009, 50:1666–1674.CrossRefPubMedGoogle Scholar
  20. 20.
    Sanchez RN, Smith AJ, Carelli V, et al.: Leber hereditary optic neuropathy possibly triggered by exposure to tire fire. J Neuroophthalmol 2006, 26:268–272.PubMedGoogle Scholar
  21. 21.
    De Marinis M: Optic neuropathy after treatment with anti-tuberculous drugs in a subject with Leber’s hereditary optic neuropathy mutation. J Neurol 2001, 248:818–819.CrossRefPubMedGoogle Scholar
  22. 22.
    Ikeda A, Ikeda T, Ikeda N, et al.: Leber’s hereditary optic neuropathy precipitated by ethambutol. Jpn J Ophthalmol 2006, 50:280–283.CrossRefPubMedGoogle Scholar
  23. 23.
    Pott JW, Wong KH: Leber’s hereditary optic neuropathy and vitamin B12 deficiency. Graefes Arch Clin Exp Ophthalmol 2006, 244:1357–1359.CrossRefPubMedGoogle Scholar
  24. 24.
    Mashima Y, Kigasawa K, Wakakura M, et al.: Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol 2000, 20:166–170.PubMedGoogle Scholar
  25. 25.
    Newman NJ, Biousse V, David R, et al.: Prophylaxis for second eye involvement in Leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol 2005, 140:407–415.PubMedGoogle Scholar
  26. 26.
    Wheeler L, WoldeMussie E, Lai R: Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol 2003, 48(Suppl 1):S47–S51.CrossRefPubMedGoogle Scholar
  27. 27.
    Lai RK, Chun T, Hasson D, et al.: Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci 2002, 19:175–185.CrossRefPubMedGoogle Scholar
  28. 28.
    Ghelli A, Porcelli AM, Zanna C, et al.: Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids. Invest Ophthalmol Vis Sci 2008, 49:671–676.CrossRefPubMedGoogle Scholar
  29. 29.
    Sala G, Trombin F, Beretta S, et al.: Antioxidants partially restore glutamate transport defect in Leber hereditary optic neuropathy cybrids. J Neurosci Res 2008, 86:3331–3337.CrossRefPubMedGoogle Scholar
  30. 30.
    Mahidol University: A randomized, double-blind, placebo-controlled trial of curcumin in Leber’s hereditary optic neuropathy (LHON). In: [Internet}. Bethesda, MD: National Library of Medicine (US). Available from:
  31. 31.
    Huang CC, Kuo HC, Chu CC, et al.: Rapid visual recovery after coenzyme q10 treatment of Leber hereditary optic neuropathy. J Neuroophthalmol 2002, 22:66.PubMedGoogle Scholar
  32. 32.
    Geromel V, Darin N, Chrétien D, et al.: Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab 2002, 77:21–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Cortelli P, Montagna P, Pierangeli G, et al.: Clinical and brain bioenergetics improvement with idebenone in a patient with Leber’s hereditary optic neuropathy: a clinical and 31P-MRS study. J Neurol Sci 1997, 148:25–31.CrossRefPubMedGoogle Scholar
  34. 34.
    Carelli V, Barboni P, Zacchini A, et al.: Leber’s hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci 1998, 160:183–188.CrossRefPubMedGoogle Scholar
  35. 35.
    Barnils N, Mesa E, Munoz S, et al.: Response to idebenone and multivitamin therapy in Leber’s hereditary optic neuropathy. Arch Soc Esp Oftalmol 2007, 82:377–380.CrossRefPubMedGoogle Scholar
  36. 36.
    Eng JG, Aggarwal D, Sadun AA: Idebenone treatment in patients with Leber hereditary optic neuropathy [abstract]. Invest Ophthalmol Vis Sci 2009, 50(Suppl):1440.Google Scholar
  37. 37.
    Chinnery P, et al.: Results of a 6-months randomized, placebo-controlled trial (RHODOS) with idebenone (Catena®) in Leber’s Hereditary Optic Neuropathy (LHON) [poster WIP-3]. Presented at the 135th Annual Meeting of the American Neurological Association. San Francisco, CA; September 14, 2010.Google Scholar
  38. 38.
    Guy J, Qi X, Koilkonda RD, et al.: Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Invest Ophthalmol Vis Sci 2009, 50:4205–4214.CrossRefPubMedGoogle Scholar
  39. 39.
    Ellouze S, Augustin S, Bouaita A, et al.: Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 2008, 83:373–387.CrossRefPubMedGoogle Scholar
  40. 40.••
    Perales-Clemente E, Fernández-Silva P, Acín-Pérez R, et al.: Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? Nucleic Acids Res 2010 Sep 7 (Epub ahead of print).This careful study demonstrates how apparent complementation of the mitochondrial dysfunction by using the approach of allotopic expression may be due to selection of mtDNA mutation revertants.Google Scholar
  41. 41.
    Figueroa-Martínez F, Vázquez-Acevedo M, Cortés-Hernández P, et al.: What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes. Mitochondrion 2010 Sep 18 (Epub ahead of print).Google Scholar
  42. 42.
    Marella M, Seo BB, Thomas BB, et al.: Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. PLoS One 2010, 5:e11472.CrossRefPubMedGoogle Scholar
  43. 43.
    Wenz T, Diaz F, Spiegelman BM, Moraes CT: Activation of the PPAR/PGC-1α pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab 2008, 8:249–256.CrossRefPubMedGoogle Scholar
  44. 44.••
    Giordano C, Montopoli M, Perli E, et al.: Estrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain 2010, in press. This study demonstrated the role of estrogens in compensating for mitochondrial dysfunction in LHON and explains the reduced penetrance in females.Google Scholar
  45. 45.
    Porcelli AM, Angelin A, Ghelli A, et al.: Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels. J Biol Chem 2009, 284:2045–2052.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Alfredo A. Sadun
    • 1
  • Chiara La Morgia
    • 2
    Email author
  • Valerio Carelli
    • 2
  1. 1.Thornton Professor of Vision, Departments of Ophthalmology and NeuroSurgeryDoheny Eye Institute and Keck-USC School of MedicineLos AngelesUSA
  2. 2.Department of Neurological SciencesUniversity of BolognaBolognaItaly

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