Leber hereditary optic neuropathy-new insights and old challenges.
Gene therapy
Haplogroup
Heteroplasmy
LHON
Mitochondrial disease
Optic neuropathy
Journal
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
ISSN: 1435-702X
Titre abrégé: Graefes Arch Clin Exp Ophthalmol
Pays: Germany
ID NLM: 8205248
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
09
06
2020
accepted:
23
10
2020
revised:
16
09
2020
pubmed:
14
11
2020
medline:
25
8
2021
entrez:
13
11
2020
Statut:
ppublish
Résumé
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of patients harboring one of three primary mtDNA point mutations, namely, m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6). LHON is characterized by bilateral subacute loss of vision due to the preferential loss of retinal ganglion cells (RGCs) within the inner retina, resulting in optic nerve degeneration. This review describes the clinical features associated with mtDNA LHON mutations and recent insights gained into the disease mechanisms contributing to RGC loss in this mitochondrial disorder. Although treatment options remain limited, LHON research has now entered an active translational phase with ongoing clinical trials, including gene therapy to correct the underlying pathogenic mtDNA mutation.
Identifiants
pubmed: 33185731
doi: 10.1007/s00417-020-04993-1
pii: 10.1007/s00417-020-04993-1
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
2461-2472Subventions
Organisme : Medical Research Council
ID : G0701386
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1002570
Pays : United Kingdom
Informations de copyright
© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Leber T (1871) Ueber hereditäre und congenital-angelegte Sehnervenleiden. Albrecht Von Graefes Arch Ophthalmol 17(2):249–291
doi: 10.1007/BF01694557
Rosenberg T, Norby S, Schwartz M, Saillard J, Magalhaes PJ, Leroy D, Kann EC, Duno M (2016) Prevalence and genetics of Leber hereditary optic neuropathy in the Danish population. Invest Ophthalmol Vis Sci 57(3):1370–1375
pubmed: 27007794
doi: 10.1167/iovs.15-18306
Ueda K, Morizane Y, Shiraga F, Shikishima K, Ishikawa H, Wakakura M, Nakamura M (2017) Nationwide epidemiological survey of Leber hereditary optic neuropathy in Japan. J Epidemiol 27(9):447–450
pubmed: 28392196
pmcid: 5565755
doi: 10.1016/j.je.2017.02.001
Newman NJ (2005) Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol 140(3):517–523
pubmed: 16083845
Giraudet S, Lamirel C, Amati-Bonneau P, Reynier P, Bonneau D, Milea D, Cochereau I (2011) Never too old to harbour a young man’s disease? Br J Ophthalmol 95(6):887 896-887
pubmed: 20675733
doi: 10.1136/bjo.2009.161539
Milea D, Amati-Bonneau P, Reynier P, Bonneau D (2010) Genetically determined optic neuropathies. Curr Opin Neurol 23(1):24–28
pubmed: 19915464
doi: 10.1097/WCO.0b013e3283347b27
Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549):1795–1809
pubmed: 17113430
doi: 10.1016/S0140-6736(06)69740-7
Mashima Y, Kimura I, Yamamoto Y, Ohde H, Ohtake Y, Tanino T, Tomita G, Oguchi Y (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(2):75–80
pubmed: 12605258
doi: 10.1007/s00417-002-0598-0
Yu-Wai-Man P, Griffiths PG, Chinnery PF (2011) Mitochondrial optic neuropathies - disease mechanisms and therapeutic strategies. Prog Retin Eye Res 30(2):81–114
pubmed: 21112411
pmcid: 3081075
doi: 10.1016/j.preteyeres.2010.11.002
Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, McDonald WI, Compston DA (1992) Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain 115(Pt 4):979–989
pubmed: 1393514
doi: 10.1093/brain/115.4.979
Pfeffer G, Burke A, Yu-Wai-Man P, Compston DA, Chinnery PF (2013) Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology 81(24):2073–2081
pubmed: 24198293
pmcid: 3863351
doi: 10.1212/01.wnl.0000437308.22603.43
Yu-Wai-Man P, Votruba M, Burte F, La Morgia C, Barboni P, Carelli V (2016) A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathol 132(6):789–806
pubmed: 27696015
pmcid: 5106504
doi: 10.1007/s00401-016-1625-2
Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6(9):805–815
pubmed: 17706564
doi: 10.1016/S1474-4422(07)70216-8
Shiraishi W, Hayashi S, Kamada T, Isobe N, Yamasaki R, Murai H, Ohyagi Y, Kira J (2014) A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber’s hereditary optic neuropathy. Mult Scler 20(2):258–260
pubmed: 24263387
doi: 10.1177/1352458513513057
Beretta S, Mattavelli L, Sala G, Tremolizzo L, Schapira AH, Martinuzzi A, Carelli V, Ferrarese C (2004) Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines. Brain 127(Pt 10):2183–2192
pubmed: 15342361
doi: 10.1093/brain/awh258
Levin LA (2007) Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy. Trans Am Ophthalmol Soc 105:379–391
pubmed: 18427623
pmcid: 2258117
Koilkonda RD, Guy J (2011) Leber’s hereditary optic neuropathy-gene therapy: from benchtop to bedside. J Ophthalmol 2011:179412
pubmed: 21253496
doi: 10.1155/2011/179412
Yu-Wai-Man P, Soiferman D, Moore DG, Burte F, Saada A (2017) Evaluating the therapeutic potential of idebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion 36:36–42
pubmed: 28093355
pmcid: 5644719
doi: 10.1016/j.mito.2017.01.004
Jancic J, Samardzic J, Stojanovic S, Stojanovic A, Milanovic AM, Nikolic B, Ivancevic N, Kostic V (2017) Leber’s hereditary optic neuropathy: novel views and persisting challenges. CNS Neurol Disord Drug Targets 16(8):927–935
pubmed: 28745242
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242(4884):1427–1430
pubmed: 3201231
doi: 10.1126/science.3201231
Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, Turnbull DM (1991) Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 49(5):939–950
pubmed: 1928099
pmcid: 1683233
Johns DR, Neufeld MJ, Park RD (1992) An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun 187(3):1551–1557
pubmed: 1417830
doi: 10.1016/0006-291X(92)90479-5
Mackey DA, Oostra RJ, Rosenberg T, Nikoskelainen E, Bronte-Stewart J, Poulton J, Harding AE, Govan G, Bolhuis PA, Norby S (1996) Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 59(2):481–485
pubmed: 8755941
pmcid: 1914749
Yu-Wai-Man P, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF (2003) The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet 72(2):333–339
pubmed: 12518276
doi: 10.1086/346066
Puomila A, Hamalainen P, Kivioja S, Savontaus ML, Koivumaki S, Huoponen K, Nikoskelainen E (2007) Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet 15(10):1079–1089
pubmed: 17406640
doi: 10.1038/sj.ejhg.5201828
Macmillan C, Kirkham T, Fu K, Allison V, Andermann E, Chitayat D, Fortier D, Gans M, Hare H, Quercia N, Zackon D, Shoubridge EA (1998) Pedigree analysis of French Canadian families with T14484C Leber’s hereditary optic neuropathy. Neurology 50(2):417–422
pubmed: 9484365
doi: 10.1212/WNL.50.2.417
Jia X, Li S, Xiao X, Guo X, Zhang Q (2006) Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy. J Hum Genet 51(10):851–856
pubmed: 16972023
doi: 10.1007/s10038-006-0032-2
Dai Y, Wang C, Nie Z, Han J, Chen T, Zhao X, Ai C, Ji Y, Gao T, Jiang P (2018) Mutation analysis of Leber’s hereditary optic neuropathy using a multi-gene panel. Biomed Rep 8(1):51–58
pubmed: 29387390
Yamada K, Oguchi Y, Hotta Y, Nakamura M, Isashiki Y, Mashima Y (1999) Multicenter study on the frequency of three primary mutations of mitochondrial DNA in Japanese pedigrees with Leber’s hereditary optic neuropathy: comparison with American and British counterparts. Neuro-Ophthalmology 22(3):187–193
doi: 10.1076/noph.22.3.187.3724
Dogulu CF, Kansu T, Seyrantepe V, Ozguc M, Topaloglu H, Johns DR (2001) Mitochondrial DNA analysis in the Turkish Leber’s hereditary optic neuropathy population. Eye 15(Pt 2):183–188
pubmed: 11339587
doi: 10.1038/eye.2001.57
Yum HR, Chae H, Shin SY, Kim Y, Kim M, Park SH (2014) Pathogenic mitochondrial DNA mutations and associated clinical features in Korean patients with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci 55(12):8095–8101
pubmed: 25342614
doi: 10.1167/iovs.14-15311
Saikia BB, Dubey SK, Shanmugam MK, Sundaresan P (2017) Whole mitochondrial genome analysis in south Indian patients with Leber’s hereditary optic neuropathy. Mitochondrion 36:21–28
pubmed: 27989883
doi: 10.1016/j.mito.2016.10.006
Mishra A, Devi S, Saxena R, Gupta N, Kabra M, Chowdhury MR (2017) Frequency of primary mutations of Leber’s hereditary optic neuropathy patients in north Indian population. Indian J Ophthalmol 65(11):1156–1160
pubmed: 29133642
pmcid: 5700584
doi: 10.4103/ijo.IJO_380_17
Guo DY, Wang XW, Hong N, Gu YS (2016) A meta-analysis of the association between different genotypes (G11778A, T14484C and G3460A) of Leber hereditary optic neuropathy and visual prognosis. Int J Ophthalmol 9(10):1493–1498
pubmed: 27803870
pmcid: 5075668
Blakely EL, de Silva R, King A, Schwarzer V, Harrower T, Dawidek G, Turnbull DM, Taylor RW (2005) LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet 13(5):623–627
pubmed: 15657614
doi: 10.1038/sj.ejhg.5201363
Patsi J, Maliniemi P, Pakanen S, Hinttala R, Uusimaa J, Majamaa K, Nystrom T, Kervinen M, Hassinen IE (2012) LHON/MELAS overlap mutation in ND1 subunit of mitochondrial complex I affects ubiquinone binding as revealed by modeling in Escherichia coli NDH-1. Biochim Biophys Acta 1817(2):312–318
pubmed: 22079202
doi: 10.1016/j.bbabio.2011.10.014
Brown MD, Zhadanov S, Allen JC, Hosseini S, Newman NJ, Atamonov VV, Mikhailovskaya IE, Sukernik RI, Wallace DC (2001) Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families. Hum Genet 109(1):33–39
pubmed: 11479733
doi: 10.1007/s004390100538
Spruijt L, Smeets HJ, Hendrickx A, Bettink-Remeijer MW, Maat-Kievit A, Schoonderwoerd KC, Sluiter W, de Coo IF, Hintzen RQ (2007) A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia. Arch Neurol 64(6):890–893
pubmed: 17562939
doi: 10.1001/archneur.64.6.890
Achilli A, Iommarini L, Olivieri A, Pala M, Hooshiar Kashani B, Reynier P, La Morgia C, Valentino ML, Liguori R, Pizza F, Barboni P, Sadun F, De Negri AM, Zeviani M, Dollfus H, Moulignier A, Ducos G, Orssaud C, Bonneau D, Procaccio V, Leo-Kottler B, Fauser S, Wissinger B, Amati-Bonneau P, Torroni A, Carelli V (2012) Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber’s hereditary optic neuropathy. PLoS One 7(8):e42242
pubmed: 22879922
pmcid: 3411744
doi: 10.1371/journal.pone.0042242
Kim JY, Hwang JM, Park SS (2002) Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber’s hereditary optic neuropathy with a good prognosis. Ann Neurol 51(5):630–634
pubmed: 12112111
doi: 10.1002/ana.10177
Wang K, Takahashi Y, Gao ZL, Wang GX, Chen XW, Goto J, Lou JN, Tsuji S (2009) Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics 10(4):337–345
pubmed: 19458970
doi: 10.1007/s10048-009-0194-0
Dombi E, Diot A, Morten K, Carver J, Lodge T, Fratter C, Ng YS, Liao C, Muir R, Blakely EL, Hargreaves I, Al-Dosary M, Sarkar G, Hickman SJ, Downes SM, Jayawant S, Yu-Wai-Man P, Taylor RW, Poulton J (2016) The m.13051G>A mitochondrial DNA mutation results in variable neurology and activated mitophagy. Neurology 86(20):1921–1923
pubmed: 27164671
pmcid: 4873683
doi: 10.1212/WNL.0000000000002688
Emperador S, Vidal M, Hernandez-Ainsa C, Ruiz-Ruiz C, Woods D, Morales-Becerra A, Arruga J, Artuch R, Lopez-Gallardo E, Bayona-Bafaluy MP, Montoya J, Ruiz-Pesini E (2018) The decrease in mitochondrial DNA mutation load parallels visual recovery in a Leber hereditary optic neuropathy patient. Front Neurosci 12:61
pubmed: 29479304
pmcid: 5811516
doi: 10.3389/fnins.2018.00061
Gropman A, Chen TJ, Perng CL, Krasnewich D, Chernoff E, Tifft C, Wong LJ (2004) Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. Am J Med Genet A 124A(4):377–382
pubmed: 14735585
doi: 10.1002/ajmg.a.20456
Howell N, Bogolin C, Jamieson R, Marenda DR, Mackey DA (1998) mtDNA mutations that cause optic neuropathy: how do we know? Am J Hum Genet 62(1):196–202
pubmed: 9443868
pmcid: 1376802
doi: 10.1086/301675
Chinnery PF, Brown DT, Andrews RM, Singh-Kler R, Riordan-Eva P, Lindley J, Applegarth DA, Turnbull DM, Howell N (2001) The mitochondrial ND6 gene is a hot spot for mutations that cause Leber’s hereditary optic neuropathy. Brain 124(Pt 1):209–218
pubmed: 11133798
doi: 10.1093/brain/124.1.209
Fauser S, Leo-Kottler B, Besch D, Luberichs J (2002) Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber’s hereditary optic neuropathy. Ophthalmic Genet 23(3):191–197
pubmed: 12324878
doi: 10.1076/opge.23.3.191.7881
Martinez-Romero I, Herrero-Martin MD, Llobet L, Emperador S, Martin-Navarro A, Narberhaus B, Ascaso FJ, Lopez-Gallardo E, Montoya J, Ruiz-Pesini E (2014) New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. Clin Exp Ophthalmol 42(9):856–864
pubmed: 24800637
doi: 10.1111/ceo.12355
Huoponen K, Lamminen T, Juvonen V, Aula P, Nikoskelainen E, Savontaus ML (1993) The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy. Hum Genet 92(4):379–384
pubmed: 7901141
doi: 10.1007/BF01247339
Howell N, Kubacka I, Xu M, McCullough DA (1991) Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 48(5):935–942
pubmed: 2018041
pmcid: 1683051
Brown MD, Torroni A, Reckord CL, Wallace DC (1995) Phylogenetic analysis of Leber’s hereditary optic neuropathy mitochondrial DNA’s indicates multiple independent occurrences of the common mutations. Hum Mutat 6(4):311–325
pubmed: 8680405
doi: 10.1002/humu.1380060405
Lamminen T, Majander A, Juvonen V, Wikstrom M, Aula P, Nikoskelainen E, Savontous ML (1995) A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy. Am J Hum Genet 56(5):1238–1240
pubmed: 7726182
pmcid: 1801467
Howell N, Oostra RJ, Bolhuis PA, Spruijt L, Clarke LA, Mackey DA, Preston G, Herrnstadt C (2003) Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 72(6):1460–1469
pubmed: 12736867
pmcid: 1180306
doi: 10.1086/375537
Johns DR, Neufeld MJ (1993) Cytochrome c oxidase mutations in Leber hereditary optic neuropathy. Biochem Biophys Res Commun 196(2):810–815
pubmed: 8240356
doi: 10.1006/bbrc.1993.2321
Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal MF, Davis RE, Howell N (2002) Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am J Hum Genet 70(5):1152–1171
pubmed: 11938495
pmcid: 447592
doi: 10.1086/339933
Horvath J, Horvath R, Karcagi V, Komoly S, Johns DR (2002) Sequence analysis of Hungarian LHON patients not carrying the common primary mutations. J Inherit Metab Dis 25(4):323–324
pubmed: 12227465
doi: 10.1023/A:1016518811940
Leo-Kottler B, Luberichs J, Besch D, Christ-Adler M, Fauser S (2002) Leber’s hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threonine) in the ND4 gene and spontaneous recovery. Graefes Arch Clin Exp Ophthalmol 240(9):758–764
pubmed: 12271374
doi: 10.1007/s00417-002-0494-7
De Vries DD, Went LN, Bruyn GW, Scholte HR, Hofstra RM, Bolhuis PA, van Oost BA (1996) 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 58(4):703–711
pubmed: 8644732
pmcid: 1914692
Mayorov V, Biousse V, Newman NJ, Brown MD (2005) The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation. Ann Neurol 58(5):807–811
pubmed: 16240359
doi: 10.1002/ana.20669
Howell N, Halvorson S, Burns J, McCullough DA, Paulton J (1993) When does bilateral optic atrophy become Leber hereditary optic neuropathy? Am J Hum Genet 53(4):959–963
pubmed: 8213825
pmcid: 1682377
Zhadanov SI, Atamanov VV, Zhadanov NI, Oleinikov OV, Osipova LP, Schurr TG (2005) A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family. Biochem Biophys Res Commun 332(4):1115–1121
pubmed: 15922297
doi: 10.1016/j.bbrc.2005.05.059
Wissinger B, Besch D, Baumann B, Fauser S, Christ-Adler M, Jurklies B, Zrenner E, Leo-Kottler B (1997) Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy. Biochem Biophys Res Commun 234(2):511–515
pubmed: 9177303
doi: 10.1006/bbrc.1997.6660
Fauser S, Luberichs J, Besch D, Leo-Kottler B (2002) Sequence analysis of the complete mitochondrial genome in patients with Leber’s hereditary optic neuropathy lacking the three most common pathogenic DNA mutations. Biochem Biophys Res Commun 295(2):342–347
pubmed: 12150954
doi: 10.1016/S0006-291X(02)00672-1
Liang M, Guan M, Zhao F, Zhou X, Yuan M, Tong Y, Yang L, Wei QP, Sun YH, Lu F, Qu J, Guan MX (2009) Leber’s hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation. Biochem Biophys Res Commun 383(3):286–292
pubmed: 19324017
pmcid: 2905379
doi: 10.1016/j.bbrc.2009.03.097
Verma IC, Bijarnia S, Saxena R, Kohli S, Puri RD, Thomas E, Chowdhary D, Jha SN, Grover AK (2005) Leber’s hereditary optic neuropathy with molecular characterization in two Indian families. Indian J Ophthalmol 53(3):167–171
pubmed: 16137960
doi: 10.4103/0301-4738.16674
Kumar M, Tanwar M, Saxena R, Sharma P, Dada R (2010) Identification of novel mitochondrial mutations in Leber’s hereditary optic neuropathy. Mol Vis 16:782–792
pubmed: 20454697
pmcid: 2862244
Sundaresan P, Kumar SM, Thompson S, Fingert JH (2010) Reduced frequency of known mutations in a cohort of LHON patients from India. Ophthalmic Genet 31(4):196–199
pubmed: 20809775
doi: 10.3109/13816810.2010.510818
Zeviani M, Di Donato S (2004) Mitochondrial disorders. Brain 127(Pt 10):2153–2172
pubmed: 15358637
doi: 10.1093/brain/awh259
Yu-Wai-Man P, Chinnery PF (1993-2020) Leber hereditary optic neuropathy. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews (R). Seattle, pp 1993-2016
Smith KH, Johns DR, Heher KL, Miller NR (1993) Heteroplasmy in Leber’s hereditary optic neuropathy. Arch Ophthalmol 111(11):1486–1490
pubmed: 8240102
doi: 10.1001/archopht.1993.01090110052022
Brown MD, Allen JC, Van Stavern GP, Newman NJ, Wallace DC (2001) Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations. Am J Med Genet 104(4):331–338
pubmed: 11754070
doi: 10.1002/1096-8628(20011215)104:4<331::AID-AJMG10054>3.0.CO;2-W
Tonska K, Kurzawa M, Ambroziak AM, Korwin-Rujna M, Szaflik JP, Grabowska E, Szaflik J, Bartnik E (2008) A family with 3460G>A and 11778G>A mutations and haplogroup analysis of Polish Leber hereditary optic neuropathy patients. Mitochondrion 8(5–6):383–388
pubmed: 18801464
doi: 10.1016/j.mito.2008.08.002
Caporali L, Iommarini L, La Morgia C, Olivieri A, Achilli A, Maresca A, Valentino ML, Capristo M, Tagliavini F, Del Dotto V, Zanna C, Liguori R, Barboni P, Carbonelli M, Cocetta V, Montopoli M, Martinuzzi A, Cenacchi G, De Michele G, Testa F, Nesti A, Simonelli F, Porcelli AM, Torroni A, Carelli V (2018) Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber’s hereditary optic neuropathy. PLoS Genet 14(2):e1007210
pubmed: 29444077
pmcid: 5828459
doi: 10.1371/journal.pgen.1007210
Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5(11):a021220
pubmed: 24186072
pmcid: 3809581
doi: 10.1101/cshperspect.a021220
MITOMAP: A Human Mitochondrial Genome Database (2019). https://mitomap.org . Accessed 23 Mar 2019
Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, Pyle A, Elson J, Howell N, La Morgia C, Valentino ML, Huoponen K, Savontaus ML, Nikoskelainen E, Sadun AA, Salomao SR, Belfort R Jr, Griffiths P, Yu-Wai-Man P, de Coo RF, Horvath R, Zeviani M, Smeets HJ, Torroni A, Chinnery PF (2007) Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet 81(2):228–233
pubmed: 17668373
pmcid: 1950812
doi: 10.1086/519394
Torroni A, Petrozzi M, D'Urbano L, Sellitto D, Zeviani M, Carrara F, Carducci C, Leuzzi V, Carelli V, Barboni P, De Negri A, Scozzari R (1997) 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 60(5):1107–1121
pubmed: 9150158
pmcid: 1712418
Ji Y, Zhang AM, Jia X, Zhang YP, Xiao X, Li S, Guo X, Bandelt HJ, Zhang Q, Yao YG (2008) Mitochondrial DNA haplogroups M7b1’2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese families with the m.11778G-->a mutation. Am J Hum Genet 83(6):760–768
pubmed: 19026397
pmcid: 2668067
doi: 10.1016/j.ajhg.2008.11.002
Ji Y, Jia X, Zhang Q, Yao YG (2007) mtDNA haplogroup distribution in Chinese patients with Leber’s hereditary optic neuropathy and G11778A mutation. Biochem Biophys Res Commun 364(2):238–242
pubmed: 17942074
doi: 10.1016/j.bbrc.2007.09.111
Zhang AM, Jia X, Bi R, Salas A, Li S, Xiao X, Wang P, Guo X, Kong QP, Zhang Q, Yao YG (2011) Mitochondrial DNA haplogroup background affects LHON, but not suspected LHON, in Chinese patients. PLoS One 6(11):e27750
pubmed: 22110754
pmcid: 3216987
doi: 10.1371/journal.pone.0027750
Khan NA, Govindaraj P, Soumittra N, Srilekha S, Ambika S, Vanniarajan A, Meena AK, Uppin MS, Sundaram C, Taly AB, Bindu PS, Gayathri N, Thangaraj K (2013) Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India. Invest Ophthalmol Vis Sci 54(6):3999–4005
pubmed: 23674761
doi: 10.1167/iovs.13-11925
Khan NA, Govindaraj P, Soumittra N, Sharma S, Srilekha S, Ambika S, Vanniarajan A, Meena AK, Uppin MS, Sundaram C, Bindu PS, Gayathri N, Taly AB, Thangaraj K (2017) Leber’s hereditary optic neuropathy-specific mutation m.11778G>A exists on diverse mitochondrial haplogroups in India. Invest Ophthalmol Vis Sci 58(10):3923–3930
pubmed: 28768321
doi: 10.1167/iovs.16-20695
Bu XD, Rotter JI (1991) 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 U S A 88(18):8198–8202
pubmed: 1896469
pmcid: 52474
doi: 10.1073/pnas.88.18.8198
Vilkki J, Ott J, Savontaus ML, Aula P, Nikoskelainen EK (1991) Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7. Am J Hum Genet 48(3):486–491
pubmed: 1998335
pmcid: 1682980
Hudson G, Keers S, Yu-Wai-Man P, Griffiths P, Huoponen K, Savontaus ML, Nikoskelainen E, Zeviani M, Carrara F, Horvath R, Karcagi V, Spruijt L, de Coo IF, Smeets HJ, Chinnery PF (2005) Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 77(6):1086–1091
pubmed: 16380918
pmcid: 1285165
doi: 10.1086/498176
Phasukkijwatana N, Kunhapan B, Stankovich J, Chuenkongkaew WL, Thomson R, Thornton T, Bahlo M, Mushiroda T, Nakamura Y, Mahasirimongkol S, Tun AW, Srisawat C, Limwongse C, Peerapittayamongkol C, Sura T, Suthammarak W, Lertrit P (2010) Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand. Hum Genet 128(1):39–49
pubmed: 20407791
doi: 10.1007/s00439-010-0821-8
Zhang AM, Jia X, Zhang Q, Yao YG (2010) No association between the SNPs (rs3749446 and rs1402000) in the PARL gene and LHON in Chinese patients with m.11778G>A. Hum Genet 128(4):465–468
pubmed: 20711738
doi: 10.1007/s00439-010-0875-7
Abu-Amero KK, Jaber M, Hellani A, Bosley TM (2010) Genome-wide expression profile of LHON patients with the 11778 mutation. Br J Ophthalmol 94(2):256–259
pubmed: 19726426
doi: 10.1136/bjo.2009.165571
Jiang P, Jin X, Peng Y, Wang M, Liu H, Liu X, Zhang Z, Ji Y, Zhang J, Liang M, Zhao F, Sun YH, Zhang M, Zhou X, Chen Y, Mo JQ, Huang T, Qu J, Guan MX (2016) The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation. Hum Mol Genet 25(3):584–596
pubmed: 26647310
doi: 10.1093/hmg/ddv498
Giordano L, Deceglie S, d'Adamo P, Valentino ML, La Morgia C, Fracasso F, Roberti M, Cappellari M, Petrosillo G, Ciaravolo S, Parente D, Giordano C, Maresca A, Iommarini L, Del Dotto V, Ghelli AM, Salomao SR, Berezovsky A, Belfort R Jr, Sadun AA, Carelli V, Loguercio Polosa P, Cantatore P (2015) Cigarette toxicity triggers Leber’s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways. Cell Death Dis 6:e2021
pubmed: 26673666
pmcid: 4720897
doi: 10.1038/cddis.2015.364
Seo JH, Hwang JM, Park SS (2010) Antituberculosis medication as a possible epigenetic factor of Leber’s hereditary optic neuropathy. Clin Exp Ophthalmol 38(4):363–366
pubmed: 20491810
doi: 10.1111/j.1442-9071.2010.02240.x
Yamada K, Itoh R, Ohta A (1989) Influence of pyrazine derivatives on the day of vaginal opening in juvenile female rats. Jpn J Pharmacol 49(4):529–530
pubmed: 2724691
doi: 10.1016/S0021-5198(19)43029-1
Sanchez RN, Smith AJ, Carelli V, Sadun AA, Keltner JL (2006) Leber hereditary optic neuropathy possibly triggered by exposure to tire fire. J Neuroophthalmol 26(4):268–272
pubmed: 17204920
doi: 10.1097/01.wno.0000249320.27110.ab
Pisano A, Preziuso C, Iommarini L, Perli E, Grazioli P, Campese AF, Maresca A, Montopoli M, Masuelli L, Sadun AA, d'Amati G, Carelli V, Ghelli A, Giordano C (2015) Targeting estrogen receptor beta as preventive therapeutic strategy for Leber’s hereditary optic neuropathy. Hum Mol Genet 24(24):6921–6931
pubmed: 26410888
Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun AA, d'Amati G, Carelli V (2011) Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain 134(Pt 1):220–234
pubmed: 20943885
doi: 10.1093/brain/awq276
Fantini M, Asanad S, Karanjia R, Sadun A (2019) Hormone replacement therapy in Leber’s hereditary optic neuropathy: accelerated visual recovery in vivo. J Curr Ophthalmol 31(1):102–105
pubmed: 30899856
doi: 10.1016/j.joco.2018.10.003
DiMauro S, Mancuso M (2007) Mitochondrial diseases: therapeutic approaches. Biosci Rep 27(1–3):125–137
pubmed: 17486439
doi: 10.1007/s10540-007-9041-4
Newman NJ (2011) Treatment of Leber hereditary optic neuropathy. Brain 134(Pt 9):2447–2450
pubmed: 21859767
pmcid: 3202309
doi: 10.1093/brain/awr192
Yu-Wai-Man P, Votruba M, Moore AT, Chinnery PF (2014) Treatment strategies for inherited optic neuropathies: past, present and future. Eye 28(5):521–537
pubmed: 24603424
pmcid: 4017118
doi: 10.1038/eye.2014.37
Pfeffer G, Horvath R, Klopstock T, Mootha VK, Suomalainen A, Koene S, Hirano M, Zeviani M, Bindoff LA, Yu-Wai-Man P, Hanna M, Carelli V, McFarland R, Majamaa K, Turnbull DM, Smeitink J, Chinnery PF (2013) New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol 9(8):474–481
pubmed: 23817350
pmcid: 4967498
doi: 10.1038/nrneurol.2013.129
Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF (2011) A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain 134(Pt 9):2677–2686
pubmed: 21788663
pmcid: 3170530
doi: 10.1093/brain/awr170
Klopstock T, Metz G, Yu-Wai-Man P, Buchner B, Gallenmuller C, Bailie M, Nwali N, Griffiths PG, von Livonius B, Reznicek L, Rouleau J, Coppard N, Meier T, Chinnery PF (2013) Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain 136(Pt 2):e230
pubmed: 23388409
pmcid: 3572931
doi: 10.1093/brain/aws279
Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagreze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, Barboni P (2017) International consensus statement on the clinical and therapeutic management of Leber hereditary optic neuropathy. J Neuroophthalmol 37(4):371–381
pubmed: 28991104
doi: 10.1097/WNO.0000000000000570
Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, Sadun F, Carta A, Guerriero S, Simonelli F, Sadun AA, Aggarwal D, Liguori R, Avoni P, Baruzzi A, Zeviani M, Montagna P, Barboni P (2011) Idebenone treatment in Leber’s hereditary optic neuropathy. Brain 134(Pt 9):e188
pubmed: 21810891
doi: 10.1093/brain/awr180
Szeto HH, Birk AV (2014) Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther 96(6):672–683
pubmed: 25188726
doi: 10.1038/clpt.2014.174
Komen JC, Thorburn DR (2014) Turn up the power - pharmacological activation of mitochondrial biogenesis in mouse models. Br J Pharmacol 171(8):1818–1836
pubmed: 24102298
pmcid: 3976607
doi: 10.1111/bph.12413
Yu-Wai-Man P (2016) Genetic manipulation for inherited neurodegenerative diseases: myth or reality? Br J Ophthalmol 100(10):1322–1331
pubmed: 27002113
doi: 10.1136/bjophthalmol-2015-308329
Manfredi G, Fu J, Ojaimi J, Sadlock JE, Kwong JQ, Guy J, Schon EA (2002) Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. Nat Genet 30(4):394–399
pubmed: 11925565
doi: 10.1038/ng851
Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS (2002) Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol 52(5):534–542
pubmed: 12402249
doi: 10.1002/ana.10354
Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M (2008) Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet 83(3):373–387
pubmed: 18771762
pmcid: 2556433
doi: 10.1016/j.ajhg.2008.08.013
Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J (2014) Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol 132(4):409–420
pubmed: 24457989
pmcid: 4266107
doi: 10.1001/jamaophthalmol.2013.7630
Yang S, Ma SQ, Wan X, He H, Pei H, Zhao MJ, Chen C, Wang DW, Dong XY, Yuan JJ, Li B (2016) Long-term outcomes of gene therapy for the treatment of Leber’s hereditary optic neuropathy. EBioMedicine 10:258–268
pubmed: 27426279
pmcid: 5006665
doi: 10.1016/j.ebiom.2016.07.002
Newman NJCV, Taiel M, Yu-Wai-Man P (2020) Visual outcomes in Leber hereditary optic neuropathy patients with the m.11778G>A (MTDN4) mitochondrial DNA mutation. J Neuroophthalmol. https://doi.org/10.1097/s0000000000001045
Yu-Wai-Man P, Newman N, Carelli V, Moster ML, Biousse V, Sadun AA, Klopstock T, Vignal-Clermont C, Sergott RC, Rudolph G, La Morgia C, Karanjia R, Taiel M, Blouin L, Burguière P, Smits G, Chevalier C, Masonson H, Salermo Y, Katz B, Picaud S, Calkins DJ, Sahel JA (2020) Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy. Sci Transl Med. In press
Limb GA, Martin KR (2011) Current prospects in optic nerve protection and regeneration: sixth ARVO/Pfizer Ophthalmics Research Institute conference. Invest Ophthalmol Vis Sci 52(8):5941–5954
pubmed: 21804096
doi: 10.1167/iovs.10-6894
Wong RCB, Lim SY, Hung SSC, Jackson S, Khan S, Van Bergen NJ, De Smit E, Liang HH, Kearns LS, Clarke L, Mackey DA, Hewitt AW, Trounce IA, Pebay A (2017) Mitochondrial replacement in an iPSC model of Leber’s hereditary optic neuropathy. Aging 9(4):1341–1350
pubmed: 28455970
pmcid: 5425131
doi: 10.18632/aging.101231
Wu YR, Wang AG, Chen YT, Yarmishyn AA, Buddhakosai W, Yang TC, Hwang DK, Yang YP, Shen CN, Lee HC, Chiou SH, Peng CH, Chen SJ (2018) Bioactivity and gene expression profiles of hiPSC-generated retinal ganglion cells in MT-ND4 mutated Leber’s hereditary optic neuropathy. Exp Cell Res 363(2):299–309
pubmed: 29366807
doi: 10.1016/j.yexcr.2018.01.020
Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL (2017) Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med 376(11):1047–1053
pubmed: 28296617
pmcid: 5551890
doi: 10.1056/NEJMoa1609583
Wallace DC, Lott MT (2017) Leber hereditary optic neuropathy: exemplar of an mtDNA disease. Handb Exp Pharmacol 240:339–376
pubmed: 28233183
doi: 10.1007/164_2017_2
Craven L, Elson JL, Irving L, Tuppen HA, Lister LM, Greggains GD, Byerley S, Murdoch AP, Herbert M, Turnbull D (2011) Mitochondrial DNA disease: new options for prevention. Hum Mol Genet 20(R2):R168–R174
pubmed: 21852248
pmcid: 3179382
doi: 10.1093/hmg/ddr373
Paull D, Emmanuele V, Weiss KA, Treff N, Stewart L, Hua H, Zimmer M, Kahler DJ, Goland RS, Noggle SA, Prosser R, Hirano M, Sauer MV, Egli D (2013) Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493(7434):632–637
pubmed: 23254936
doi: 10.1038/nature11800
Hyslop LA, Blakeley P, Craven L, Richardson J, Fogarty NM, Fragouli E, Lamb M, Wamaitha SE, Prathalingam N, Zhang Q, O'Keefe H, Takeda Y, Arizzi L, Alfarawati S, Tuppen HA, Irving L, Kalleas D, Choudhary M, Wells D, Murdoch AP, Turnbull DM, Niakan KK, Herbert M (2016) Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature 534(7607):383–386
pubmed: 27281217
pmcid: 5131843
doi: 10.1038/nature18303
Lee HS, Ma H, Juanes RC, Tachibana M, Sparman M, Woodward J, Ramsey C, Xu J, Kang EJ, Amato P, Mair G, Steinborn R, Mitalipov S (2012) Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Rep 1(5):506–515
pubmed: 22701816
pmcid: 3372871
doi: 10.1016/j.celrep.2012.03.011
Tachibana M, Amato P, Sparman M, Woodward J, Sanchis DM, Ma H, Gutierrez NM, Tippner-Hedges R, Kang E, Lee HS, Ramsey C, Masterson K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer R, Mitalipov S (2013) Towards germline gene therapy of inherited mitochondrial diseases. Nature 493(7434):627–631
pubmed: 23103867
doi: 10.1038/nature11647
Kang E, Wu J, Gutierrez NM, Koski A, Tippner-Hedges R, Agaronyan K, Platero-Luengo A, Martinez-Redondo P, Ma H, Lee Y, Hayama T, Van Dyken C, Wang X, Luo S, Ahmed R, Li Y, Ji D, Kayali R, Cinnioglu C, Olson S, Jensen J, Battaglia D, Lee D, Wu D, Huang T, Wolf DP, Temiakov D, Belmonte JC, Amato P, Mitalipov S (2016) Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature 540(7632):270–275
pubmed: 27919073
doi: 10.1038/nature20592
Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK, Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell NW, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AOM, Williamson C, Ashford S, Penkett CJ, Stirrups KE, Rendon A, Ouwehand WH, Bradley JR, Raymond FL, Caulfield M, Turro E, Chinnery PF (2019) Germline selection shapes human mitochondrial DNA diversity. Science 364(6442): eaau6520. https://doi.org/10.1126/science.aau6520
Newson AJ, Wilkinson S, Wrigley A (2016) Ethical and legal issues in mitochondrial transfer. EMBO Mol Med 8(6):589–591
pubmed: 27137493
pmcid: 4888849
doi: 10.15252/emmm.201606281
Zhang J, Liu H, Luo S, Lu Z, Chavez-Badiola A, Liu Z, Yang M, Merhi Z, Silber SJ, Munne S, Konstantinidis M, Wells D, Tang JJ, Huang T (2017) Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod BioMed Online 34(4):361–368
pubmed: 28385334
doi: 10.1016/j.rbmo.2017.01.013