Advertisement

Hereditary Optic Neuropathies

Chapter
  • 1.1k Downloads

Abstract

Optic neuropathies of either hereditary or acquired origin are characterized by similar clinical manifestations due to a common underlying pathophysiology of mitochondrial dysfunction. These optic neuropathies demonstrate preferential involvement of the papillomacular bundle (PMB) fibers, which are most energy dependent and most susceptible to oxidative injury. The hallmark of a mitochondrial optic neuropathy (MON) is characterized by symmetric visual loss, loss of high spatial frequency contrast sensitivity, early and profound loss of color vision, central or cecocentral visual field defects, preferential loss of the PMB, and eventual temporal pallor of the optic disc.

MONs can be grouped into nonsyndromic and syndromic disease based on the presence of associated multisystemic mitochondrial disorders. Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA) are the paradigm of hereditary nonsyndromic MONs. Syndromic optic neuropathies can be further divided into mitochondrial DNA (mtDNA)-based disorders and nuclear DNA-based disorders.

While LHON is caused by point mutations in the mtDNA, DOA is caused by mutations in the nuclear gene OPA1, which encodes for a mitochondrial protein. Nevertheless, both conditions share strikingly similar presentations and outcomes as mitochondrial biogenesis requires coordinated interaction of both nuclear and mitochondrial genomes. Optical coherence tomography has become an important diagnostic tool, allowing us to visualize the natural history and characterize different stages of the disease.

Although there is no proven treatment for these diseases, some studies have demonstrated promising results with pharmaceutical agents such as idebenone and EPI-743. Exciting new advancements in gene therapy have also provided hope that the genetic, biochemical, and physiological relationships of this spectrum of disorders may be delineated, providing a new platform for therapeutic and prophylactic strategies. Genetically determined animal models have been created to help us better evaluate and manage these disorders.

Keywords

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

References

  1. 1.
    Carelli V. Leber’s hereditary optic neuropathy. In: Schapira AHV, DiMauro S, editors. Mitochondrial disorders in neurology. Boston, MA: Butterworth-Heinemann; 2002. p. 115–42.Google Scholar
  2. 2.
    Sadun AA. Mitochondrial optic neuropathies. J Neurol Neurosurg Psychiatry. 2002;72:423–5.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Sadun AA, Carelli V. The role of mitochondria in health, ageing, and diseases affecting vision. Br J Ophthalmol. 2006;90:809–10.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Fontaine E, Bernardi P. Progress on the mitochondrial permeability transition pore: regulation by complex I and ubiquinone analogs. J Bioenerg Biomembr. 1999;31:335–45.PubMedGoogle Scholar
  5. 5.
    Sadun AA. Optic neuropathies and retinal ganglion cell death. J Neuroophthalmol. 2000;24:387–94.Google Scholar
  6. 6.
    Sadun AA. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc. 1998;96:881–923.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23:53–89.PubMedGoogle Scholar
  8. 8.
    Zoumalan CI, Agarwal M, Sadun AA. OCT can measure axonal loss in patients with ethambutol-induced optic neuropathy. Graefe’s Arch Clin Exp Ophthalmol. 2005;243:410–6.Google Scholar
  9. 9.
    Sadun AA, Martone JF, Muci-Mendoza R, Reyes L, DuBois L, Silva JC, et al. Epidemic optic neuropathy in Cuba. Eye findings. Arch Ophthalmol. 1994;112:691–9.PubMedGoogle Scholar
  10. 10.
    Pan BX, Ross-Cisneros FN, Carelli V, Rue KS, Salomao SR, Moraes-Filho MN, et al. Mathemati-cally modeling the involvement of axons in Leber’s hereditary optic neuropathy. Investig Ophthalmol Vis Sci. 2012;53:7608–17.Google Scholar
  11. 11.
    Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology ofmitochondrial disease. Surv Ophthalmol. 2010;55:299–334.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, et al. Mitochondrial DNA mutations associated with Leber’s hereditary optic neuropathy. Science. 1988;242:1427–30.PubMedGoogle Scholar
  13. 13.
    Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, et al. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet. 1991;49:939–50.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Johns DR, Neufeld MJ, Park RD. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun. 1992;187:1551–7.PubMedGoogle Scholar
  15. 15.
    Carelli V, Ghelli A, Bucchi L, Montagna P, De Negri A, Leuzzi V, et al. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber’s hereditary optic neuropathy. Ann Neurol. 1999;45:320–8.PubMedGoogle Scholar
  16. 16.
    Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, et al. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000;48:188–93.PubMedGoogle Scholar
  17. 17.
    Man PY, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the northeast of England. Am J Hum Genet. 2003;72:333–9.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Spruijt L, Kolbach DN, de Coo RF, Plomp AS, Bauer NJ, Smeets HJ, et al. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol. 2006;141:676–82.PubMedGoogle Scholar
  19. 19.
    Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet. 2007;15:1079–89.PubMedGoogle Scholar
  20. 20.
    Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros P, Sadun F, et al. A very large Brazilian pedigree with 11778 Leber’s hereditary optic neuropathy. Trans Am Ophthalmol Soc. 2002;100:169–78. discussion 178–9.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Wallace DC, Lott MT. Maternally inherited diseases. In: DiMauro S, Wallace DC, editors. Mitochondrial DNA in human pathology. New York, NY: Raven; 1993. p. 63–83.Google Scholar
  22. 22.
    Brown MD, Allen JC, Van Stavern GP, et al. Clinical, genetic, and biochemical characterization of a Leber hereditary optic neuropathy family containing both the 11778 and 14484 primary mutations. Am J Med Genet. 2001;104:331–8.PubMedGoogle Scholar
  23. 23.
    Seedorff T. The inheritance of Leber’s disease. A genealogical follow-up study. Acta Ophthalmol (Copenh). 1985;63:135–45.Google Scholar
  24. 24.
    Giles RE, Blanc H, Cann HM, et al. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1980;77:6715–9.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Mackey DA, Oostra RJ, Rosenberg T, et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic. Am J Hum Genet. 1996;59:481–5.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Howell N, Halvorson S, Burns J, et al. When does bilateral optic atrophy become Leber hereditary optic neuropathy? Am J Hum Genet. 1993;53:959–63.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Wissinger B, Besch D, Baumann B, et al. Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy. Biochem Biophys Res Commun. 1997;234:511–5.PubMedGoogle Scholar
  28. 28.
    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;111:750–62.PubMedGoogle Scholar
  29. 29.
    Singh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber’s hereditary optic neuropathy. N Engl J Med. 1989;320:1300–5.PubMedGoogle Scholar
  30. 30.
    Huoponen K, Lamminen T, Juvonen V, et al. The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy. Hum Genet. 1993;92:379–84.PubMedGoogle Scholar
  31. 31.
    Lott MT, Voljavec AS, Wallace DC. Variable genotype of Leber’s hereditary optic neuropathy patients. Am J Ophthalmol. 1990;109:625–31.PubMedGoogle Scholar
  32. 32.
    Huoponen K, Vilkki J, Aula P, et al. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1991;48:1147–53.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Johns DR, Heher KL, Miller NR, et al. Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol. 1993;111:495–8.PubMedGoogle Scholar
  34. 34.
    Novotny Jr EJ, Singh G, Wallace DC, et al. Leber's disease and dystonia: a mitochondrial disease. Neurology. 1986;36:1053–60.PubMedGoogle Scholar
  35. 35.
    Wallace DC, Singh G, Hopkins LC, et al. Maternally inherited diseases of man. In: Quagliariello E, Slater EC, Palmieri F, Saccone C, Kroon AM, editors. Achievements and perspectives of mitochondrial research. Amsterdam: Elsevier; 1985. p. 427–36.Google Scholar
  36. 36.
    Brown MD, Voljavec AS, Lott MT, et al. Leber’s hereditary optic neuropathy; a model for mitochondrial neurodegenerative diseases. FASEB J. 1992;6:2791–9.PubMedGoogle Scholar
  37. 37.
    Howell N, Kubacka I, Halvorson S, et al. Leber’s hereditary optic neuropathy: the etio-logical role of a mutation in the mitochondrial cytochrome b gene [Letter]. Genetics. 1993;133:133–6.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Carelli V, Achilli A, Valentino ML, Rengo C, Semino O, Pala M, et al. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am J Hum Genet. 2006;78:564–74.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007;81:228–33.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Shankar SP, Fingert JH, Carelli V, Valentino ML, King TM, Daiger SP, et al. Evidence for a novel x-linked modifier locus for Leber hereditary optic neuropathy. Ophthalmic Genet. 2008;29:17–24.PubMedGoogle Scholar
  41. 41.
    Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF. X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy. Mol Vis. 2007;13:2339–43.PubMedGoogle Scholar
  42. 42.
    Sadun AA, Carelli V, Salomao SR, Berezovsky A, Quiros PA, Sadun F, et al. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2003;136:231–8.PubMedGoogle Scholar
  43. 43.
    Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain. 2009;132:2317–26.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Sanchez RN, Smith AJ, Carelli V, Sadun AA, Keltner JL, et al. Leber hereditary optic neuropathy possibly triggered by exposure to tire fire. J Neuroophthalmol. 2006;26:268–72.PubMedGoogle Scholar
  45. 45.
    Wang MY, Sadun AA. Drug-related mitochondrial optic neuropathies. J Neuroophthalmol. 2013;33:172–8.PubMedGoogle Scholar
  46. 46.
    Mackey DA, Fingert JH, Luzhansky JZ, McCluskey PJ, Howell N, Hall AJ, et al. Leber’s hereditary optic neuropathy triggered by antiretroviral therapy for human immunodeficiency virus. Eye. 2003;17:312–7.PubMedGoogle Scholar
  47. 47.
    Ikeda A, Ikeda T, Ikeda N, Kawakami Y, Mimura O, et al. Leber’s hereditary optic neuropathy precipitated by ethambutol. Jpn J Ophthalmol. 2006;50:280–3.PubMedGoogle Scholar
  48. 48.
    Carelli V, Franceschini F, Venturi S, Barboni P, Savini G, Barbieri G, et al. Grand rounds: could occupational exposure to n-hexane and other solvents precipitate visual failure in leber hereditary optic neuropathy? Environ Health Perspect. 2007;115:113–5.PubMedPubMedCentralGoogle Scholar
  49. 49.
    De Marinis M. Optic neuropathy after treatment with anti-tuberculous drugs in a subject with Leber’s hereditary optic neuropathy mutation. J Neurol. 2001;248:818–9.PubMedGoogle Scholar
  50. 50.
    Cullom ME, Heher KL, Miller NR, et al. Leber’s hereditary optic neuropathy masquerading as tobacco-alcohol amblyopia. Arch Ophthalmol. 1993;111:1482–5.PubMedGoogle Scholar
  51. 51.
    Carelli V, La Morgia C, Valentino ML, Barboni P, Ross-Cisneros FN, Sadun AA, et al. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta. 2009;1787:518–28.PubMedGoogle Scholar
  52. 52.
    Barboni P, Savini G, Valentino ML, La Morgia C, Bellusci C, De Negri AM, et al. Leber’s hereditary optic neuropathy with childhood onset. Investig Ophthalmol Vis Sci. 2006;47:5303–9.Google Scholar
  53. 53.
    Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease mechanisms and therapeutic strategies. Prog Retin Eye Res. 2011;30:81–114.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Oostra RJ, Bolhuis PA, Wijburg FA, Zorn-Ende G, Bleeker-Wagemakers EM, et al. Leber’s hereditary optic neuropathy: correlations between mitochondrial genotype and visual outcome. J Med Genet. 1994;31:280–6.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002;40:573–84.PubMedGoogle Scholar
  56. 56.
    Hannibal J, Hindersson P, Knudsen SM, Georg B, Fahrenkrug J, et al. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci. 2002;22:RC191.PubMedGoogle Scholar
  57. 57.
    Hattar S, Liao HW, Takao M, Berson DM, Yau KW, et al. Melanopsincontaining retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science. 2002;295:1065–70.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Moura AL, Nagy BV, La Morgia C, Barboni P, Oliveira AG, Salomão SR, et al. The pupil light reflex in Leber’s hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells. Investig Ophthalmol Vis Sci. 2013;54:4471–7.Google Scholar
  59. 59.
    La Morgia C, Ross-Cisneros FN, Hannibal J, Montagna P, Sadun AA, Carelli V. Melanopsin-expressing retinal ganglion cells: implications for human diseases. Vision Res. 2011;51:296–302.PubMedGoogle Scholar
  60. 60.
    La Morgia C, Ross-Cisneros FN, Sadun AA, Hannibal J, Munarini A, Mantovani V, et al. Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain. 2010;133:2426–38.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Ventura DF, Gualtieri M, Oliveira AG, Costa MF, Quiros P, Sadun F, et al. Male prevalence of acquired color vision defects in asymptomatic carriers of Leber’s hereditary optic neuropathy. Investig Ophthalmol Vis Sci. 2007;48:2362–70.Google Scholar
  62. 62.
    Gualtieri M, Bandeira M, Hamer RD, Costa MF, Oliveira AG, Moura AL, et al. Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber’s hereditary optic neuropathy. Vis Neurosci. 2008;25:469–74.PubMedGoogle Scholar
  63. 63.
    Ventura DF, Quiros P, Carelli V, Salomão SR, Gualtieri M, Oliveira AG, et al. Chromatic and luminance contrast sensitivities in asymptomatic carriers from a large Brazilian pedigree of 11778 Leber hereditary optic neuropathy. Investig Ophthalmol Vis Sci. 2005;46:4809–14.Google Scholar
  64. 64.
    Sadun AA. Optic disc pits and associated serous macular detachment. In: Ryan SJ, editor. Retina, vol. 2. St. Louis: CV Mosby; 2006. p. 1883–9.Google Scholar
  65. 65.
    Quiros PA, Torres RJ, Salomao S, Berezovsky A, Carelli V, Sherman J, et al. Colour vision defects in asymptomatic carriers of the Leber’s hereditary optic neuropathy (LHON) mtDNA 11778 mutation from a large Brazilian LHON pedigree: a case–control study. Br J Ophthalmol. 2006;90:150–3.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Sadun F, De Negri AM, Carelli V, Salomao SR, Berezovsky A, Andrade R, et al. Ophthalmologic findings in a large pedigree of 11778/Haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol. 2004;137:271–7.PubMedGoogle Scholar
  67. 67.
    Mann ES, Handler SP, Chung SM. Leber’s hereditary optic neuropathy masquerading as retinal vasculitis. Arch Ophthalmol. 2000;118:1587–9.PubMedGoogle Scholar
  68. 68.
    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;118:319–37.PubMedGoogle Scholar
  69. 69.
    Sadun AA, Carelli V. Mitochondrial function and dysfunction within the optic nerve. Arch Ophthalmol. 2003;121:1342–3.PubMedGoogle Scholar
  70. 70.
    Burde RM. Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1993;116:759–64.PubMedGoogle Scholar
  71. 71.
    Ramos Cdo V, Bellusci C, Savini G, Carbonelli M, Berezovsky A, Tamaki C, et al. Association of optic disc size with development and prognosis of Leber’s hereditary optic neuropathy. Investig Ophthalmol Vis Sci. 2009;50:1666–74.Google Scholar
  72. 72.
    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.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Nikoskelainen E, Hoyt WF, Nummelin K. Ophthalmoscopic findings in Leber’s hereditary optic neuropathy. I. Fundus findings in asymptomatic family members. Arch Ophthalmol. 1982;100:1597–602.PubMedGoogle Scholar
  74. 74.
    Sadun AA, Win PH, Ross-Cisneros FN, Walker SO, Carelli V, et al. Leber’s hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc. 2000;98:223–32. Discussion 232–5.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Nikoskelainen E, Hassinen IE, Paljärvi L, et al. Leber’s hereditary optic neuroretinopathy, a mitochondrial disease? Lancet. 1984;2:1474.PubMedGoogle Scholar
  76. 76.
    Kerrison JB, Howell N, Miller NR, et al. Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case. Ophthalmology. 1995;102:1509–16.PubMedGoogle Scholar
  77. 77.
    Barboni P, Carbonelli M, Savini G, Ramos Cdo V, Carta A, Berezovsky A, et al. Natural history of Leber’s hereditary optic neuropathy: longitudinal analysis of the retinal nerve fiber layer by optical coherence tomography. Ophthalmology. 2010;117:623–7.PubMedGoogle Scholar
  78. 78.
    Barboni P, Savini G, Valentino ML, Montagna P, Cortelli P, De Negri AM, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy. Ophthalmology. 2005;112:120–6.PubMedGoogle Scholar
  79. 79.
    Savini G, Barboni P, Valentino ML, Montagna P, Cortelli P, De Negri AM, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations. Ophthalmology. 2005;112:127–31.PubMedGoogle Scholar
  80. 80.
    Barboni P, Savini G, Feuer WJ, Budenz DL, Carbonelli M, Chicani F, et al. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers. Eur J Ophthalmol. 2012;22:985–91.PubMedGoogle Scholar
  81. 81.
    Sadun AA, La Morgia C, Carelli V. Leber’s Hereditary Optic Neuropathy. Curr Treat Options Neurol. 2011;13:109–17.PubMedGoogle Scholar
  82. 82.
    Harding AE, Sweeney MG, Miller DH, Mumford CJ, Kellar-Wood H, Menard D, et al. Occurrence of a multiple sclerosis-like illness in women who have a Leber’s hereditary optic neuropathy mitochondrial DNA mutation. Brain. 1992;115:979–89.PubMedGoogle Scholar
  83. 83.
    Ortiz RG, Newman NJ, Manoukian SV, Diesenhouse MC, Lott MT, Wallace DC, et al. Optic disk cupping and electrocardiographic abnormalities in an American pedigree with Leber’s hereditary optic neuropathy. Am J Ophthalmol. 1992;113:561–6.PubMedGoogle Scholar
  84. 84.
    Olsen NK, Hansen AW, Norby S, et al. Leber’s hereditary optic neuropathy associated with a disorder indistinguishable from multiple sclerosis in a male harbouring the mitochondrial DNA 11778 mutation. Acta Neurol Scand. 1995;91:326–9.PubMedGoogle Scholar
  85. 85.
    Flanigan KM, Johns DR. Association of the 11778 mitochondrial DNA mutation and demyelinating disease. Neurology. 1993;43:2720–2.PubMedGoogle Scholar
  86. 86.
    Kellar-Wood H, Robertson N, Govan GG, et al. Leber’s hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol. 1994;36:109–12.PubMedGoogle Scholar
  87. 87.
    Nikoskelainen EK, Marttila RJ, Huoponen K, et al. Leber’s “plus”: neurological abnormalities in patients with Leber’s hereditary optic neuropathy. J Neurol Neurosurg Psychiatry. 1995;59:160164.Google Scholar
  88. 88.
    Nikoskelainen E, Hoyt WF, Nummelin K. Fundus findings in Leber’s hereditary optic neuroretinopathy. Ophthalmic Paediatr Genet. 1985;5:125–30.PubMedGoogle Scholar
  89. 89.
    McLeod JG, Low PA, Morgan JA. Charcot-Marie-Tooth disease with Leber optic atrophy. Neurology. 1978;28:179–84.PubMedGoogle Scholar
  90. 90.
    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;93:121–32.PubMedGoogle Scholar
  91. 91.
    Funalot B, Reynier P, Vighetto A, et al. Leigh-like encephalopathy complicating Leber’s hereditary optic neuropathy. Ann Neurol. 2002;52:374–7.PubMedGoogle Scholar
  92. 92.
    Paulus W, Straube A, Bauer W, et al. Central nervous system involvement in Leber’s optic neuropathy. J Neurol. 1993;240:251–3.PubMedGoogle Scholar
  93. 93.
    Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, et al. A randomized placebocontrolled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134:2677–86.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Carelli V, La Morgia C, Valentino ML, Rizzo G, Carbonelli M, De Negri AM, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. 2011;134:e188.PubMedGoogle Scholar
  95. 95.
    Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol. 2012;69:331–8.PubMedGoogle Scholar
  96. 96.
    Guy J, Qi X, Koilkonda RD, Arguello T, Chou TH, Ruggeri M, et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Investig Ophthalmol Vis Sci. 2009;50:4205–14.Google Scholar
  97. 97.
    Pott JW, Wong KH. Leber’s hereditary optic neuropathy and vitamin B12 deficiency. Graefes Arch Clin Exp Ophthalmol. 2006;244:1357–9.PubMedGoogle Scholar
  98. 98.
    Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neuroprotection. Surv Ophthalmol. 2003;48:S47–51.PubMedGoogle Scholar
  99. 99.
    Yoles E, Wheeler LA, Schwartz M. Alpha-2-adenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration. Investig Ophthalmol Vis Sci. 1999;40:65–73.Google Scholar
  100. 100.
    WoldeMussie E, Ruiz G, Wijono M, Wheeler LA. Neuro-protection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Investig Ophthalmol Vis Sci. 2001;42:2849–55.Google Scholar
  101. 101.
    Lai RK, Chun T, Hasson D, Lee S, Mehrbod F, Wheeler L. Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci. 2002;19:175–85.PubMedGoogle Scholar
  102. 102.
    Newman NJ, Biousse V, David R, Bhatti MT, Hamilton SR, Farris BK, et al. Prophylaxis for second eye involvement in Leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol. 2005;140:407–15.PubMedGoogle Scholar
  103. 103.
    Ghelli A, Porcelli AM, Zanna C, Martinuzzi A, Carelli V, Rugolo M, et al. Protection against oxidant-induced apoptosis by exogenous glutathione in Leber hereditary optic neuropathy cybrids. Investig Ophthalmol Vis Sci. 2008;49:671–6.Google Scholar
  104. 104.
    Sala G, Trombin F, Beretta S, et al. Antioxidants partially restore glutamate transport defect in Leber hereditary optic neuropathy cybrids. J Neurosci Res. 2008;86:3331–7.PubMedGoogle Scholar
  105. 105.
    Huang CC, Kuo HC, Chu CC, Kao LY. Rapid visual recovery after coenzyme q10 treatment of leber hereditary optic neuropathy. J Neuroophthalmol. 2002;22:66.PubMedGoogle Scholar
  106. 106.
    Geromel V, Darin N, Chrétien D, Bénit P, DeLonlay P, Rötig A, et al. Coenzyme Q (10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab. 2002; 77:21–30.PubMedGoogle Scholar
  107. 107.
    Di Prospero NA, Baker A, Jeffries N, Fischbeck KH. Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6:878–86.PubMedGoogle Scholar
  108. 108.
    Meier T, Perlman SL, Rummey C, Coppard NJ, Lynch DR. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol. 2012;259:284–91.PubMedGoogle Scholar
  109. 109.
    Lekoubou A, Kouamé-Assouan AE, Cho TH, Luauté J, Nighoghossian N, Derex L. Effect of long-term oral treatment with l-arginine and idebenone on the prevention of stroke-like episodes in an adult MELAS patient. Rev Neurol (Paris). 2011;167:852–5.Google Scholar
  110. 110.
    Bababeygy SR, Wang MY, Khaderi KR, Sadun AA. Visual improvement with the use of idebenone in the treatment of Wolfram syndrome. J Neuroophthalmol. 2012;32:386–9.PubMedGoogle Scholar
  111. 111.
    Mashima Y, Hiida Y, Oguchi Y. Remission of Leber’s hereditary optic neuropathy with idebenone. Lancet. 1992;340:368–9.PubMedGoogle Scholar
  112. 112.
    Mashima Y, Kigasawa K, Wakakura M, Oguchi Y, et al. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J Neuroophthalmol. 2000;20:166–70.PubMedGoogle Scholar
  113. 113.
    Cortelli P, Montagna P, Pierangeli G, Lodi R, Barboni P, Liguori R, et al. Clinical and brain bioenergetics improvement with idebenone in a patient with Leber’s hereditary optic neuropathy: a clinical and 31P-MRS study. J Neurol Sci. 1997;148:25–31.PubMedGoogle Scholar
  114. 114.
    Carelli V, Barboni P, Zacchini A, Mancini R, Monari L, Cevoli S, et al. Leber’s hereditary optic neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci. 1998;160:183–8.PubMedGoogle Scholar
  115. 115.
    Eng JG, Aggarwal D, Sadun AA. Idebenone treatment in patients with Leber’s hereditary optic neuropathy. Vis Sci. 2009;50:1440.Google Scholar
  116. 116.
    Shrader WD, Amagata A, Barnes A, Enns GM, Hinman A, Jankowski O, et al. α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg Med Chem Lett. 2011;21:3693–8.PubMedGoogle Scholar
  117. 117.
    Kerr DS. Review of clinical trials for mitochondrial disorders: 1997–2012. Neurotherapeutics. 2013;10:307–19.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Floreani M, Napoli E, Martinuzzi A, Pantano G, De Riva V, Trevisan R, et al. Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber’s hereditary optic neuropathy. FEBS J. 2005;272:1124–35.PubMedGoogle Scholar
  119. 119.
    Enns GM, Kinsman SL, Perlman SL, Spicer KM, Abdenur JE, Cohen BH, et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab. 2012;105:91–102.PubMedGoogle Scholar
  120. 120.
    Blankenberg FG, Kinsman SL, Cohen BH, Goris ML, Spicer KM, Perlman SL, et al. Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease. Mol Genet Metab. 2012;107:690–9.PubMedGoogle Scholar
  121. 121.
    Porcelli AM, Angelin A, Ghelli A, Mariani E, Martinuzzi A, Carelli V, et al. Respiratory complex I dysfunction due to mitochondrial DNA mutations shifts the voltage threshold for opening of the permeability transition pore toward resting levels. J Biol Chem. 2009;284:2045–52.PubMedGoogle Scholar
  122. 122.
    Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, et al. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain. 2011;134:220–34.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8:249–56.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Gray RE, Law RH, Devenish RJ, Nagley P. Allotopic expression of mitochondrial ATP synthase genes in nucleus of Saccharomyces cerevisiae. Methods Enzymol. 1996;264:369–89.PubMedGoogle Scholar
  125. 125.
    Guy J, Qi X, Pallotti F, Schon EA, Manfredi G, Carelli V, et al. Rescue of a mitochondrial deficiency causing Leber hereditary optic neuropathy. Ann Neurol. 2002;52:534–42.PubMedGoogle Scholar
  126. 126.
    Qi X, Sun L, Lewin AS, Hauswirth WW, Guy J. The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse. Invest Ophthalmol Vis Sci. 2007;48:1–10.PubMedGoogle Scholar
  127. 127.
    Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, et al. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008;83:373–87.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Lam BL, Feuer WJ, Abukhalil F, Porciatti V, Hauswirth WW, Guy J. Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. Arch Ophthalmol. 2010;128:1129–35.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Perales-Clemente E, Fernández-Silva P, Acín-Pérez R, Pérez-Martos A, Enríquez JA. Allotopic expression of mitochondrial-encoded genes in mammals: achieved goal, undemonstrated mechanism or impossible task? Nucleic Acids Res. 2011;39:225–34.PubMedPubMedCentralGoogle Scholar
  130. 130.
    Oca-Cossio J, Kenyon L, Hao H, Moraes CT. Limitations of allotopic expression of mitochondrial genes in mammalian cells. Genetics. 2003;165:707–20.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Iyer S, Bergquist K, Young K, Gnaiger E, Rao RR, Bennett Jr JP. Mitochondrial gene therapy improves respiration, biogenesis, and transcription in G11778A Leber’s hereditary optic neuropathy and T8993G Leigh’s syndrome cells. Hum Gene Ther. 2012;23:647–57.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Yu H, Koilkonda RD, Chou TH, Porciatti V, Ozdemir SS, Chiodo V, et al. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model. Proc Natl Acad Sci U S A. 2012;109:E1238–47.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Lin CS, Sharpley MS, Fan W, Waymire KG, Sadun AA, Carelli V, et al. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. Proc Natl Acad Sci U S A. 2012;109:20065–70.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Marella M, Seo BB, Matsuno-Yagi A, Yagi T. Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line. J Biol Chem. 2007;282:24146–56.PubMedGoogle Scholar
  135. 135.
    Park JS, Li YF, Bai Y. Yeast NDI1 improves oxidative phosphorylation capacity and increases protection against oxidative stress and cell death in cells carrying a Leber’s hereditary optic neuropathy mutation. Biochim Biophys Acta. 2007;1772:533–42.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Marella M, Seo BB, Thomas BB, Matsuno-Yagi A, Yagi T. Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model. PLoS One. 2010;5:e11472.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Chadderton N, Palfi A, Millington-Ward S, Gobbo O, Overlack N, Carrigan M, et al. Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy. Eur J Hum Genet. 2013;21:62–8.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Newman NJ. Dominant optic atrophy. In: Newman NJ, Miller NR, editors. Walsh and Hoyt’s clinical neuro-ophthalmology. Baltimore, MD: Williams & Wilkins; 1998. p. 753–6.Google Scholar
  139. 139.
    Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, et al. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet. 2000;26:211–5.PubMedGoogle Scholar
  140. 140.
    Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, et al. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet. 2000;26:207–10.PubMedGoogle Scholar
  141. 141.
    Eiberg H, Kjer B, Kjer P, Rosenberg T, et al. Dominant optic atrophy (OPA1) mapped to chromosome 3q region. I. Linkage analysis. Hum Mol Genet. 1994;3:977–80.PubMedGoogle Scholar
  142. 142.
    Olichon A, Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ, et al. Mitochondrial dynamics and disease, OPA1. Biochim Biophys Acta. 2006;1763:500–9.PubMedGoogle Scholar
  143. 143.
    Mantyjarvi MI, Nerdrum K, Tuppurainen K. Color vision in dominant optic atrophy. J Clin Neuro Ophthalmol. 1992;12:98–103.Google Scholar
  144. 144.
    Simunovic MP, Votruba M, Regan BC, et al. Colour discrimination ellipses in patients with dominant optic atrophy. Vision Res. 1998;38:3413–9.PubMedGoogle Scholar
  145. 145.
    Hoyt CS. Autosomal dominant optic atrophy. A spectrum of disability. Ophthalmology. 1980;87:245–51.PubMedGoogle Scholar
  146. 146.
    Votruba M, Aijaz S, Moore AT. A review of primary hereditary optic neuropathies. J Inherit Metab Dis. 2003;26:209–27.PubMedGoogle Scholar
  147. 147.
    Kok-van Alphen CC. Four families with the dominant infantile form of optic nerve atrophy. Acta Ophthalmol (Copenh). 1970;48:905–16.Google Scholar
  148. 148.
    Votruba M, Thiselton D, Bhattacharya SS. Optic disc morphology of patients with OPA1 autosomal dominant optic atrophy. Br J Ophthalmol. 2003;87:48–53.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Ito Y, Nakamura M, Yamakoshi T, Lin J, Yatsuya H, Terasaki H, et al. Reduction of inner retinal thickness in patients with autosomal dominant optic atrophy associated with OPA1 mutations. Investig Ophthalmol Vis Sci. 2007;48:4079–86.Google Scholar
  150. 150.
    Manchester Jr PT, Calhoun Jr FP. Dominant hereditary optic atrophy with bitemporal field defects. AMA Arch Ophthalmol. 1958;60:479–84.PubMedGoogle Scholar
  151. 151.
    Buono LM, Foroozan R, Sergott RC, et al. Is normal tension glaucoma actually an unrecognized hereditary optic neuropathy? New evidence from genetic analysis. Curr Opin Ophthalmol. 2002;13:362–70.PubMedGoogle Scholar
  152. 152.
    Weiner NC, Newman NJ, Lessell S, et al. Atypical Leber’s hereditary optic neuropathy with molecular confirmation. Arch Neurol. 1993;50:470–3.PubMedGoogle Scholar
  153. 153.
    Mashima Y, Kimura I, Yamamoto Y, et al. Optic disc excavation in the atrophic stage of Leber’s hereditary optic neuropathy: comparison with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol. 2003;241:75–80.PubMedGoogle Scholar
  154. 154.
    Li Y, Deng T, Tong Y, et al. Identification of two novel OPA1 mutations in Chinese families with autosomal dominant optic atrophy. Mol Vis. 2008;14:2451–7.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Votruba M, Moore AT, Bhattacharya SS. Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. J Med Genet. 1998;35:793–800.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Fournier AV, Damji KF, Epstein DL, et al. Disc excavation in dominant optic atrophy. Ophthalmology. 2001;108:1595–602.PubMedGoogle Scholar
  157. 157.
    Johnston PB, Gaster RN, Smith VC, et al. A clinicopathologic study of autosomal dominant optic atrophy. Am J Ophthalmol. 1979;88:868–75.PubMedGoogle Scholar
  158. 158.
    Kjer P, Jensen OA, Klinken L. Histopathology of eye, optic nerve and brain in a case of dominant optic atrophy. Acta Ophthalmol (Copenh). 1983;61:300–12.Google Scholar
  159. 159.
    Payne M, Yang Z, Katz BJ, et al. Dominant optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia: a syndrome caused by a mis-sense mutation in OPA1. Am J Ophthalmol. 2004;138:749–55.PubMedGoogle Scholar
  160. 160.
    Lodi R, Tonon C, Valentino ML, et al. Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy. Ann Neurol. 2004;56:719–23.PubMedGoogle Scholar
  161. 161.
    Kim JY, Hwang J-M, Ko HS, et al. Mitochondrial DNA content is decreased in autosomal dominant optic atrophy. Neurology. 2005;64:966–72.PubMedGoogle Scholar
  162. 162.
    Kerrison JB, Arnould VJ, Ferraz Sallum JM, et al. Genetic heterogeneity of dominant optic atrophy, Kjer type: identification of a second locus on chromosome 18q12.2-12.3. Arch Ophthalmol. 1999;117:805–10.PubMedGoogle Scholar
  163. 163.
    Barbet F, Hakiki S, Orssaud C, Gerber S, Perrault I, Hanein S, et al. A third locus for dominant optic atrophy on chromosome 22q. J Med Genet. 2005;42:e1.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Carelli V, Schimpf S, Fuhrmann N, Valentino ML, Zanna C, Iommarini L, et al. A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16. Hum Mol Genet. 2011;20:1893–905.PubMedGoogle Scholar
  165. 165.
    Ozden S, Duzcan F, Wollnik B, et al. Progressive autosomal dominant optic atrophy and sensori-neural hearing loss in a Turkish family. Ophthalmic Genet. 2002;23:29–36.PubMedGoogle Scholar
  166. 166.
    Toomes C, Marchbank NJ, Mackey DA, et al. Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. Hum Mol Genet. 2001;10:1369–78.PubMedGoogle Scholar
  167. 167.
    Delettre C, Griffoin JM, Kaplan J, et al. Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet. 2001;109:584–91.PubMedGoogle Scholar
  168. 168.
    Thiselton DL, Alexander C, Morris A, et al. A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect. Hum Genet. 2001;109:498–502.PubMedGoogle Scholar
  169. 169.
    Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, et al. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain. 2008;131:352–67.PubMedGoogle Scholar
  170. 170.
    Yu-Wai-Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, et al. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133:771–86.PubMedPubMedCentralGoogle Scholar
  171. 171.
    Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissière A, et al. OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain. 2008;131:338–51.PubMedGoogle Scholar
  172. 172.
    Hudson G, Amati-Bonneau P, Blakely EL, Stewart JD, He L, Schaefer AM, et al. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain. 2008;131:329–37.PubMedGoogle Scholar
  173. 173.
    Marchbank NJ, Craig JE, Leek JP, et al. Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease. J Med Genet. 2002;39:e47.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Hogewind BF, Pennings RJ, Hol FA, Kunst HP, Hoefsloot EH, Cruysberg JR, et al. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1. Mol Vis. 2010;16:26–35.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Eiberg H, Hansen L, Kjer B, Hansen T, Pedersen O, Bille M, et al. Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. J Med Genet. 2006;43:435–40.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Delettre C, Lenaers G, Pelloquin L, et al. OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Mol Genet Metab. 2002;75:97–107.PubMedGoogle Scholar
  177. 177.
    Williams PA, Morgan JE, Votruba M. Mouse models of dominant optic atrophy: what do they tell us about the pathophysiology of visual loss? Vision Res. 2011;51:229–34.PubMedGoogle Scholar
  178. 178.
    Alavi MV, Bette S, Schimpf S, Schuettauf F, Schraermeyer U, Wehrl HF, et al. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy. Brain. 2007;130:1029–42.PubMedGoogle Scholar
  179. 179.
    Davies VJ, Hollins AJ, Piechota MJ, Yip W, Davies JR, White KE, et al. Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Hum Mol Genet. 2007;16:1307–18.PubMedGoogle Scholar
  180. 180.
    Yarosh W, Monserrate J, Tong JJ, Tse S, Le PK, Nguyen K, et al. The molecular mechanisms of OPA1-mediated optic atrophy in Drosophila model and prospects for antioxidant treatment. PLoS Genet. 2008;4:e6.PubMedPubMedCentralGoogle Scholar
  181. 181.
    Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004;119:873–87.PubMedGoogle Scholar
  182. 182.
    Williams PA, Morgan JE, Votruba M. Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy. Brain. 2010;133:2942–51.PubMedGoogle Scholar
  183. 183.
    Williams PA, Piechota M, von Ruhland C, Taylor E, Morgan JE, Votruba M. Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity. Brain. 2012;135:493–505.PubMedGoogle Scholar
  184. 184.
    Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002;419:367–74.PubMedGoogle Scholar
  185. 185.
    Bouaita A, Augustin S, Lechauve C, Cwerman-Thibault H, Bénit P, Simonutti M, et al. Downregulation of apoptosis-inducing factor in Harlequin mice induces progressive and severe optic atrophy which is durably prevented by AAV2-AIF1 gene therapy. Brain. 2012;135:35–52.PubMedGoogle Scholar
  186. 186.
    DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci. 2008;31:91–123.PubMedGoogle Scholar
  187. 187.
    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 U S A. 1994;91:6206–10.PubMedPubMedCentralGoogle Scholar
  188. 188.
    Kirby DM, Kahler SG, Freckmann ML, Reddihough D, Thorburn DR. Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. Ann Neurol. 2000;48:102–4.PubMedGoogle Scholar
  189. 189.
    Santorelli FM, Tanji K, Kulikova R, Shanske S, Vilarinho L, Hays AP, et al. Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun. 1997;238:326–8.PubMedGoogle Scholar
  190. 190.
    Corona P, Antozzi C, Carrara F, D’Incerti L, Lamantea E, Tiranti V, et al. A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol. 2001;49:106–10.PubMedGoogle Scholar
  191. 191.
    Sakuta R, Nonaka I. Vascular involvement in mitochondrial myopathy. Ann Neurol. 1989;25:594–601.PubMedGoogle Scholar
  192. 192.
    Cavanagh JB, Harding BN. Pathogenic factors underlying the lesions in Leigh’s disease. Tissue responses to cellular energy deprivation and their clinico-pathological consequences. Brain. 1994;117:1357–76.PubMedGoogle Scholar
  193. 193.
    Barrett TG, Bundey SE, Macleod AF. Neurode-generation and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346:1458–63.PubMedGoogle Scholar
  194. 194.
    Scolding NJ, Kellar-Wood HF, Shaw C, et al. Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol. 1996;39:352–60.PubMedGoogle Scholar
  195. 195.
    Hardy C, Khanim F, Torres R, et al. Clinical and molecular genetic analysis of 19 Wolfram syn-drome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet. 1999;65:1279–90.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Kinsley BT, Swift M, Dumont RH, et al. Morbidity and mortality in the Wolfram syndrome. Diabetes Care. 1995;18:1566–70.PubMedGoogle Scholar
  197. 197.
    Ito S, Sakakibara R, Hattori T. Wolfram syndrome presenting marked brain MR imaging abnormalities with few neurologic abnormalities. AJNR Am J Neuroradiol. 2007;28:305–6.PubMedGoogle Scholar
  198. 198.
    Sylvestor PE. Some unusual findings in a family with Friedreich ataxia. Arch Dis Child. 1958;33:217–21.Google Scholar
  199. 199.
    Jensen PK, Reske-Nielsen E, Hein-Sørensen O, Warburg M. The syndrome of opticoacoustic nerve atrophy with dementia. Am J Med Genet. 1987;28:517–8.PubMedGoogle Scholar
  200. 200.
    Hagemoser K, Weinstein J, Bresnick G, Nellis R, Kirkpatrick S, Pauli RM. Optic atrophy, hearing loss, and peripheral neuropathy. Am J Med Genet. 1989;33:61–5.PubMedGoogle Scholar
  201. 201.
    Barrientos A, Volpini V, Casademont J, et al. A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome. J Clin Invest. 1996;97:1570–6.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, et al. WFS1 protein modulates the free Ca(2+) concentration in the endoplasmic reticulum. FEBS Lett. 2006;16(580):5635–40.Google Scholar
  203. 203.
    Rotig A, Cormier V, Chatelain P, et al. Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300). J Clin Invest. 1993;91:1095–8.PubMedPubMedCentralGoogle Scholar
  204. 204.
    Durr A, Cossee M, Agid Y, et al. Clinical and genetic abnormalities in patients with Friedreich’s ataxia. N Engl J Med. 1996;335:1169–75.PubMedGoogle Scholar
  205. 205.
    Harding AE. Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain. 1981;104:589–620.PubMedGoogle Scholar
  206. 206.
    Fortuna F, Barboni P, Liguori R, Valentino ML, Savini G, Gellera C, et al. Visual system involvement in patients with Friedreich’s ataxia. Brain. 2009;132:116–23.PubMedGoogle Scholar
  207. 207.
    Camacho LM, Wenzel W, Aschoff JC. The pattern-reversal visual evoked potential in the clinical study of lesions of the optic chiasm and visual pathway. Adv Neurol. 1982;32:49–59.PubMedGoogle Scholar
  208. 208.
    Boyer IV SH, Chisolm AW, McKusick VA. Cardiac aspects of Friedreich’s ataxia. Circulation. 1962;25:493–505.PubMedGoogle Scholar
  209. 209.
    Chamberlain S, Shaw J, Rowland A, et al. Mapping of mutation causing Friedreich's ataxia to human chromosome 9. Nature. 1988;334:248–50.PubMedGoogle Scholar
  210. 210.
    Fujita R, Agid Y, Trouillas P, et al. Confirmation of linkage of Friedreich ataxia to chromosome 9 and identification of a new closely linked marker. Genomics. 1989;4:110–1.PubMedGoogle Scholar
  211. 211.
    Forrest SM, Knight M, Delatycki MB, et al. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998;1:253–7.PubMedGoogle Scholar
  212. 212.
    Koeppen AH. The hereditary ataxias. J Neuropathol Exp Neurol. 1998;57:531–43.PubMedGoogle Scholar
  213. 213.
    Voncken M, Ioannou P, Delatycki MB. Friedreich ataxia: update on pathogenesis and possible therapies. Neurogenetics. 2004;5:1–8.PubMedGoogle Scholar
  214. 214.
    Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1:1151–5.PubMedGoogle Scholar
  215. 215.
    Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell. 1998;93:973–83.PubMedGoogle Scholar
  216. 216.
    Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004;36:449–51.PubMedGoogle Scholar
  217. 217.
    Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, et al. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276–81.PubMedGoogle Scholar
  218. 218.
    Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, Leonard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007;356:1736–41.PubMedGoogle Scholar
  219. 219.
    Dyck PJ, Chance P, Lebo R, et al. Hereditary motor and sensory neuropathies. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, editors. Peripheral neuropathy, vol. 2. Philadelphia, PA: Saunders; 1993. p. 1094–123.Google Scholar
  220. 220.
    Voo I, Allf BE, Udar N, et al. Hereditary motor and sensory neuropathy type VI with optic atrophy. Am J Ophthalmol. 2003;136:670–7.PubMedGoogle Scholar
  221. 221.
    Pizzatto MR, Pascual-Castroviejo I. Sindrome de Behr. Presentacion de siete casos. Rev Neurol. 2001;32:721–4.PubMedGoogle Scholar
  222. 222.
    Horoupian DS, Zucker DK, Moshe S, et al. Behr syndrome: a clinicopathologic report. Neurology. 1979;29:323–7.PubMedGoogle Scholar
  223. 223.
    Gillis L, Kaye E. Diagnosis and management of mitochondrial diseases. Pediatr Clin. 2002;49:203–19.Google Scholar
  224. 224.
    Georgy BA, Snow RD, Brogdon BG, Wertelecki W. Neuroradiologic findings in Marinesco-Sjögren syndrome. AJNR Am J Neuroradiol. 1998;19:281–3.PubMedGoogle Scholar
  225. 225.
    Delague V, Bareil C, Bouvagnet P, Salem N, Chouery E, Loiselet J, et al. A new autosomal recessive non-progressive congenital cerebellar ataxia associated with mental retardation, optic atrophy, and skin abnormalities (CAMOS) maps to chromosome 15q24-q26 in a large consanguineous Lebanese Druze family. Neurogenetics. 2002;4:23–7.PubMedGoogle Scholar
  226. 226.
    Nicolaides P, Appleton RE, Fryer A. Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. J Med Genet. 1996;33:419–21.PubMedPubMedCentralGoogle Scholar
  227. 227.
    Felicio AC, Godeiro-Junior C, Alberto LG, Pinto AP, Sallum JM, Teive HG, et al. Familial Behr syndrome-like phenotype with autosomal dominantinheritance. Parkinsonism Relat Disord. 2008;14:370–2.PubMedGoogle Scholar
  228. 228.
    Sheffer RN, Zlotogora J, Elpeleg ON, Raz J, Ben-Ezra D. Behr's syndrome and 3-methylglutaconic aciduria. Am J Ophthalmol. 1992;114:494–7.PubMedGoogle Scholar
  229. 229.
    Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. 2001;69:1218–24.PubMedPubMedCentralGoogle Scholar
  230. 230.
    Ho G, Walter JH, Christodoulou J. Costeff optic atrophy syndrome: new clinical case and novel molecular findings. J Inherit Metab Dis. 2008;31:S419–23.PubMedGoogle Scholar
  231. 231.
    Costeff H, Gadoth N, Apter N, et al. A familial syndrome of infantile optic atrophy, movement disorder, and spastic paraplegia. Neurology. 1989;39:595–7.PubMedGoogle Scholar
  232. 232.
    Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993;4:221–6.PubMedGoogle Scholar
  233. 233.
    Burk K, Abele M, Fetter M, et al. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain. 1996;119:1497–505.PubMedGoogle Scholar
  234. 234.
    Buttner N, Geschwind D, Jen JC, et al. Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol. 1998;55:1353–7.PubMedGoogle Scholar
  235. 235.
    Robitaille Y, Schut L, Kish SJ. Structural and immunocytochemical features of olivoponto-cerebellar atrophy caused by the spinocerebellar ataxia type 1 (SCA-1) mutation define a unique phenotype. Acta Neuropathol. 1995;90:572–81.PubMedGoogle Scholar
  236. 236.
    Vig PJ, Subramony SH, Burright EN, et al. Reduced immunoreactivity to calcium-binding proteins in Purkinje cells precedes onset of ataxia in spinocerebellar ataxia-1 transgenic mice. Neurology. 1998;50:106–13.PubMedGoogle Scholar
  237. 237.
    Iwashita H, Inoue N, Araki S, et al. Optic atrophy, neural deafness, and distal neurogenic amyotrophy: report of a family with two affected siblings. Arch Neurol. 1970;22:357–64.PubMedGoogle Scholar
  238. 238.
    Rosenberg RN, Chutorian A. Familial opti-coacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32.PubMedGoogle Scholar
  239. 239.
    Kim H-J, Hong SH, Ki C-S, et al. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology. 2005;64:1964–7.PubMedGoogle Scholar
  240. 240.
    Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. 2001;68:598–605.PubMedPubMedCentralGoogle Scholar
  241. 241.
    Riley CM, Day RL, Greeley DM, et al. Central autonomic dysfunction with defective lacrimation: report of five cases. Pediatrics. 1949;3:468–78.PubMedGoogle Scholar
  242. 242.
    Pearson J, Pytel BA, Grover-Johnson N, et al. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci. 1978;35:77–92.PubMedGoogle Scholar
  243. 243.
    Axelrod FB, Pearson J, Tepperberg J, et al. Congenital sensory neuropathy with skeletal dysplasia. J Pediatr. 1983;102:727–30.PubMedGoogle Scholar
  244. 244.
    Rizzo 3rd JF, Lessell S, Liebman SD. Optic atrophy in familial dysautonomia. Am J Ophthlamol. 1986;102:463–7.Google Scholar
  245. 245.
    Groom M, Kay MD, Corrent GF. Optic neuropathy in familial dysautonomia. J Neuroophthalmol. 1997;17:101–2.PubMedGoogle Scholar
  246. 246.
    Schnitzler A, Witte OW, Kunesch E, et al. Early-onset multisystem degeneration with central motor, autonomic and optic nerve disturbances: unusual Riley-Day syndrome or new clinical entity? J Neurol Sci. 1998;154:205–8.PubMedGoogle Scholar
  247. 247.
    Salonen R, Somer M, Haltia M, et al. Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO syndrome). Clin Genet. 1991;39:287–93.PubMedGoogle Scholar
  248. 248.
    Scott HS, Bunge S, Gal A, et al. Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat. 1995;6:288–302.PubMedGoogle Scholar
  249. 249.
    Collins ML, Traboulsi EI, Maumenee IH. Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology. 1990;97:1445–9.PubMedGoogle Scholar
  250. 250.
    Hall CW, Liebaers I, Di Natale P, et al. Enzymic diagnosis of the genetic mucopolysac-charide storage disorders. Methods Enzymol. 1978;50:439–56.PubMedGoogle Scholar
  251. 251.
    Fairbairn LJ, Lashford LS, Spooncer E, et al. Long-term in vitro correction of alpha-l-iduronidase deficiency (Hurler syndrome) in human bone marrow. Proc Natl Acad Sci. 1996;93:2025–30.PubMedPubMedCentralGoogle Scholar
  252. 252.
    Somer M. Diagnostic criteria and genetics of the PEHO syndrome. J Med Genet. 1993;30:932–6.PubMedPubMedCentralGoogle Scholar
  253. 253.
    Morgan NV, Westaway SK, Morton JE, et al. PLA2G6, encoding a phospholipase A(2), is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752–4.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Farina L, Nardocci N, Bruzzone MG, et al. Infantile neuroaxonal dystrophy: neuroradio-logical studies in 11 patients. Neuroradiology. 1999;41:376–80.PubMedGoogle Scholar
  255. 255.
    Aicardi J, Castelein P. Infantile neuroaxonal dystrophy. Brain. 1979;102:727–48.PubMedGoogle Scholar
  256. 256.
    Schaumburg HH, Powers JM, Raine CS, et al. Adrenoleukodystrophy: a clinical and pathological study of 17 cases. Arch Neurol. 1975;32:577–91.PubMedGoogle Scholar
  257. 257.
    Aubourg P, Chaussain JL, Dulac O, et al. Adrenoleukodystrophy in children: apropos of 20 cases. Arch Fr Pediatr. 1982;39:663–9.PubMedGoogle Scholar
  258. 258.
    Moser HW, Moser AB, Frayer KK, et al. Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids. Neurology. 1981;31:1241–9.PubMedGoogle Scholar
  259. 259.
    Kolodny EH. The adrenoleukodystrophy-adrenomyeloneuropathy complex: is it treatable? [Editorial]. Ann Neurol. 1987;21:230–1.PubMedGoogle Scholar
  260. 260.
    Aubourg P, Blanche S, Jambaque I, et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation. N Engl J Med. 1990;322:1860–6.PubMedGoogle Scholar
  261. 261.
    Malm G, Ringden O, Anvret M, et al. Treatment of adrenoleukodystrophy with bone marrow transplantation. Acta Paediatr. 1997;86:484–92.PubMedGoogle Scholar
  262. 262.
    Percy AK, Brady RO. Metachromatic leukodystrophy: diagnosis with samples of venous blood. Science. 1968;161:594–5.PubMedGoogle Scholar
  263. 263.
    Austin J, McAfee D, Armstrong D, et al. Abnormal sulphatase activities in two human diseases (metachromatic leukodystrophy and gargoylism). Biochem J. 1964;93:15C–7.PubMedGoogle Scholar
  264. 264.
    Bayever E, Ladisch S, Philippart M, et al. Bone marrow transplantation for meta-chromatic leukodystrophy. Lancet. 1985;II:471–3.Google Scholar
  265. 265.
    Krivit W, Shapiro E, Kennedy W, et al. Treatment of late infantile metachromatic leukodys-trophy by bone marrow transplantation. N Engl J Med. 1990;322:28–32.PubMedGoogle Scholar
  266. 266.
    Zlotogora J, Chakraborty S, Knowlton RG, et al. Krabbe disease locus mapped to chromosome 14 by genetic linkage. Am J Hum Genet. 1990;47:37–44.PubMedPubMedCentralGoogle Scholar
  267. 267.
    D’Agostino AN, Sayre GP, Hayles AB. Krabbe's disease: globoid cell type of leukodystrophy. Arch Neurol. 1963;8:82–96.PubMedGoogle Scholar
  268. 268.
    Husain AM, Altuwaijri M, Aldosari M. Krabbe disease: neurophysiologic studies and MRI cor-relations. Neurology. 2004;63:617–20.PubMedGoogle Scholar
  269. 269.
    Krivit W, Shapiro EG, Peters C, et al. Hematopoietic stem-cell transplantation in globoid cell leukodystrophy. N Engl J Med. 1998;338:1119–26.PubMedGoogle Scholar
  270. 270.
    Renier WO, Gabreels FJM, Hustinx TWJ, et al. Connatal Pelizaeus-Merzbacher disease with congenital stridor in two maternal cousins. Acta Neuropathol. 1981;54:11–7.PubMedGoogle Scholar
  271. 271.
    Schinzel A, Boltshauser E, Wichmann W, Haller D, et al. Pelizaeus-Merzbacher disease: magnetic resonance imaging as a potential tool for carrier detection [Abstract]. J Med Genet. 1988;25:276–7.Google Scholar
  272. 272.
    Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet. 1993;5:118–23.PubMedGoogle Scholar
  273. 273.
    Matalon R, Michals K, Sebesta D, et al. Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet. 1988;29:463–71.PubMedGoogle Scholar
  274. 274.
    Matalon R, Kaul R, Casanova J, et al. Aspartoacylase deficiency: the enzyme defect in Canavan disease. J Inherit Metab Dis. 1989;12:329–31.PubMedGoogle Scholar
  275. 275.
    Wittsack HJ, Kugel H, Roth B, et al. Quantitative measurements with localized 1H MR spectroscopy in children with Canavan’s disease. J Magn Reson Imaging. 1996;6:889–93.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of OphthalmologyDoheny Eye InstituteLos AngelesUSA
  2. 2.Department of Neurology, Neuro-OphthalmologyUniversity of Nevada School of MedicineRenoUSA

Personalised recommendations