Advertisement

Der Ophthalmologe

, Volume 108, Issue 12, pp 1179–1194 | Cite as

Lebersche Optikusneuropathie

  • B. Leo-Kottler
  • B. Wissinger
CME Weiterbildung · Zertifizierte Fortbildung

Zusammenfassung

Die Lebersche hereditäre Optikusneuropathie (LHON; http://omim.org/entry 535000) ist eine seltene erbliche Erkrankung der Ganglienzellen der Netzhaut mit der Folge einer meist bleibenden hochgradigen beidseitigen Visusminderung mit großen zentralen Gesichtsfeldausfällen. Im Anfangsstadium wird die Erkrankung nur in Ausnahmefällen diagnostiziert, meist wird zunächst eine Retrobulbärneuritis angenommen und der LHON-Patient der für eine Neuritis nervi optici üblichen Diagnostik und Therapie unterzogen. Erst dann, wenn sich die Befunde trotz aller therapeutischen Bemühungen nicht bessern, sondern z. B. durch den Befall des zweiten Auges verschlimmern, wird an eine LHON gedacht und die erforderliche beweisführende molekulargenetische Analyse veranlasst. Eine sorgfältige Anamnese inklusive Stammbaumerhebung sowie die Beachtung von Besonderheiten der Papillen des Patienten und seiner Angehörigen können helfen, die klinische Verdachtsdiagnose früher zu stellen. Aber auch bei exakter klinischer und molekulargenetischer Diagnosesicherung gibt die Erkrankung heute noch Rätsel auf.

Schlüsselwörter

Lebersche hereditäre Optikusneuropathie Sehnerv Mitochondriales Genom mtDNA Idebenon 

Leber’s hereditary optic neuropathy

Abstract

Leber’s hereditary optic neuropathy (LHON) is a rare disease primarily affecting the retinal ganglion cells. In most cases patients with LHON develop permanent visual loss with a large central scotoma in the visual field of both eyes. The optic disc becomes partially or completely pale. At the onset of the disease many patients are considered to suffer from an optic neuritis and are treated under the diagnostic and therapeutic regimen of optic neuritis. LHON is mostly only considered when high dose cortisone therapy fails to be effective or the second eye is affected. Thereafter, molecular genetic analysis will prove LHON in these cases. Detailed anamnesis including pedigree analysis in combination with observance of the peripapillary microangiopathic alterations at the fundus will help to speed up the diagnosis of LHON, but even after exact clinical and molecular genetic diagnosis of LHON some aspects of the disease still remain a mystery today.

Keywords

Leber’s hereditary optic neuropathy Optic nerve Mitochondrial genome mtDNA Idebenone 

Notes

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Literatur

  1. 1.
    Baracca A, Solaini G, Sgarbi G et al (2005) Severe impairment of complex I-driven adenosine triphosphate synthesis in Leber hereditary optic neuropathy cybrids. Arch Neurol 62:730–736PubMedCrossRefGoogle Scholar
  2. 2.
    Barboni P, Carbonelli M, Savini G et al (2010) Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology 177:623–627CrossRefGoogle Scholar
  3. 3.
    Barboni P, Savini G, Valentino ML et al (2006) Leber’s hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci 47:5303–5309PubMedCrossRefGoogle Scholar
  4. 4.
    Barnils GN, Mesa E, Munoz S et al (2007) Response to idebenone and multivitamin therapy in Leber’s hereditary optic neuropathy. Arch Soc Esp Oftalmol 82:377–380PubMedCrossRefGoogle Scholar
  5. 5.
    Blakely EL, Silva R de, King A et al (2005) LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet 13:623–627PubMedCrossRefGoogle Scholar
  6. 6.
    Bremner FD, Shallo-Hoffmann J, Riordan-Eva P et al (1999) Comparing pupil function and visual function in patients with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 40:2528–2534PubMedGoogle Scholar
  7. 7.
    Carelli V, Franceschini F, Venturi S et al (2007) Grand rounds: Could occupational exposure to n-hexane and other solvents precipitate visual failure in Leber hereditary optic neuropathy? Environ Health Perspect 115:113–115PubMedCrossRefGoogle Scholar
  8. 8.
    Carelli V, La Morgia C, Iommarini et al (2004) Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 23:53–89PubMedCrossRefGoogle Scholar
  9. 9.
    Carelli V, La Morgia C, Valentino ML et al (2011) Idebenone treatment in Leber’s hereditary optic neuropathy. Letter to the editor. Brain 134:e188PubMedCrossRefGoogle Scholar
  10. 10.
    Chinnery PF, Brown DT, Andrews RM et al (2001) The mitochondrial ND6 gene is a hot spot for mutations that cause Leber’s hereditary optic neuropathy. Brain 124:209–218PubMedCrossRefGoogle Scholar
  11. 11.
    Floreani M, Napoli E, Martinuzzi A et al (2005) Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber’s hereditary optic neuropathy. FEBS J 272:1124–1135PubMedCrossRefGoogle Scholar
  12. 12.
    Fraser JA, Biousse V, Newman NJ (2010) The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol 55:299–334PubMedCrossRefGoogle Scholar
  13. 13.
    Fruhman G, Landsverk ML, Lotze TE et al (2011) Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation. Mol Genet Metab 103:153–160PubMedCrossRefGoogle Scholar
  14. 14.
    Funalot B, Reynier P, Vighetto A et al (2002) Leigh-like encephalopathy complicating Leber’s hereditary optic neuropathy. Ann Neurol 52:374–377PubMedCrossRefGoogle Scholar
  15. 15.
    Giraudet S, Lamirel C, Amati-Bonneau P et al (2011) Never too old to harbour a young man’s disease? Br J Ophthalmol 95:887, 896–897PubMedCrossRefGoogle Scholar
  16. 16.
    Harding AE, Sweeney MG, Govan GG et al (1995) Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet 57:77–86PubMedGoogle Scholar
  17. 17.
    Harding AE, Sweeney MG, Miller DH et al (1992) Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 115:979–989PubMedCrossRefGoogle Scholar
  18. 18.
    Honda H, Tsujhata M, Ochi M et al (2006) Hyperintense optic nerve lesion on T2-weighted MRI imaging in the acute stage of Leber’s hereditary optic neuropathy: a case report. Rinsho Shinkeigaku 46:294–296PubMedGoogle Scholar
  19. 19.
    Howell N, Miller NR, Mackey DA et al (2002) Lightning strikes twice: Leber hereditary optic neuropathy with two pathogenic mtDNA mutations. J Neuroophthalmol 22:262–269PubMedCrossRefGoogle Scholar
  20. 20.
    Hudson G, Carelli V, Spruijt L et al (2007) Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet 81:228–233PubMedCrossRefGoogle Scholar
  21. 21.
    Hudson G, Keers S, Man PYW (2005) Identification of an X-chromosomal locus and haplotypes modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 77:1086–1091PubMedCrossRefGoogle Scholar
  22. 22.
    Huoponen K (2001) Leber hereditary optic neuropathy: clinical and molecular genetic findings. Neurogenetics 3:119–125PubMedCrossRefGoogle Scholar
  23. 23.
    Hwang JM, Park HW (1996) Carbon monoxide poisoning as an epigenetic factor for Leber’s herediary optic neuropathy. Korean J Ophthalmol 10:122–123PubMedGoogle Scholar
  24. 24.
    Johns DR, Heher KL, Miller NR et al (1993) Leber’s hereditary optic neuropathy: clinical manifestations of the 14484 mutation. Arch Ophthalmol 111:495–498PubMedCrossRefGoogle Scholar
  25. 25.
    Kawasaki A, Herbst K, Sander B et al (2010). Selective wavelength pupillometry in Leber hereditary optic neuropathy. Clin Experiment Ophthalmol 38:322–324PubMedGoogle Scholar
  26. 26.
    Kirkman MA, Korsten A, Leonhardt M et al (2009) Quality of life in patients with Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 50:3112–3115PubMedCrossRefGoogle Scholar
  27. 27.
    Kirkman MA, Yu-Wai-Man P, Korsten A et al (2009) Gene-enviroment interactions in Leber hereditary optic neuropathy. Brain 132:2317–2326PubMedCrossRefGoogle Scholar
  28. 28.
    Klopstock T, Yu-Wai-Man P, Dimitriadis K et al (2011) A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 134:2677–2686PubMedCrossRefGoogle Scholar
  29. 29.
    Koilkonda RD, Guy J (2011) Leber’s hereditary optic neuropathy-gene therapy: from benchtop to bedside. J Ophthalmol 179412Google Scholar
  30. 30.
    Küker W, Weir A, Quaghebeur G et al (2007) White matter changes in Leber’s hereditary optic neuropathy: MRI findings. Eur J Neurol 14:591–593PubMedCrossRefGoogle Scholar
  31. 31.
    Kurtenbach A, Leo-Kottler B, Zrenner E (2004) Inner retinal contributions to the multifocal electroretinogramm: patients with Leber’s hereditary optic neuropathy (LHON). Multifocal electroretinogramm in LHON. Doc Ophthalmol 108:231–240PubMedCrossRefGoogle Scholar
  32. 32.
    La Morgia C, Ross-Cisneros FN, Sadun AA et al (2010) Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain 133:2426–2438CrossRefGoogle Scholar
  33. 33.
    Leber T (1871) Ueber hereditäre und congenital-angelegte Sehnervenleiden. Graefes Arch Ophthalmol 17:249–291CrossRefGoogle Scholar
  34. 34.
    Leo-Kottler B, Christ-Adler M, Baumann B et al (1996) Leber’s hereditary optic neuropathy: clinical and molecular genetic results obtained in a family with a new point mutation at nucleotide position 14498 in the ND6 gene. Ger J Ophthalmol 5:233–240PubMedGoogle Scholar
  35. 35.
    Leo-Kottler B, Jacobi F, Christ-Adler M (2000) Lebersche Optikusneuropathie mit klinischer Besserung. Ophthalmologe 97:849–854PubMedCrossRefGoogle Scholar
  36. 36.
    Leo-Kottler B, Jägle H, Küpker T et al (2007) Autosomal-dominant erbliche Optikusatrophie vs. Lebersche Optikusneuropathie. Wie kann man sie unterscheiden? Ophthalmologe 104:1060–1065PubMedCrossRefGoogle Scholar
  37. 37.
    Mackey DA, Fingert JH, Luzhansky JZ et al (2003) Leber’s hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus. Eye 17:312–317PubMedCrossRefGoogle Scholar
  38. 38.
    Mackey DA, Oostra RJ, Rosenberg T et al (1996) Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 59:481–485PubMedGoogle Scholar
  39. 39.
    Man PY, Griffiths PG, Brown DT et al (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72:333–339PubMedCrossRefGoogle Scholar
  40. 40.
    Mashima Y, Kigasawa K, Wakakura M et al (2000) Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol 20:166–170PubMedCrossRefGoogle Scholar
  41. 41.
    Mashima Y, Kimura I, Yamamoto Y et al (2003) Optic disc excavation in the atrophic stage of Leber’s hereditary optic neuropathy: comparison with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol 241:75–80PubMedCrossRefGoogle Scholar
  42. 42.
    Mashima Y, Yamada K, Wakakura M et al (1998) Spectrum of pathogenic DNA mitochondrial mutations and clinical features in Japanese families with Leber’s hereditary optic neuropathy. Curr Eye Res 17:403–408PubMedCrossRefGoogle Scholar
  43. 43.
    Newman NJ (1993) Leber’s hereditary optic neuropathy. Arch Neurol 50:540–548PubMedCrossRefGoogle Scholar
  44. 44.
    Newman NJ (2011) Treatment of Leber hereditary optic neuropathy. Brain 134:2447–2455PubMedCrossRefGoogle Scholar
  45. 45.
    Newman NJ (2005) Hereditary optic neuropathies. In: Miller NR, Newman NJ, Biousse V, Kerrison JB (Hrsg) Walsh and Hoyt’s clinical neuro-ophthalmology, 6. Aufl. Williams & Wilkins, Baltimore, S 465–501Google Scholar
  46. 46.
    Newman-Toker DE, Horton JC, Lessell S (2003) Recurrent vision loss in Leber hereditary optic neuropathy. Arch Ophthalmol 232:288–291Google Scholar
  47. 47.
    Nikoskelainen EK, Huoponen K, Juvonen V et al (1996) Ophthalmologic findings in Leber hereditary optic neuropathy with special reference to mtDNA mutations. Ophthalmology 103:504–514PubMedGoogle Scholar
  48. 48.
    Nikoskelainen EK, Marttila RJ, Huoponen K et al (1995) Leber’s „plus“: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 59:160–164PubMedCrossRefGoogle Scholar
  49. 49.
    Nikoskelainen E, Wanne O, Dahl M (1985) Pre-excitation syndrome and Leber’s hereditary optic neuroretinopathy (Letter). Lancet 325:696CrossRefGoogle Scholar
  50. 50.
    Parry-Jones AR, Mitchell JD, Gunarwardena WJ et al (2008) Leber’s hereditary optic neuropathy associated with multiple sclerosis: Harding’s syndrome. Pract Neurol 8:118–121PubMedCrossRefGoogle Scholar
  51. 51.
    Phillips PH, Vaphiades M, Glasier CM et al (2003) Chiasmal enlargement and optic nerve enhancement on magnetic resonance imaging in Leber hereditary optic neuropathy. Arch Ophthalmol 121:577–579PubMedCrossRefGoogle Scholar
  52. 52.
    Pott JWR, Wong KH (2006) Leber’s hereditary optic neuropathy and vitamin B 12 deficiency. Graefes Arch Clin Exp Ophthalmol 244:1357–1359PubMedCrossRefGoogle Scholar
  53. 53.
    Puomila A, Hämäläinen P, Kivioja S et al (2007) Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet 15:1079–1089PubMedCrossRefGoogle Scholar
  54. 54.
    Ramos Cdo V, Bellusci C, Savini G et al (2009) Association of optic disc size with development and prognosis of Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 50:1666–1674PubMedCrossRefGoogle Scholar
  55. 55.
    Riodan-Eva P, Sanders MD, Govan GG et al (1995) The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118:319–337CrossRefGoogle Scholar
  56. 56.
    Sadun AA, Carelli V, Salomao SR et al (2003) Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 136:231–238PubMedCrossRefGoogle Scholar
  57. 57.
    Sanchez RN, Smith AJ, Carelli V et al (2006) Leber hereditary optic neuropathy possibly triggered by exposure to tire fire. J Neuroophthalmol 26:268–272PubMedCrossRefGoogle Scholar
  58. 58.
    Shankar SP, Fingert JH, Carelli V et al (2008) Evidence for a novel x-linked modifier locus for Leber hereditary optic neuropathy. Ophthalmic Genet 29:17–24PubMedCrossRefGoogle Scholar
  59. 59.
    Smith JL, Hoyt WF, Susac JO (1973) Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol 90:349–354PubMedCrossRefGoogle Scholar
  60. 60.
    Smith KH, Johns DR, Heher KL et al (1993) Heteroplasmy in Leber’s hereditary optic neuropathy. Arch Ophthalmol 111:1486–1490PubMedCrossRefGoogle Scholar
  61. 61.
    Sorajja P, Sweeney MG, Chalmers R et al (2003) Cardiac abnormalities in patients with Leber’s hereditary optic neuropathy. Heart 89:791–792PubMedCrossRefGoogle Scholar
  62. 62.
    Spruijt L, Kolbach DN, Coo RF de et al (2007) A MELAS-associated ND1 mutation causing Leber hereditary optic neuropathy and spastic dystonia. Arch Neurol 64:890–893PubMedCrossRefGoogle Scholar
  63. 63.
    Valentino ML, Barboni P, Ghelli A et al (2004) The ND1 gene of complex I is a mutational hot spot for Leber’s hereditary optic neuropathy. Ann Neurol 56:631–641PubMedCrossRefGoogle Scholar
  64. 64.
    Vaphiades MS, Phillips PH, Turbin RE (2003) Optic nerve and chiasmal enhancement in Leber hereditary optic nerve neuropathy. J Neuroophthalmol 23:104–105PubMedCrossRefGoogle Scholar
  65. 65.
    Wakakura M, Yokoe J (1995) Evidence for preserved direct pupillary light response in Leber’s hereditary optic neuropathy. Br J Ophthalmol 79:442–446PubMedCrossRefGoogle Scholar
  66. 66.
    Wallace DC, Singh G, Lott MT et al (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242:1427–1430PubMedCrossRefGoogle Scholar
  67. 67.
    Yen MY, Wang AG, Chang WL et al (2002) Leber’s hereditary optic neuropathy – the spectrum of mitochondrial DNA mutations in Chinese patients. Jpn J Ophthalmol 46:45–51PubMedCrossRefGoogle Scholar
  68. 68.
    Yen MY, Wang AG, Wei YH (2006) Leber’s hereditary optic neuropathy: a multifactorial disease. Prog Retin Eye Res 25:381–396PubMedCrossRefGoogle Scholar
  69. 69.
    Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30:81–114PubMedCrossRefGoogle Scholar
  70. 70.
    Zanna C, Ghelli A, Porcelli AM et al (2005) Caspase-independent death of Leber’s hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G. Apoptosis 10:997–1007PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department für AugenheilkundeAugenklinikTübingenDeutschland
  2. 2.Department für AugenheilkundeForschungsinstitut für AugenheilkundeTübingenDeutschland

Personalised recommendations