Leberʼsche hereditäre Optikusneuropathie

Zusammenfassung

Die Leberʼsche hereditäre Optikusneuropathie (LHON) betrifft typischerweise junge Erwachsene mit einer Prädilektion für das männliche Geschlecht, kann letztlich aber in jedem Alter auftreten. Die Erkrankung beruht auf Punktmutationen der mitochondrialen DNA, die zu einem Defekt des Komplexes I der mitochondrialen Atmungskette führen. Dieser verursacht wiederum eine Dysfunktion und später Degeneration retinaler Ganglienzellen, gefolgt von einer aufsteigenden Optikusatrophie. Klinische Merkmale der LHON sind ein zunächst meist unilateraler subakuter Visusverlust, Farbsinnstörungen im Rot-Grün-Bereich und Gesichtsfeldausfälle in Form eines Zentral- oder Zentrozökalskotoms. Das Partnerauge ereilt innerhalb von 3 – 6 Monaten nach Erkrankungsbeginn meist eine ähnliche Symptomatik. In 25% der Fälle beginnt die Erkrankung jedoch bilateral. Im natürlichen Verlauf bleibt ein Großteil der Patienten bei einem Visus < 0,1, auch wenn ein kleiner Anteil eine spontane Visusverbesserung erfährt. Im Jahr 2015 wurde das Ubiquinonanalogon Idebenon von der Europäischen Arzneimittel-Agentur (EMA) für die Behandlung der LHON zugelassen. Ausschlaggebend für den Therapieerfolg sind ein früher Therapiebeginn und eine ausreichende Therapiedauer. Dabei ist zu beachten, dass es bei einem Anteil der Patienten zu einem verzögerten Therapieansprechen kommen kann. Eine vollständige Visuserholung ist allerdings auch unter Therapie selten. Da es sich meist um junge Erwachsene im erwerbsfähigen Alter handelt, die weitgehend akut erblinden, ist weiterhin eine umgehende Unterstützung mit vergrößernden Sehhilfen und Beratung zur sozialen und beruflichen Rehabilitation essenziell. Alternative Therapieansätze wie Gentherapie, Neuroprotektion oder stammzellbasierte Aspekte sind derzeit bereits Gegenstand von klinischen Studien und lassen auf weitere Perspektiven für die Betroffenen hoffen. Obwohl für die LHON mit Idebenon bereits eine kausale Therapie zugelassen wurde, sind gerade die Pathogenese der Erkrankung betreffend noch viele Fragen nicht restlos geklärt. Dies betrifft insbesondere die Geschlechterprävalenz und mögliche zusätzliche Trigger oder protektive Faktoren. In dieser Übersicht werden die klinischen Verlaufsformen der LHON, Diagnostik und aktuelle Therapieempfehlungen sowie die Besonderheiten und gegenwärtigen Erklärungsansätze zur inkompletten Penetranz und Symptomatik der LHON erläutert.

Abstract

Leberʼs hereditary optic neuropathy (LHON) typically affects young adults with a higher prevalence in men, but can ultimately occur at any age and also in women. LHON is caused by point mutations in the mitochondrial DNA, which lead to a defect in complex I of the mitochondrial respiratory chain. This in turn causes dysfunction and later degeneration of retinal ganglion cells, followed by ascending optic atrophy. Classically, LHON presents as a subacute unilateral loss of visual acuity, dyschromatopsia in the red-green axis and a central or centrocecal scotoma. The partner eye usually develops similar symptoms within 3 – 6 months of onset of the disease. In 25% of cases, however, the disease begins bilaterally. In the natural course of the disease, the majority of patients remain with a visual acuity less than 0.1, even though a small proportion may experience a spontaneous improvement in visual acuity. In 2015, the ubiquinone analogue Idebenone was approved by the European Medicines Agency for the treatment of LHON. The decisive factors for therapeutic success are an early start and an appropriate treatment duration. It should also be noted that a proportion of patients may experience a delayed response to therapy. However, a complete recovery of visual acuity is rare even under therapy. Since patients affected by LHON are mostly young adults of working age, who go largely blind more or less acutely, immediate support with magnifying vision aids and advice on social and vocational rehabilitation is essential. Alternative therapeutic approaches such as gene therapy, neuroprotection or stem cell-based aspects are currently the subject of clinical studies and offer hope for further perspectives for those affected. Although with Idebenone a causal therapy has already been approved for LHON, many questions regarding the pathogenesis of the disease have not yet been completely clarified. This particularly concerns gender prevalence and possible additional triggers or protective factors. In this overview, the clinical course of LHON, diagnostics and current therapy recommendations as well as the special features and current explanatory approaches to incomplete penetrance and symptoms of LHON are explained.

Schlüsselwörter

Neuroophthalmologie - Genetik - Optikusneuropathie - Mitochondriopathie

Key words

neuroophthalmology - genetics - optic neuropathy - mitochondriopathy

• Literatur

• 1 Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004; 23: 53-89 doi:10.1016/j.preteyeres.2003.10.003
• 2 Wallace DC, Singh G, Lott MT. et al. Mitochondrial DNA mutation associated with Leberʼs hereditary optic neuropathy. Science 1988; 242: 1427-1430
• 3 Wissinger B. [Genetic causes and genetic diagnostic testing of inherited optic atrophies]. Klin Monatsbl Augenheilkd 2018; 235: 1235-1241 doi:10.1055/a-0759-2094
• 4 Yu-Wai-Man P, Griffiths PG, Howell N. et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 2016; 98: 1271 doi:10.1016/j.ajhg.2016.05.015
• 5 Barboni P, Savini G, Valentino ML. et al. Leberʼs hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci 2006; 47: 5303-5309 doi:10.1167/iovs.06-0520
• 6 Dimitriadis K, Leonhardt M, Yu-Wai-Man P. et al. Leberʼs hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients. Orphanet J Rare Dis 2014; 9: 158 doi:10.1186/s13023-014-0158-9
• 7 Majander A, Bowman R, Poulton J. et al. Childhood-onset Leber hereditary optic neuropathy. Br J Ophthalmol 2017; 101: 1505-1509 doi:10.1136/bjophthalmol-2016-310072
• 8 Ruther K. [Hereditary optic neuropathies]. Klin Monatsbl Augenheilkd 2018; 235: 747-763 doi:10.1055/a-0583-6290
• 9 Harding AE, Sweeney MG, Govan GG. et al. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet 1995; 57: 77-86
• 10 Zeviani M, Di Donato S. Mitochondrial disorders. Brain 2004; 127: 2153-2172 doi:10.1093/brain/awh259
• 11 Neuhann T, Rautenstrauss B. Genetic and phenotypic variability of optic neuropathies. Expert Rev Neurother 2013; 13: 357-367 doi:10.1586/ern.13.19
• 12 Margulis L. Genetic and evolutionary consequences of symbiosis. Exp Parasitol 1976; 39: 277-349
• 13 Luo S, Valencia CA, Zhang J. et al. Biparental inheritance of mitochondrial DNA in humans. Proc Natl Acad Sci U S A 2018; 115: 13039-13044 doi:10.1073/pnas.1810946115
• 14 Carelli V, dʼAdamo P, Valentino ML. et al. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain 2016; 139: e17 doi:10.1093/brain/awv339
• 15 Kirkman MA, Yu-Wai-Man P, Korsten A. et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain 2009; 132: 2317-2326 doi:10.1093/brain/awp158
• 16 Kogachi K, Ter-Zakarian A, Asanad S. et al. Toxic medications in Leberʼs hereditary optic neuropathy. Mitochondrion 2018;
• 17 Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res 2011; 30: 81-114 doi:10.1016/j.preteyeres.2010.11.002
• 18 Caporali L, Maresca A, Capristo M. et al. Incomplete penetrance in mitochondrial optic neuropathies. Mitochondrion 2017; 36: 130-137 doi:10.1016/j.mito.2017.07.004
• 19 Chinnery PF, Andrews RM, Turnbull DM. et al. Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation?. Am J Med Genet 2001; 98: 235-243
• 20 Ghelli A, Porcelli AM, Zanna C. et al. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leberʼs hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS One 2009; 4: e7922 doi:10.1371/journal.pone.0007922
• 21 Ji Y, Jia X, Li S. et al. Evaluation of the X-linked modifier loci for Leber hereditary optic neuropathy with the G11778A mutation in Chinese. Mol Vis 2010; 16: 416-424
• 22 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 doi:10.1080/13816810701867607
• 23 Giordano C, Iommarini L, Giordano L. et al. Efficient mitochondrial biogenesis drives incomplete penetrance in Leberʼs hereditary optic neuropathy. Brain 2014; 137: 335-353 doi:10.1093/brain/awt343
• 24 Giordano L, Deceglie S, dʼAdamo P. et al. Cigarette toxicity triggers Leberʼs hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways. Cell Death Dis 2015; 6: e2021 doi:10.1038/cddis.2015.364
• 25 Liu SF, Kuo HC, Tseng CW. et al. Leukocyte mitochondrial DNA copy number is associated with chronic obstructive pulmonary disease. PLoS One 2015; 10: e0138716 doi:10.1371/journal.pone.0138716
• 26 Giordano C, Montopoli M, Perli E. et al. Oestrogens ameliorate mitochondrial dysfunction in Leberʼs hereditary optic neuropathy. Brain 2011; 134: 220-234 doi:10.1093/brain/awq276
• 27 Pisano A, Preziuso C, Iommarini L. et al. Targeting estrogen receptor beta as preventive therapeutic strategy for Leberʼs hereditary optic neuropathy. Hum Mol Genet 2015; 24: 6921-6931 doi:10.1093/hmg/ddv396
• 28 Carelli V, Carbonelli M, de Coo IF. et al. International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol 2017; 37: 371-381 doi:10.1097/wno.0000000000000570
• 29 Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leberʼs hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. Arch Ophthalmol 1982; 100: 1597-1602
• 30 Savini G, Barboni P, Valentino ML. et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leberʼs hereditary optic neuropathy mutations. Ophthalmology 2005; 112: 127-131 doi:10.1016/j.ophtha.2004.09.033
• 31 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
• 32 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 doi:10.1167/iovs.05-0455
• 33 Newman NJ, Biousse V, Newman SA. et al. Progression of visual field defects in Leber hereditary optic neuropathy: experience of the LHON treatment trial. Am J Ophthalmol 2006; 141: 1061-1067 doi:10.1016/j.ajo.2005.12.045
• 34 Yu-Wai-Man P, Griffiths PG, Hudson G. et al. Inherited mitochondrial optic neuropathies. J Med Genet 2009; 46: 145-158 doi:10.1136/jmg.2007.054270
• 35 Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol 2015; 9: 1165-1176 doi:10.2147/OPTH.S62021
• 36 Rudolph G, Dimitriadis K, Buchner B. et al. Effects of idebenone on color vision in patients with Leber hereditary optic neuropathy. J Neuroophthalmol 2013; 33: 30-36 doi:10.1097/WNO.0b013e318272c643
• 37 La Morgia C, Carelli V, Carbonelli M. Melanopsin retinal ganglion cells and pupil: clinical implications for neuro-ophthalmology. Front Neurol 2018; 9: 1047 doi:10.3389/fneur.2018.01047
• 38 Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leberʼs hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991; 111: 750-762
• 39 Balducci N, Savini G, Cascavilla ML. et al. Macular nerve fibre and ganglion cell layer changes in acute Leberʼs hereditary optic neuropathy. Br J Ophthalmol 2016; 100: 1232-1237 doi:10.1136/bjophthalmol-2015-307326
• 40 Barboni P, Carbonelli M, Savini G. et al. Natural history of Leberʼs hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology 2010; 117: 623-627 doi:10.1016/j.ophtha.2009.07.026
• 41 Guy J, Feuer WJ, Porciatti V. et al. Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2014; 55: 841-848 doi:10.1167/iovs.13-13365
• 42 Emperador S, Vidal M, Hernandez-Ainsa C. et al. The decrease in mitochondrial DNA mutation load parallels visual recovery in a Leber hereditary optic neuropathy patient. Front Neurosci 2018; 12: 61 doi:10.3389/fnins.2018.00061
• 43 Carelli V, Valentino ML, Liguori R. et al. Leberʼs hereditary optic neuropathy (LHON/11778) with myoclonus: report of two cases. J Neurol Neurosurg Psychiatry 2001; 71: 813-816
• 44 Harding AE, Riordan-Eva P, Govan GG. Mitochondrial DNA diseases: genotype and phenotype in Leberʼs hereditary optic neuropathy. Muscle Nerve Suppl 1995; 3: S82-S84
• 45 La Morgia C, Caporali L, Gandini F. et al. Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. BMC Neurol 2014; 14: 116 doi:10.1186/1471-2377-14-116
• 46 Britze J, Pihl-Jensen G, Frederiksen JL. Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis. J Neurol 2017; 264: 1837-1853 doi:10.1007/s00415-017-8531-y
• 47 Xu SC, Kardon RH, Leavitt JA. et al. Optical coherence tomography is highly sensitive in detecting prior optic neuritis. Neurology 2019; 92: e527-e535 doi:10.1212/wnl.0000000000006873
• 48 Nolan RC, Liu M, Akhand O. et al. Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: an international study. Ann Neurol 2019; 85: 618-629 doi:10.1002/ana.25462
• 49 Barboni P, Savini G, Cascavilla ML. et al. Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation. Am J Ophthalmol 2014; 158: 628-636.e3 doi:10.1016/j.ajo.2014.05.034
• 50 Li Y, Li J, Jia X. et al. Genetic and clinical analyses of DOA and LHON in 304 Chinese patients with suspected childhood-onset hereditary optic neuropathy. PLoS One 2017; 12: e0170090 doi:10.1371/journal.pone.0170090
• 51 Kim US, Jurkute N, Yu-Wai-Man P. Leber hereditary optic neuropathy-light at the end of the tunnel?. Asia Pac J Ophthalmol (Phila) 2018; 7: 242-245 doi:10.22608/apo.2018293
• 52 Yu-Wai-Man P, Soiferman D, Moore DG. et al. Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion 2017; 36: 36-42 doi:10.1016/j.mito.2017.01.004
• 53 Gueven N, Woolley K, Smith J. Border between natural product and drug: comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biol 2015; 4: 289-295 doi:10.1016/j.redox.2015.01.009
• 54 Carelli V, La Morgia C, Valentino ML. et al. Idebenone treatment in Leberʼs hereditary optic neuropathy. Brain 2011; 134: e188 doi:10.1093/brain/awr180
• 55 Klopstock T, Metz G, Yu-Wai-Man P. et al. Persistence of the treatment effect of idebenone in Leberʼs hereditary optic neuropathy. Brain 2013; 136: e230 doi:10.1093/brain/aws279
• 56 Klopstock T, Yu-Wai-Man P, Dimitriadis K. et al. A randomized placebo-controlled trial of idebenone in Leberʼs hereditary optic neuropathy. Brain 2011; 134: 2677-2686 doi:10.1093/brain/awr170
• 57 Sadun AA, Chicani CF, Ross-Cisneros FN. et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol 2012; 69: 331-338 doi:10.1001/archneurol.2011.2972
• 58 Guy J, Feuer WJ, Davis JL. et al. Gene therapy for Leber hereditary optic neuropathy: low- and medium-dose visual results. Ophthalmology 2017; 124: 1621-1634 doi:10.1016/j.ophtha.2017.05.016
• 59 Vignal C, Uretsky S, Fitoussi S. et al. Safety of rAAV2/2-ND4 gene therapy for Leber hereditary optic neuropathy. Ophthalmology 2018; 125: 945-947 doi:10.1016/j.ophtha.2017.12.036
• 60 Jurkute N, Harvey J, Yu-Wai-Man P. Treatment strategies for Leber hereditary optic neuropathy. Curr Opin Neurol 2019; 32: 99-104 doi:10.1097/wco.0000000000000646
• 61 Sharma LK, Tiwari M, Rai NK. et al. Mitophagy activation repairs Leberʼs hereditary optic neuropathy-associated mitochondrial dysfunktion and improves cell survival. Hum Mol Genet 2019; 28: 422-433 doi:10.1093/hmg/ddy354
• 62 Finsterer J, Mancuso M, Pareyson D. et al. Mitochondrial disorders of the retinal ganglion cells and the optic nerve. Mitochondrion 2018; 42: 1-10 doi:10.1016/j.mito.2017.10.003