Leber hereditary optic neuropathy

Expert Opinion on Medical Diagnostics

Volumn 2, Issue 7, 2008, Pages 789-799

  Hudson, Gavin ^a   Yu Wai Man, Patrick ^a   Chinnery, Patrick F ^a,b  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Leber hereditary optic neuropathy; Mitochondria; Optic atrophy; Optic neuropathy

Indexed keywords

8 HYDROXYDEOXYGUANOSINE; ALPHA TOCOPHEROL; ANTIRETROVIRUS AGENT; APOPTOSIS INDUCING FACTOR; ASCORBIC ACID; BIOLOGICAL MARKER; CELL NUCLEUS DNA; CYANOCOBALAMIN; ENDONUCLEASE G; IDEBENONE; MITOCHONDRIAL DNA; QUINONE DERIVATIVE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); SMALL INTERFERING RNA; SUPEROXIDE DISMUTASE; TUBERCULOSTATIC AGENT;

AMINO ACID SUBSTITUTION; BLOOD CHEMISTRY; CLINICAL FEATURE; CLINICAL TRIAL; COLOR VISION DEFECT; DIET SUPPLEMENTATION; DRUG EFFICACY; DYSTONIA; ELECTRORETINOGRAM; EPIGENETICS; EXTRACHROMOSOMAL INHERITANCE; FAMILY HISTORY; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC COUNSELING; GENETIC PREDISPOSITION; HETEROPLASMY; HUMAN; LEBER HEREDITARY OPTIC NEUROPATHY; MELAS SYNDROME; MICROANGIOPATHY; NONHUMAN; OCCUPATIONAL THERAPY; OPTIC NERVE ATROPHY; OPTIC NERVE DISEASE; PATHOPHYSIOLOGY; PERIMETRY; PHOTORECEPTOR POTENTIAL; POINT MUTATION; PSYCHOSOCIAL CARE; RACE DIFFERENCE; RETINA DISEASE; RETINA FLUORESCEIN ANGIOGRAPHY; RETINA GANGLION CELL; REVIEW; SEX RATIO; VISUAL ACUITY; VISUAL AID; VISUAL IMPAIRMENT; X CHROMOSOME LINKED DISORDER;

EID: 77953422962     PISSN: 17530059     EISSN: 17530067     Source Type: Journal    
DOI: 10.1517/17530059.2.7.789     Document Type: Review

References (113)

1. Leber T. Ueber hereditaere und congenital angelegte Sehnervenleiden. Graefes Arch Clin Exp Ophthalmol 171;17:249-91
2. Man PYW, Griffiths PG, Brown DT, et al. The epidemiology of Leber heriditary optic neuropathy in the north east of England. Am J Hum Genet 2003;72:333-9
3. Puomila A, Hamalainen P, Kivioja S, et al. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Hum Genet 2007;15:1079-89
4. Spruijt L, Smeets HJ, Hendrickx A, et al. A MELAS-associated ND1 mutation causing Leber hereditary optic neuropathy and spastic dystonia. Arch Neurol 2007;64:890-3
5. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988;242:1427-30
6. Howell N, Kubacka I, Xu M, et al. Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 1991;48:935-42
7. 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
8. Mackey DA, Buttery RG. Leber hereditary optic neuropathy in Australia. Aust N Z J Ophthalmol 1992;20:177-84
9. Mackey DA, Oostra RJ, Rosengerg T, et al. Primary Pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 1996;59:481-5
10. Newman NJ. Leber's hereditary optic neuropathy: New genetic considerations. Arch Neurol 1993;50:540-8
11. Starikovskaya EB, Sukernik RI, Derbeneva OA, et al. Mitochondrial DNA diversity in indigenous populations of the southern extent of Siberia, and the origins of Native American haplogroups. Ann Hum Genet 2005;69:67-89
12. Mashima Y, Yamada K, Wakakura M, et al. Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy. Curr Eye Res 1998;17:403-8
13. Yen MY, Wang AG, Chang WL, et al. Leber's hereditary optic neuropathy - the spectrum of mitochondrial DNA mutations in Chinese patients. Jpn J Ophthalmol 2002;46:45-51
14. Macmillan C, Johns TA, Fu K, et al. Predominance of the T14484 mutation in French-Canadian families with Leber hereditary optic neuropathy [letter]. Am J Hum Genet 2000;59:481-5
15. Macmillan C, Kirkham T, Fu K, et al. Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy. Neurology 1998;50:417-22
16. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 2004;23:53-89
17. Valentino ML, Barboni P, Ghelli A, et al. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Ann Neurol 2004;56:631-41
18. Zhadanov SI, Atamanov VV, Zhadanov NI, et al. A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family. Biochem Biophys Res Commun 2005;332:1115-21
19. Chinnery PF, Howell N, Andrews RM, et al. Mitochondrial DNA analysis: polymorphisms and pathogenicity. J Med Genet 1999;36:505-10
20. Carroll J, Fearnley IM, Shannon RJ, et al. Analysis of the subunit composition of complex I from bovine heart mitochondria. Mol Cell Proteomics 2003;2:117-26
21. King MP, Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 1989;246:500-3
22. Brown MD, Trounce IA, Jun AS, et al. Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. J Biol Chem 2000;275(51):39831-6
23. Carelli V, Ghelli A, Bucchi L, et al. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. Ann Neurol 1999;45:320-8
24. Cock HR, Cooper JM, Schapira AH. Functional conseqeunces of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. J Neurol Sci 1999;165(1):10-7
25. Carelli V, Vergani L, Bernazzi B, et al. Respiratory function in cybrid cell lines carrying European mtDNA haplogroups: implications for Leber's hereditary optic neuropathy. Biochim Biophys Acta 2002;1588:7-14
26. Barbiroli B, Montagna P, Cortelli P, et al. Defective brain and muscle energy metabolism shown by in vivo 31P magnetic resonance spectroscopy in nonaffected carriers of 11778 mtDNA mutation. Neurology 1995;45:1364-9
27. Lodi R, Carelli V, Cortelli P, et al. Phosphorus MR spectroscopy shows a tissue specific in vivo distribution of biochemical expression of the G3460A mutation in Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2002;72:805-7
28. Baracca A, Solaini G, Sgarbi G, et al. Severe impairment of complex I-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. Arch Neurol 2005;62:730-6
29. Gajewski CD, Yang L, Schon EA, et al. New insights into the bioenergetics of mitochondrial disorders using intracellular ATP reporters. Mol Biol Cell 2003;14:3628-35
30. Zanna C, Ghelli A, Porcelli AM, et al. Apoptotic cell death of cybrid cells bearing Leber's hereditary optic neuropathy mutations is caspase independent. Ann NY Acad Sci 2003;1010:213-7
31. Kudin AP, Bimpong-Buta NY, Vielhaber S, et al. Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem 2004;279:4127-35
32. Degli Esposti M, Carelli V, Ghelli A, et al. Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy. FEBS Lett 1994;352:375-9
33. Pitkanen S, Raha S, Robinson BH. Diagnosis of complex I deficiency in patients with lactic acidemia using skin fibroblast cultures. Biochem Mol Med 1996;59:134-7
34. Robinson BH. Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect. Biochim Biophys Acta 1998;1364:271-86
35. Wong A, Cavelier L, Collins-Schramm HE, et al. Differentiation-specific effects of LHON mutations introduced into
36. neuronal NT2 cells. Hum Mol Genet 2002;11:431-8
37. Carelli V, Rugolo M, Sgarbi G, et al. Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy: a model of mitochondrial neurodegeneration. Biochim Biophys Acta 2004;1658:172-9
38. Floreani M, Napoli E, Martinuzzi A, et al. Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. FEBS J 2005;272:1124-35
39. Qi X, Lewin AS, Hauswirth WW, et al. Optic neuropathy induced by reductions in mitochondrial superoxide dismutase. Invest Ophthalmol Vis Sci 2003;44:1088-96
40. Klivenyi P, Karg E, Rozsa C, et al. alpha-Tocopherol/lipid ratio in blood is decreased in patients with Leber's hereditary optic neuropathy and asymptomatic carriers of the 11778 mtDNA mutation. J Neurol Neurosurg Psychiatry 2001;70:359-62
41. Yen MY, Kao SH, Wang AG, et al. Increased 8-hydroxy-2′-deoxyguanosine in leukocyte DNA in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci 2004;45:1688-91
42. Hofhaus G, Johns DR, Hurko O, et al. Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy. J Biol Chem 1996;271:13155-61
43. Battisti C, Formichi P, Cardaioli E, et al. Cell response to oxidative stress induced apoptosis in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2004;75:1731-6
44. Ghelli A, Zanna C, Porcelli AM, et al. Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium. J Biol Chem 2003;278:4145-50
45. Hollenbeck PJ. The pattern and mechanism of mitochondrial transport in axons. Front Biosci 1996;1:d91-102
46. Wang L, Dong J, Cull G, et al. Varicosities of intraretinal ganglion cell axons in human and nonhuman primates. Invest Ophthalmol Vis Sci 2003;44:2-9
47. Sadun AA, Dao J. Annual review in neuro-ophthalmology: the anterior visual pathways. J Neuroophthalmol 1994;14:141-54
48. Andrews RM, Griffiths PG, Johnson MA, et al. Histochemical localisation of mitochondrial enzyme activity in human optic nerve and retina. Br J Ophthalmol 1999;83:231-5
49. Barron MJ, Johnson MA, Andrews RM, et al. Mitochondrial abnormalities in ageing macular photoreceptors. Invest Ophthalmol Vis Sci 2001;42:3016-22
50. Yu Wai Man CY, Chinnery PF, Griffiths PG. Optic neuropathies - importance of spatial distribution of mitochondria as well as function. Med Hypotheses 2005;65:1038-42
51. Torroni A, Richards M, Macaulay V, et al. mtDNA haplogroups and frequency patterns in Europe. Am J Hum Genet 2000;66:1173-7
52. Brown MD, Sun F, Wallace DC. Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage. Am J Hum Genet 1997;60;381-7
53. Man PY, Chinnery PF, Turnbull DM. Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees. J Med Genet 2004;41:e41
54. Torroni A, Petrozzi M, L DU, et al. Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet 1997;60:1107-21
55. Howell N, Herrnstadt C, Shults C, et al. Low penetrance of the 14484 LHON mutation when it arises in a non-haplogroup J mtDNA background. Am J Med Genet A 2003;119:147-51
56. Vergani L, Martinuzzi A, Carelli V, et al. MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells. Biochem Biophys Res Commun 1995;210:880-8
57. Oostra RJ, Bolhuis PA, Wijburg FA, et al. Leber's hereditary optic neuropathy: correlations between mitochondrial genotype and visual outcome. J Med Genet 1994;31:280-6
58. Bu X, Rotter JI. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: evidence from segregation analysis for dependence on X chromosome inactivation. Proc Natl Acad Sci USA 1991;88:8198-202
59. 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
60. Nakamura M, Fujiwara Y, Yamamoto M. The two locus control of Leber hereditary optic neuropathy and a high penetrance in Japanese pedigrees. Hum Genet 1993;91:339-41
61. Chalmers RM, Davis RM, Sweeney MG, et al. Evidence against an X linked visual loss susceptibility locus in Leber hereditary optic neuropathy. Am J Hum Genet 1996;59(1):103-8
62. Sweeney MG, Davis MB, Lashwood A, et al. Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy. Am J Hum Genet 1992;51(4):741-8
63. Oostra RJ, Kemp S, Bolhuis PA, et al. No evidence for 'skewed' inactivation of the X-chromosome as cause of Leber's hereditary optic neuropathy in female carriers. Hum Genet 1996;97:500-5
64. Pegoraro E, Carelli V, Zeviani M, et al. X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant. Am J Med Genet 1996;61:356-62
65. Handoko HY, Wirapati PJ, Sudoyo HA, et al. Meiotic breakpoint mapping of a proposed X linked visual loss susceptibility locus in Leber's hereditary optic neuropathy. J Med Genet 1998;35:668-71
66. Hudson G, Keers S, Yu Wai Man P, et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am J Hum Genet 2005;77:1086-91
67. Shankar SP, Fingert JH, Carelli V, et al. Evidence for a novel x-linked modifier locus for Leber hereditary optic neuropathy. Ophthalmic Genet 2008;29:17-24
68. Sadun AA, Carelli V, Salomao SR, et al. Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy. Am J Ophthalmol 2003;136:231-8
69. Tsao K, Aitken PA, Johns DR. Smoking as an aetiological factor in a pedigree with Leber's hereditary optic neuropathy. Br J Ophthalmol 1999;83:577-81
70. Isashiki Y, Tabata Y, Kamimura K, et al. Genotypes of aldehyde dehydrogenase and alcohol dehydrogenase polymorphisms in patients with Leber's hereditary optic neuropathy. Jpn J Hum Genet 1997;42:187-91
71. Kerrison JB, Miller NR, Hsu F, et al. A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol 2000;130:803-12
72. Newman JM, Lott MT, Wallace DC. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 17778 mutation. Am J Ophthalmol 1991;111:750-62
73. Nikoskelanien EK, Huoponen K, Juvonen V, et al. Ophthalmic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations. Ophthalmology 1996;103:504-14
74. Howell N. Leber Hereditrary Optic Neruopathy: mitochondrial mutations and degenration of the optic nerve. Vision Res 1997;37:3495-507
75. Stone EM, Newman NJ, Miller NR, et al. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuroophthalmol 1992;12:12-4
76. Mackey DA, Howell N. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet 1992;51:1218-28
77. Flanigan KM, Johns DR. Association of the 11778 mitochondrial DNA mutation and demyelinating disease. Neurology 1993;43:2720-2
78. Nikoskelainen EK, Savontaus ML, Huoponen K, et al. Pre-excitation syndrome in Leber's hereditary optic neuropathy. Lancet 1994;344:857-8
79. McFarland R, Chinnery PF, Blakely EL, et al. Homoplasmy, heteroplasmy, and mitochondrial dystonia. Neurology 2007;69:911-6
80. Ortiz RC, Newman NJ, Manoukian S, et al. Optic disk cupping and electro-cardiographic abnormalities in an American pedigree with Leber's hereditary optic neuropathy. Am J Ophthalmol 1992;113:561-6
81. Funakawa I, Kato H, Terao A, et al. Cerebellar ataxia in patients with Leber's hereditary optic neuropathy. J Neurol 1995;242:75-7
82. Nikoskelainen EK, Marttila RJ, Huoponen K, et al. Leber's "plus": Neurologic abnormalities in patients with Leber's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 1995;59:160-4
83. Van Senus AHC. Leber's disease in the Netherlands. Doc Ophthalmol 1963;17:1-163
84. Wilson J. Leber's hereditary optic atrophy-some clinical and etiological considerations. Brain 1963;86:347-62
85. Chalmers RM, Harding AE. A case control study of Leber's hereditary optic neuropathy. Brain 1996;119:1481-6
86. Howell N, MacKey DA. Low-penetrance branches in matrilineal pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 1998;63:1220-4
87. Chinnery PF, Andrews RM, Turnbull DM, et al. Leber hereditary optic neuropathy: Does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Hum Genet 2001;98:235-43
88. Sadun AA, Carelli V, Salomao SR, et al. A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy. Tram Am Ophthalmol Soc 2002;100:169-78; discussion 178-9
89. Hudson G, Carelli V, Spruijt L, 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
90. de Gottrau P, Buchi ER, Daicker B. Distended optic nerve sheaths in Leber's hereditary optic neuropathy. J Clin Neuroophthalmol 1992;12:89-93
91. Inglese M, Rovaris M, Bianchi S, et al. Magnetization transfer and diffusion tensor MR imaging of the optic radiations and calcarine cortex from patients with Leber's hereditary optic neuropathy. J Neurol Sci 2001;188:33-6
92. Inglese M, Rovaris M, Bianchi S, et al. Magnetic resonance imaging, magnetisation transfer imaging, and diffusion weighted imaging correlates of optic nerve, brain, and cervical cord damage in Leher's hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2001;70:444-9
93. Smith JL, Tse DT, Byrne SF, et al. Optic nerve sheath distention in Leber's optic neuropathy and the significance of the "Wallace mutation". J Clin Neuroophthalmol 1990;10:231-8
94. Vaphiades MS, Newman NJ. Optic nerve enhancement on orbital magnetic resonance imaging in Leber's hereditary optic neuropathy. J Neuroophthalmol 1999;19:238-9
95. Howell N, Kubacka I, Halvorson S, et al. Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees. Genetics 1995;140:285-302
96. Blakely EL, de Silva R, King A, et al. LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet 2005;13:623-7
97. Mashima Y, Kigasawa K, Wakakura M, 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
98. Leber Hereditary Optic Neuropathy Idebenone Trial. Available from: http://lhon.ncl.ac.uk
99. Therapeutic trial of Idebenone in LHON. Available from: http://www.lhon.de/
100. Nikoskelainen EK. Clinical picture of LHON. Clin Neurosci 1994;2:115-20
101. Newman NJ, Biousse V, David R, et al. Prophylaxis for second eye involvement in Leber hereditary optic neuropathy: an open-labeled, nonrandomized multicenter trial of topical brimonidine purite. Am J Ophthalmol 2005;140:407-15
102. 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
103. Kim JY, Hwang JM, Park SS. Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber's hereditary optic neuropathy with a good prognosis. Ann Neurol 2002;51:630-4
104. De Vries DD, Went LN, Bruyn GW, et al. Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 1996;58:703-11
105. Leo-Kottler B, Luberichs J, Besch D, et al. 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 2002;240:758-64
106. Brown MD, Starikovskaya E, Derbeneva O, et al. The role of mtDNA background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup. J Hum Genet 2002;110:130-8
107. Mayorov V, Biousse V, Newman NJ, et al. The role of the ND5 gene in LHON: characterization of a new, heteroplasmic LHON mutation. Ann Neurol 2005;58:807-11
108. 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
109. Besch D, Leo-Kottler B, Zrenner E, et al. Leber's hereditary optic neuropathy: clinical and molecular genetic findings in a patient with a new mutation in the ND6 gene. Graefes Arch Clin Exp Ophthalmol 1999;237:745-52
110. 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 Nat Acad Sci 1994;91:6206-10
111. Howell N, Bogolin C, Jamieson R, et al. mtDNA mutations that cause optic neuropathy: how do we know? Am J Hum Genet 1998;62:196-202
112. Chinnery PF, Brown DT, Andrews RM, et al. The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy. Brain 2001;124:209-18
113. 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