Skip to main content
SpringerLink
Log in

Leber Hereditary Optic Neuropathy: How Do Mitochondrial DNA Mutations Cause Degeneration of the Optic Nerve?

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary—but not sufficient—for development of the optic neuropathy, and secondary genetic and/or epigenetic risk factors must also be present although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11778, and 14484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangements may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of the optic neuropathy may arise from a “chokepoint” in the optic nerve in the region of the nerve head and lamina cribosa, and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Ames, A., III, Li, Y.-Y, Heher, E. C., and Kimble, C. R. (1992). “Energy metabolism of rabbit retina as related to function: high cost of Na+ transport,” J. Neurosci. 12, 840–853.

    Google Scholar 

  • Beal, M. F. (1995). “Aging, energy, and oxidative stress in neurode-generative diseases,” Ann. Neurol. 38, 357–366.

    Google Scholar 

  • Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I., and Wallace, D. C. (1992). “Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases,” FASEB J. 6, 2791–2799.

    Google Scholar 

  • Brown, M. D., and Wallace, D. C. (1994). “Spectrum of mitochondrial DNA mutations in Leber's hereditary optic neuropathy,” Clin. Neurosci. 2, 138–145.

    Google Scholar 

  • Brown, M. D., Torroni, A., Reckord, C. L., and Wallace, D. C. (1995). “Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations,” Hum. Mutat. 6, 311–325.

    Google Scholar 

  • Burde, R. M. (1993). “Optic disk risk factors for nonarteritic anterior ischemic optic neuropathy,” Am. J. Ophthalmol. 116, 759–764.

    Google Scholar 

  • Chalmers, R. M., and Harding, A. E. (1996). “A case-control study of Leber's hereditary optic neuropathy,” Brain 119, 1481–1486.

    Google Scholar 

  • Cock, H. R., Cooper, J. M., and Schapira, A. H. V. (1995). “The 14484 ND6 mtDNA mutation in Leber hereditary optic neuropathy does not affect fibroblast complex I activity,” Am. J. Hum. Genet. 57, 1501–1502.

    Google Scholar 

  • De Vries, D. D., Went, L. N., Bruyn, G. W., Scholte, H. R., Hofstra, R. M. W., Bolhuis, P. A., and van Oost, B. A. (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, 703–711.

    Google Scholar 

  • Fechtner, R. D., and Weinreb, R. N. (1994). “Mechanisms of optic nerve damage in primary open angle glaucoma,” Surv. Ophthalmol. 39, 23–42.

    Google Scholar 

  • Flanigan, K. M., and Johns, D. R. (1993). “Association of the 11778 mitochondrial DNA mutation and demyelinating disease,” Neurology 43, 2720–2722.

    Google Scholar 

  • Gao, H., and Hollyfield, J. G. (1992). “Aging and the human retina. Differential loss of neurons and retinal pigment epithelial cells,” Invest. Ophthalmol. Vis. Sci. 33, 1–17.

    Google Scholar 

  • Ghosh, S. S., Fahy, E., Bodis-Wollner, I., Sherman, J., and Howell, N. (1996). “Longitudinal study of a heteroplasmic 3460 Leber hereditary optic neuropathy family by multiplexed primer-extension analysis and nucleotide sequencing,” Am. J. Hum. Genet. 58, 325–334.

    Google Scholar 

  • Harding, A. E., Sweeney, M. G., Miller, D. H., Mumford, C. J., Kellar-Wood, H., Menard, D., McDonald, W. I., and Compston, D. A. S. (1992). “Occurrence of a multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation.” Brain 115, 979–989.

    Google Scholar 

  • Hofhaus, G., Johns, D. R., Hurko, O., Attardi, G., and Chomyn, A. (1996). “Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy,” J. Biol. Chem. 271, 13155–13161.

    Google Scholar 

  • Hollander, H., Makarov, F., Stefani, F. H., and Stone, J. (1995). “Evidence of constriction of optic nerve axons at the lamina cribosa in the normotensive eye in humans and other mammals,” Ophthalmic Res. 27, 296–309.

    Google Scholar 

  • Howell, N. (1994a). “Mitochondrial gene mutations and human diseases: a prolegomenon,” Am. J. Hum. Genet. 55, 219–224.

    Google Scholar 

  • Howell, N. (1994b). “Primary LHON mutations: trying to separate “fruyt” from “chaf,” Clin. Neurosci. 2, 130–137.

    Google Scholar 

  • Howell, N. (1997). “Leber hereditary optic neuropathy: mitochondrial mutations and degeneration of the optic nerve,” Vision Res., in press.

  • Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., and Turnbull, D. M. (1991). “Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees,” Am. J. Hum. Genet. 49, 939–950.

    Google Scholar 

  • Howell, N., Kubacka, I., Halvorson, S., and Mackey, D. (1993a). “Leber's hereditary optic neuropathy: the etiological role of a mutation in the mitochondrial cytochrome b gene,” Genetics 133, 133–136.

    Google Scholar 

  • Howell, N., Halvorson, S., Burns, J., McCullough, D. A., and Poulton, J. (1993b). “When does bilateral optic atrophy become Leber hereditary optic neuropathy?” Am. J. Hum. Genet. 53, 959–963.

    Google Scholar 

  • Howell, N., Kubacka, I., Halvorson, S., Howell, B., McCullough, D. A., and Mackey, D. (1995). “Phylogenetic analysis of mitochondrial genomes from Leber hereditary optic neuropathy pedigrees,” Genetics 140, 285–302.

    Google Scholar 

  • Johns, D. R. (1994). “Genotype-specific phenotypes in Leber's hereditary optic neuropathy,” Clin. Neurosci. 2, 146–150.

    Google Scholar 

  • Johns, D. R., and Berman, J. (1991). “Alternative simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy,” Biochem. Biophys. Res. Commun. 174, 1324–1330.

    Google Scholar 

  • Johns, D. R., Heher, K. L., Miller, N. R., and Smith, K. H. (1993). “Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation,” Arch. Ophthalmol. 111, 495–498.

    Google Scholar 

  • Jun, A. S., Trounce, I. A., Brown, M. D., Shoffner, J. M., and Wallace, D. C. (1996). “Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia,” Mol. Cell. Biol. 16, 771–777.

    Google Scholar 

  • Juvonen, V., Vilkki, J., Aula, P., Nikoskelainen, E., and Savontaus, M.-L. (1993). “Reevaluation of the linkage of an optic atrophy susceptibility gene to X-chromosomal markers in Finnish families with Leber hereditary optic neuroretinopathy (LHON),” Am. J. Hum. Genet. 53, 289–292.

    Google Scholar 

  • Kageyama, G. H., and Wong-Riley, M. T. T. (1984). “The histochemical localization of cytochrome oxidase in the retina and lateral geniculate nucleus of the ferret, cat, and monkey, with particular reference to retinal mosaics and on/off-center visual channels,” J. Neurosci. 4, 2445–2459.

    Google Scholar 

  • Larsson, N. G., Andersen, O., Holme, E., Oldfors, A., and Wahlstrom, J. (1991). “Leber's hereditary optic neuropathy and complex I deficiency in muscle,” Ann. Neurol. 30, 701–708.

    Google Scholar 

  • Leber, T. (1871). “Uber hereditare und congenital-angelegte Sehner-venleiden,” Graefe's Arch. Ophthalmol. 17, 249–291.

    Google Scholar 

  • Leo-Kottler, B., Christ-Adler, M., Baumann, B., Zrenner, E., and Wissinger, B. (1996). “Leber's hereditary optic neuropathy: clinical and molecular genetic results obtained in a family with a new point mutation at nucleotide position 14498 in the ND6 gene,” German J. Ophthalmol. 5, 233–240.

    Google Scholar 

  • Lowry, O., Roberts, N. R., and Lewis, C. (1956). “The quantitative histochemistry of the retina,” J. Biol. Chem. 220, 879–892.

    Google Scholar 

  • Mackey, D. A., and Howell, N. (1992). “A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology,” Am. J. Hum. Genet. 51, 1218–1228.

    Google Scholar 

  • Mackey, D. A., Oostra, R.-J., Rosenberg, T., Nikoskelainen, E., Bronte-Stewart, J., Poulton, J., Harding, A. E., Govan, G., Bolhuis, P. A., Norby, S., Bleeker-Wagemakers, E. M., Savontaus, M.-L., Chan, C., and Howell, N. (1996). “Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy,” Am. J. Hum. Genet. 59, 481–485.

    Google Scholar 

  • Majander, A., Huoponen, K., Savontaus, M.-L., Nikoskelainen, E., and Wikstrom, M. (1991). “Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and ND4/1178 mutations of the Leber hereditary optic neuroretinopathy (LHON),” FEBS Lett. 292, 289–292.

    Google Scholar 

  • Nikoskelainen, E. K. (1994). “Clinical picture of LHON,” Clin. Neurosci. 2, 115–120.

    Google Scholar 

  • Nikoskelainen, E. K., Marttila, R. J., Huoponen, K., Juvonen, V., Lamminen, T., Sonninen, P., and Savontaus, M.-L. (1995). “Leber's ‘plus’: neurological abnormalities in patients with Leber's hereditary optic neuropathy,” J. Neurol. Neurosurg. Psychiat. 59, 160–164.

    Google Scholar 

  • Nikoskelainen, E. K., Huoponen, K., Juvonen, V., Lamminen, T., Nummelin, K., and Savontaus, M.-L. (1996). “Ophthalmologic findings in Leber hereditary optic neuropathy, with special reference to mtDNA mutations,” Ophthalmology 103, 504–514.

    Google Scholar 

  • Oostra, R. J., Bolhuis, P. A., Wijburg, F. A., Zom-Ende, G., and Bleeker-Wagemakers, E. M. (1994). “Leber's hereditary optic neuropathy: correlations between mitochondrial genotype and visual outcome.” J. Med. Genet. 31, 280–286.

    Google Scholar 

  • Oostra, R. J., Van Galen, M. J. M. Bolhuis, P. A., Bleeker-Wagemakers, E. M., and Van den Bogert, C. (1995). “The mitochondrial DNA mutation ND6*14,484C associated with Leber hereditary optic neuropathy leads to deficiency of complex I of the respiratory chain,” Biochem. Biophys. Res. Commun. 215, 1001–1005.

    Google Scholar 

  • Parker, W. D., Jr., Oley, C. A., and Parks, J. K. (1989). “A defect in mitochondrial electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber's hereditary optic neuropathy,” New Eng. J. Med. 320, 1331–1333.

    Google Scholar 

  • Pegoraro, E., Carelli, V., Zeviani, M., Cortelli, P., Montagna, P., Barboni, P., Angelini, C., and Hoffman, E. P. (1996). “X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant,” Am. J. Med. Genet. 61, 356–362.

    Google Scholar 

  • Riordan-Eva, P., Sanders, M. D., Govan, G. G., Sweeney, M. G., Da Costa, J., and Harding, A. E. (1995). “The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation,” Brain 118, 319–338.

    Google Scholar 

  • Rizzo, J. F., III. (1995). “Adenosine triphosphate deficiency: a genre of optic neuropathy,” Neurology 45, 11–16.

    Google Scholar 

  • Rungger-Brandle, E., Kolb, H., and Niemeyer, G. (1996). “Histochemical demonstration of glycogen in neurons of the cat retina,” Invest. Ophthalmol. Vis. Sci. 37, 702–715.

    Google Scholar 

  • Sadun, A. A., and Dao, J. (1994). “Annual review in neuro-ophthalmology. The anterior visual pathways,” J. Neuro-ophthalmol 14, 141–154.

    Google Scholar 

  • Sherman, J., and Kleiner, L. (1994). “Visual system dysfunction in Leber's hereditary optic neuropathy,” Clin. Neurosci. 2, 121–129.

    Google Scholar 

  • Shoffner, J. M., Brown, M. D., Stugard, C., Jun, A. S., Pollock, S., Haas, R. H., Kaufman, A., Koontz, D., Kim, Y., Graham, J. R., Smith, E., Dixon, J., and Wallace, D. C. (1995). “Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation,” Ann. Neurol. 38, 163–169.

    Google Scholar 

  • Smith, P. R., Cooper, J. M., Govan, G. G., Harding, A. E., and Schapira, A. H. V. (1994). “Platelet mitochondrial function in Leber's hereditary optic neuropathy,” J. Neurol. Sci. 122, 80–83.

    Google Scholar 

  • Smith, P. R., Cooper, J. M., Govan, G. G., Riordan-Eva, P., Harding, A. E., and Schapira, A. H. V. (1995). “Antibodies to human optic nerve in Leber's hereditary optic neuropathy,” J. Neurol. Sci. 130, 134–138.

    Google Scholar 

  • Torroni, A., Carelli, V., Petrozzi, M., Terracina, M., Barboni, P., Malpassi, P., Wallace, D. C., and Scozzari, R. (1996). “Detection of the mtDNA 14484 mutation on an African-specific haplotype: implications about its role in causing Leber hereditary optic neuropathy,” Am. J. Hum. Genet. 59, 248–252.

    Google Scholar 

  • Vergani, L., Martinuzzi, A., Carelli, V., Cortelli, P., Montagna, P., Schievano, G., Carrozzo, R., Angelini, C., and Lugaresi, E. (1995). “MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells,” Biochem. Biophys. Res. Commun. 210, 880–888.

    Google Scholar 

  • Vilkki, J., Ott, J., Savontaus, M.-L., Aula, P., and Nikoskelainen, E. K. (1991). “Optic atrophy Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7,” Am. J. Hum. Genet. 48, 486–491.

    Google Scholar 

  • Wakakura, M., and Yokoe, J. (1995). “Evidence for preserved direct pupillary light response in Leber's hereditary optic neuropathy,” Br. J. Ophthalmol. 79, 442–446.

    Google Scholar 

  • Wallace, D. C. (1970). “A new manifestation of Leber's disease and a new explanation for the agency responsible for its unusual pattern of inheritance,” Brain 93, 121–132.

    Google Scholar 

  • Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. S., Elsas, L. J., and Nikoskelainen, E. (1988). “Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy,” Science 242, 1427–1430.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, Texas, 77555

    Neil Howell

Authors
  1. Neil Howell
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Howell, N. Leber Hereditary Optic Neuropathy: How Do Mitochondrial DNA Mutations Cause Degeneration of the Optic Nerve?. J Bioenerg Biomembr 29, 165–173 (1997). https://doi.org/10.1023/A:1022690030664

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022690030664

Search

Navigation