Leber Hereditary Optic Neuropathy

Česká verzia

Authors: H. Kolářová ¹; T. Honzík ¹; Ľ. Ďuďáková ²; B. Kousal ³; J. Kulhánek ¹; P. Diblík ³; M. Tesařová ¹; P. Havránková ⁴; M. Forgáč ⁴; J. Zeman ¹; P. Lišková ^2,3
Authors place of work: Klinika dětského a dorostového lékařství 1. LF UK a VFN v Praze ¹; Ústav dědičných metabolických poruch, 1. LF UK a VFN v Praze ²; Oční klinika 1. LF UK a VFN v Praze ³; Neurologická klinika 1. LF UK a VFN v Praze ⁴
Published in the journal: Cesk Slov Neurol N 2017; 80/113(5): 534-544
Category: Review Article
doi: https://doi.org/10.14735/amcsnn2017534

Summary

Leber hereditary optic neuropathy (LHON) is maternally inherited disorder characterized by subacute loss of vision due to impairment of retinal ganglion cells eventually leading to optic atrophy. Three prevalent point mutations in mitochondrial DNA: m.11778G>A, m.3460G>A, and m.14484T>C, are causative in the majority (95%) of cases. All of these mutations affect one of the subunits of complex I, NADH-ubiquinone oxidoreductase, the first enzyme of the mitochondrial respiratory chain. The presence of a mutation is necessary but not sufficient to cause visual loss. The penetrance is incomplete with only about 50% of men and 10% of women event. developing clinical signs of the disease. Recently, it was proven that early initiation of therapy with idebenone in patients manifesting LHON ameliorates visual functions and clinical trials testing several other promising therapies are underway. Incomplete penetrance, similarites with other disorders affecting the optic nerve and a great variability of clinical features cause considerable diagnostic difficulties. Often there is a delay in therapy initiation, as late as in the phase of the irreversible optic nerve damage. In 2013, we established a multidisciplinary medical care centre dedicated to patients with mitochondrial optic neuropathies in General University Hospital in Prague to develop effective diagnostic and treatment algorithms and to study the underlying pathogenetic mechanisms.

Key words:
LHON – optic neuropathy – optic atrophy – mitochondria – mtDNA – multiple sclerosis

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Zdroje

1. Schaefer AM, Taylor RW, Turnbull DM, et al. The epidemiology of mitochondrial disorders – past, present and future. Biochim Biophys Acta 2004;1659(2– 3):115– 20.

2. Leber T. About hereditary and congenital optic neuropathy. Albrecht Von Grafes Arch Ophthalmol 1871;17:249– 91.

3. Wallace DC. A new manifestation of Leber‘s disease and a new explanation for the agency responsible for its unusual pattern of inheritance. Brain 1970;93(1):121– 32.

4. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber‘s hereditary optic neuropathy. Science 1988;242(4884):1427– 30.

5. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004;23(1):53– 89.

6. Yu-Wai-Man P, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet 2002;39(3):162– 9.

7. Yu-Wai-Man P, Griffiths PG, Brown DT, et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 2003;72(2):333– 9.

8. Gorman GS, Schaefer AM, Ng Y, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015;77(5): 753– 9. doi: 10.1002/ ana.24362.

9. Spruijt L, Kolbach DN, de Coo RF, et al. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol 2006;141(4):676– 82.

10. Puomila A, Hamalainen P, Kivioja S, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet 2007;15(10):1079– 89.

11. Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. In: Pagon RA, Adam MP, Ardinger HH, et al. eds. Seattle: Seattle University of Washington 1993.

12. Nikoskelainen EK, Huoponen K, Juvonen V, et al. Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 1996;103(3):504– 14.

13. Riordan-Eva P, Sanders MD, Govan GG, et al. The clinical features of Leber‘s hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 1995; 118(Pt 2):319– 37.

14. Dimitriadis K, Leonhardt M, Yu-Wai-Man P, et al. Leber‘s 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.

15. 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– 27. doi: 10.1016/ j.ophtha.2009.07.026.

16. Wakakura M, Yokoe J. Evidence for preserved direct pupillary light response in Leber‘s hereditary optic neuropathy. Br J Ophthalmol 1995;79(5):442– 6.

17. Kawasaki A, Herbst K, Sander B, et al. Selective wavelength pupillometry in Leber hereditary optic neuropathy. Clin Exp Ophthalmol 2010;38(3):322– 4. doi: 10.1111/ j.1442-9071.2010.02212.x.

18. Ziccardi L, Sadun F, De Negri AM, et al. Retinal function and neural conduction along the visual pathways in affected and unaffected carriers with Leber‘s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2013;54(10):6893– 901. doi: 10.1167/ iovs.13-12894.

19. Nikoskelainen E, Sogg RL, Rosenthal AR, et al. The early phase in Leber hereditary optic atrophy. Arch Ophthalmol 1977;95(6):969– 78.

20. 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(1):77– 86.

21. 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(1):120– 6.

22. Balducci N, Savini G, Cascavilla ML, et al. Macular nerve fibre and ganglion cell layer changes in acute Leber‘s hereditary optic neuropathy. Br J Ophthalmol 2016;100(9):1232– 7. doi: 10.1136/ bjophthalmol-2015-307326.

23. Kirkman MA, Yu-Wai-Man P, Korsten A, et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain 2009;132(Pt 9):2317– 26. doi: 10.1093/ brain/ awp158.

24. Barboni P, Savini G, Valentino ML, et al. Leber‘s hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci 2006;47(12):5303– 9. doi: 10.1167/ iovs.06-0520.

25. Ramos Cdo V, 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(4):1666–74. doi: 10.1167/ iovs.08-2695.

26. Riordan-Eva P, Harding AE. Leber‘s hereditary optic neuropathy: the clinical relevance of different mitochondrial DNA mutations. J Med Genet 1995;32(2):81– 7.

27. Johns DR, Heher KL, Miller NR, et al. Leber‘s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol 1993;111(4):495– 8.

28. Macmillan C, Kirkham T, Fu K, et al. Pedigree analysis of French Canadian families with T14484C Leber‘s hereditary optic neuropathy. Neurology 1998;50(2):417– 22.

29. Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 1992;187(3):1551– 7.

30. Lam BL, Feuer WJ, Schiffman JC, et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy : preparation for gene therapy clinical trial. JAMA Ophthalmology 2014;132(4):428– 36. doi: 10.1001/ jamaophthalmol.2013.7971.

31. Newman NJ, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber‘s hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol 1991;111(6):750– 62.

32. 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;104:751– 61.

33. Barboni P, Savini G, 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(1):127– 31.

34. Salomao SR, Berezovsky A, Andrade RE, et al. Visual electrophysiologic findings in patients from an extensive Brazilian family with Leber‘s hereditary optic neuropathy. Doc Ophthalmol 2004;108(2):147– 55.

35. Sacai PY, Salomao SR, Carelli V, et al. Visual evokedpotentials findings in non-affected subjects from a large Brazilian pedigree of 11778 Leber‘s hereditary optic neuropathy. Doc Ophthalmol 2010;121(2):147– 54. doi: 10.1007/ s10633-010-9241-2.

36. Livingstone IR, Mastaglia FL, Howe JW, et al. Leber‘s optic neuropathy: clinical and visual evoked response studies in asymptomatic and symptomatic members of a 4-generation family. Br J Ophthalmol 1980;64(10):751– 7.

37. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res 2011;30(2):81– 114. doi: 10.1016/ j.preteyeres.2010.11.002.

38. Blakely EL, de Silva R, King A, et al. LHON/ MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet 2005;13(5):623– 7.

39. Kolarova H, Liskova P, Tesarova M et al. Unique presentation of LHON/ MELAS overlap syndrome caused by m.13046T>C in MTND5. Ophthalmic Genet 2016;37(4):419– 23.

40. Howell N, Kubacka I, Xu M, et al. Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 1991;48(5):935– 42.

41. De Vries DD, Went LN, Bruyn GW, et al. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 1996;58(4):703– 11.

42. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci USA 1994;91(13):6206– 10.

43. Gropman A, Chen TJ, Perng CL, et al. Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. Am J Med Genet A 2004;124A(4):377– 82.

44. Tarnopolsky MA, Baker SK, Myint T, et al. Clinical variability in maternally inherited leber hereditary optic neuropathy with the G14459A mutation. Am J Med Genet A 2004; 124A(4):372– 6. doi: 10.1002/ ajmg.a.20449.

45. Newman NJ. Leber‘s hereditary optic neuropathy. New genetic considerations. Arch Neurol 1993;50(5):540– 8.

46. Harding AE, Sweeney MG, Miller DH, et al. Occurrence of a multiple sclerosis-like illness in women who have a Leber‘s hereditary optic neuropathy mitochondrial DNA mutation. Brain 1992;115(Pt 4):979– 89.

47. Dotti MT, Caputo N, Signorini E, et al. Magnetic resonance imaging findings in Leber‘s hereditary optic neuropathy. Eur Neurol 1992;32(1):17– 9.

48. Mashima Y, Oshitari K, Imamura Y, et al. Orbital high resolution magnetic resonance imaging with fast spin echo in the acute stage of Leber‘s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1998;64(1):124– 7.

49. Kellar-Wood H, Robertson N, Govan GG, et al. Leber‘s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 1994;36(1):109– 12.

50. Jansen PH, van der Knaap MS, de Coo IF. Leber‘s hereditary optic neuropathy with the 11,778 mtDNA mutation and white matter disease resembling multiple sclerosis: clinical, MRI and MRS findings. J Neurol Sci 1996;135(2):176– 80.

51. Vanopdenbosch L, Dubois B, D‘Hooghe MB, et al. Mitochondrial mutations of Leber‘s hereditary optic neuropathy: a risk factor for multiple sclerosis. J Neurol 2000;247(7):535– 43.

52. Pfeffer G, Burke A, Yu-Wai-Man P, et al. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology 2013;81(24):2073– 81. doi: 10.1212/ 01.wnl.0000437308.22603.43.

53. Matthews L, Enzinger C, Fazekas F, et al. MRI in Leber‘s hereditary optic neuropathy: the relationship to multiple sclerosis. J Neurol Neurosurg Psychiatry 2015;86(5):537– 42. doi: 10.1136/ jnnp-2014-308186.

54. Palace J. Multiple sclerosis associated with Leber‘s Hereditary Optic Neuropathy. J Neurol Sci 2009;286(1-2):24– 7. doi: 10.1016/ j.jns.2009.09.009.

55. Bristow EA, Griffiths PG, Andrews RM, et al. The distribution of mitochondrial activity in relation to optic nerve structure. Arch Ophthalmol 2002;120(6):791– 6.

56. Howell N. Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve. Vision Res 1998;38(10):1495– 504.

57. Lowry OH, Roberts NR, Lewis C. The quantitative histochemistry of the retina. J Biol Chem 1956;220(2):879– 92.

58. Kageyama GH, Wong-Riley MT. The histochemical localization of cytochrome oxidase in the retina and lateral geniculate nucleus of the ferret, cat, and monkey, with particular reference to retinal mosaics and ON/ OFF-center visual channels. J Neurosci 1984;4(10):2445– 59.

59. Klivenyi P, Karg E, Rozsa C, et al. Alpha-Tocopherol/ lipid ratio in blood is decreased in patients with Leber‘s hereditary optic neuropathy and asymptomatic carriers of the 11778 mtDNA mutation. J Neurol Neurosurg Psychiatry 2001;70(3):359– 62.

60. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 2000;26(2):211– 5.

61. Delettre C, Lenaers G, Griffoin JM, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 2000;26(2):207– 10.

62. Giordano C, Iommarini L, Giordano L, et al. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber‘s hereditary optic neuropathy. Brain 2014;137(Pt 2):335– 53. doi: 10.1093/ brain/ awt343.

63. Sadun AA, La Morgia C, Carelli V. Mitochondrial optic neuropathies: our travels from bench to bedside and back again. Clin Exp Ophthalmol 2013;41(7):702– 12. doi: 10.1111/ ceo.12086.

64. Vidrova V, Tesarova M, Trefilova E, et al. Mitochondrial DNA haplogroups in the Czech population compared to other European countries. Hum Biol 2008;80(6):669–74. doi: 10.3378/ 1534-6617-80.6.669.

65. Wallace DC, Brown MD, Lott MT. Mitochondrial DNA variation in human evolution and disease. Gene 1999;238(1):211– 30.

66. Howell N, Kubacka I, Halvorson S, et al. Leber‘s hereditary optic neuropathy: the etiological role of a mutation in the mitochondrial cytochrome b gene. Genetics 1993;133(1):133– 6.

67. Brown MD, Torroni A, Reckord CL, et al. Phylogenetic analysis of Leber‘s hereditary optic neuropathy mitochondrial DNA‘s indicates multiple independent occurrences of the common mutations. Hum Mutat 1995;6(4):311–25.

68. Vergani L, Martinuzzi A, Carelli V, et al. MtDNA mutations associated with Leber‘s hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells. Biochem Biophys Res Commun 1995;210(3):880– 8.

69. Brown MD, Sun F, Wallace DC. Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage. Am J Hum Genet 1997;60(2):381– 7.

70. Torroni A, Petrozzi M, D‘Urbano L, et al. Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet 1997;60(5):1107– 21.

71. Torroni A, Wallace DC. Mitochondrial DNA variation in human populations and implications for detection of mitochondrial DNA mutations of pathological significance. J Bioenerg Biomembr 1994;26(3):261– 71.

72. Smith KH, Johns DR, Heher KL, et al. Heteroplasmy in Leber‘s hereditary optic neuropathy. Arch Ophthalmol 1993;111(11):1486– 90.

73. 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(3):235– 43.

74. Black GC, Morten K, Laborde A, et al. Leber‘s hereditary optic neuropathy: heteroplasmy is likely to be significant in the expression of LHON in families with the 3460 ND1 mutation. Br J Ophthalmol 1996;80(10):915– 7.

75. Jacobi FK, Leo-Kottler B, Mittelviefhaus K, et al. Segregation patterns and heteroplasmy prevalence in Leber‘s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2001;42(6):1208– 14.

76. Howell N, Xu M, Halvorson S, et al. A heteroplasmic LHON family: tissue distribution and transmission of the 11778 mutation. Am J Hum Genet 1994;55(1):203– 6.

77. Weber K, Wilson JN, Taylor L, et al. A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle. Am J Hum Genet 1997;60(2):373– 80.

78. Howell N, Ghosh SS, Fahy E, et al. Longitudinal analysis of the segregation of mtDNA mutations in heteroplasmic individuals. J Neurol Sci 2000;172(1):1– 6.

79. Bu XD, Rotter JI. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: evidence from segregation analysis for dependence on X chromosome inactivation. Proc Natl Acad Sci USA 1991;88(18):8198– 202.

80. Nakamura M, Fujiwara Y, Yamamoto M. The two locus control of Leber hereditary optic neuropathy and a high penetrance in Japanese pedigrees. Hum Genet 1993;91(4):339– 41.

81. Carvalho MR, Muller B, Rotzer E, et al. Leber‘s hereditary optic neuroretinopathy and the X-chromosomal susceptibility factor: no linkage to DXs7. Hum Hered 1992;42(5):316– 20.

82. Chen JD, Cox I, Denton MJ. Preliminary exclusion of an X-linked gene in Leber optic atrophy by linkage analysis. Hum Genet 1989;82(3):203– 7.

83. Sweeney MG, Davis MB, Lashwood A, et al. Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy. Am J Hum Genet 1992;51(4):741– 8.

84. Handoko HY, Wirapati PJ, Sudoyo HA, et al. Meiotic breakpoint mapping of a proposed X linked visual loss susceptibility locus in Leber‘s hereditary optic neuropathy. J Med Genet 1998;35(8):668– 71.

85. Giordano C, Montopoli M, Perli E, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber‘s hereditary optic neuropathy. Brain 2011;134(Pt 1):220– 34. doi: 10.1093/ brain/ awq276.

86. Pott JW, Wong KH. Leber‘s hereditary optic neuropathy and vitamin B12 deficiency. Graefes Arch Clin Exp Ophthalmol 2006;244(10):1357– 9.

87. Jalil A, Usmani HA, Khan MI, et al. Bilateral paediatric optic neuropathy precipitated by vitamin B12 deficiency and a novel mitochondrial DNA mutation. Int Ophthalmol 2013;33(6):687– 90. doi: 10.1007/ s10792-013-9773-z.

88. Saini M, Khurana D. Chronic relapsing inflammatory optic neuropathy. Ann Indian Acad Neurol 2010;13(1):61– 3. doi: 10.4103/ 0972-2327.61280.

89. Scolding N. The differential diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry 2001;71(Suppl 2):ii9– 15.

90. Kidd D, Burton B, Plant GT, et al. Chronic relapsing inflammatory optic neuropathy (CRION). Brain 2003;126(Pt 2):276– 84.

91. Germann CA, Baumann MR, Hamzavi S. Ophthalmic diagnoses in the ED: optic neuritis. Am J Emerg Med 2007;25(7):834– 7.

92. Igarashi Y, Oyachi H, Nakamura Y, et al. Neuromyelitis optica. Ophthalmologica 1994;208(4):226– 9.

93. Arnold TW, Myers GJ. Neuromyelitis optica (Devic syndrome) in a 12-year-old male with complete recovery following steroids. Pediatr Neurol 1987;3(5):313– 5.

94. Hinson SR, Pittock SJ, Lucchinetti CF, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 2007;69(24):2221– 31.

95. Saadoun S, Waters P, Bell BA, et al. Intra-cerebralinjection of neuromyelitis optica immunoglobulin Gand human complement produces neuromyelitis optica lesions in mice. Brain 2010;133(Pt 2):349– 61. doi: 10.1093/ brain/ awp309.

96. Waters P, Vincent A. Detection of anti-aquaporin-4 antibodies in neuromyelitis optica: current status of the assays. Int MS J 2008;15(3):99– 105.

97. Votruba M, Moore AT, Bhattacharya SS. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. J Med Genet 1998;35(10):793– 800.

98. Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol 2015;9:1165– 76. doi: 10.2147/ opth.s62021.

99. Geromel V, Darin N, Chretien D, et al. Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab 2002;77(1– 2):21– 30.

100. Lyseng-Williamson KA. Idebenone: A Review in Leber‘s Hereditary Optic Neuropathy. Drugs 2016;76(7):805– 13. doi: 10.1007/ s40265-016-0574-3.

101. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber‘s hereditary optic neuropathy. Brain 2011;134(Pt 9):2677– 86. doi: 10.1093/ brain/ awr170.

102. 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(3):331– 8. doi: 10.1001/ archneurol.2011.2972.

103. GenSight. GenSight Biologics Receives IND Acceptance from FDA to Enter Phase III with GS010. Paris, France; 2015.

104. Wan X, Pei H, Zhao MJ, et al. Efficacy and Safety of rAAV2-ND4 Treatment for Leber‘s Hereditary Optic Neuropathy. Sci Rep 2016;6:21587. doi: 10.1038/ srep21587.

105. La Morgia C, Carbonelli M, Barboni P, et al. Medical management of hereditary optic neuropathies. Front Neurol 2014;5:141. doi: 10.3389/ fneur.2014.00141.

106. Pisano A, Preziuso C, Iommarini L, et al. Targeting estrogen receptor beta as preventive therapeutic strategy for Leber‘s hereditary optic neuropathy. Hum Mol Genet 2015;24(24):6921– 31. doi: 10.1093/ hmg/ ddv396.

107. Saylor M, McLoon LK, Harrison AR, et al. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol 2009;127(4):402– 6. doi: 10.1001/ archophthalmol.2009.9.

108. 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(3):407– 15. doi: 10.1016/ j.ajo.2005.03.058.

109. Thouin A, Griffiths PG, Hudson G, et al. Raised intraocular pressure as a potential risk factor for visual loss in Leber Hereditary Optic Neuropathy. PLoS One 2013;8(5):e63446. doi: 10.1371/ journal.pone.0063446.

110. Liskova P, Tesarova M, Dudakova L, et al. OPA1 analysis in an international series of probands with bilateral optic atrophy. Acta Ophthalmol 2017;95(4):363– 9. doi: 10.1111/ aos.13285.

111. Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 1989;320(20):1293– 9.

112. Nikoskelainen EK. Clinical picture of LHON. ClinNeurosci 1994;2:115– 20.