Skip to main content
NCBI home page
Transactions of the American Ophthalmological Society logoLink to Transactions of the American Ophthalmological Society
. 2002;100:169–179.

A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy.

Alfredo A Sadun 1, Valerio Carelli 1, Solange R Salomao 1, Adriana Berezovsky 1, Peter Quiros 1, Federico Sadun 1, Anna-Maria DeNegri 1, Rafael Andrade 1, Stan Schein 1, Rubens Belfort 1
PMCID: PMC1358960  PMID: 12545691

Abstract

PURPOSE: We conducted extensive epidemiological, neuro-ophthalmological, psychophysical, and blood examinations on a newly discovered, very large pedigree with molecular analysis showing mtDNA mutation for Leber's hereditary optic neuropathy (LHON). METHODS: Four patients representing four index cases from a remote area of Brazil were sent to Sao Paulo, where complete ophthalmological examinations strongly suggested LHON. Molecular analysis of their blood demonstrated that they were LHON, homoplasmic 11778, J-haplogroup. They had an extensive family that all lived in one rural area in Brazil. To investigate this family, we drew on a number of international experts to form a team that traveled to Brazil. This field team also included several members of the Federal University of Sao Paulo, and together we evaluated 273 of the 295 family members that were still alive. We conducted epidemiological interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmological examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for both mitochondrial genetic analysis and nuclear gene linkage analysis. RESULTS: The person representing the first-generation case immigrated from Verona, Italy, to Colatina. Subsequent generations demonstrated penetrance rates of 71%, 60%, 34%, 15%, and 9%. The percentages of males were 60%, 50%, 64%, 100%, and 100%. Age at onset varied from 10 to 64 years, and current visual acuities varied from LP to 20/400. CONCLUSIONS: Almost 95% of a nearly 300-member pedigree with LHON 11778 were comprehensively studied. Analysis of environmental risk factors and a nuclear modifying factor from this group may help address the perplexing mystery of LHON: Why do only some of the genetically affected individuals manifest the disease? This fully described database may also provide an excellent opportunity for future clinical trials of any purported neuroprotective agent.

Full Text

The Full Text of this article is available as a PDF (210.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barrientos A., Moraes C. T. Titrating the effects of mitochondrial complex I impairment in the cell physiology. J Biol Chem. 1999 Jun 4;274(23):16188–16197. doi: 10.1074/jbc.274.23.16188. [DOI] [PubMed] [Google Scholar]
  2. Brown M. D., Trounce I. A., Jun A. S., Allen J. C., Wallace D. C. 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 Dec 22;275(51):39831–39836. doi: 10.1074/jbc.M006476200. [DOI] [PubMed] [Google Scholar]
  3. Carelli V., Ghelli A., Bucchi L., Montagna P., De Negri A., Leuzzi V., Carducci C., Lenaz G., Lugaresi E., Degli Esposti M. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. Ann Neurol. 1999 Mar;45(3):320–328. [PubMed] [Google Scholar]
  4. Carelli V., Ghelli A., Ratta M., Bacchilega E., Sangiorgi S., Mancini R., Leuzzi V., Cortelli P., Montagna P., Lugaresi E. Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Neurology. 1997 Jun;48(6):1623–1632. doi: 10.1212/wnl.48.6.1623. [DOI] [PubMed] [Google Scholar]
  5. Carelli Valerio, Ross-Cisneros Fred N., Sadun Alfredo A. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002 May;40(6):573–584. doi: 10.1016/s0197-0186(01)00129-2. [DOI] [PubMed] [Google Scholar]
  6. Chalmers R. M., Schapira A. H. Clinical, biochemical and molecular genetic features of Leber's hereditary optic neuropathy. Biochim Biophys Acta. 1999 Feb 9;1410(2):147–158. doi: 10.1016/s0005-2728(98)00163-7. [DOI] [PubMed] [Google Scholar]
  7. Charlmers R. M., Harding A. E. A case-control study of Leber's hereditary optic neuropathy. Brain. 1996 Oct;119(Pt 5):1481–1486. doi: 10.1093/brain/119.5.1481. [DOI] [PubMed] [Google Scholar]
  8. Danielson Steven R., Wong Alice, Carelli Valerio, Martinuzzi Andrea, Schapira Anthony H. V., Cortopassi Gino A. Cells bearing mutations causing Leber's hereditary optic neuropathy are sensitized to Fas-Induced apoptosis. J Biol Chem. 2001 Dec 11;277(8):5810–5815. doi: 10.1074/jbc.M110119200. [DOI] [PubMed] [Google Scholar]
  9. Funakawa I., Kato H., Terao A., Ichihashi K., Kawashima S., Hayashi T., Mitani K., Miyazaki S. Cerebellar ataxia in patients with Leber's hereditary optic neuropathy. J Neurol. 1995 Jan;242(2):75–77. doi: 10.1007/BF00887819. [DOI] [PubMed] [Google Scholar]
  10. Howell N., Bindoff L. A., McCullough D. A., Kubacka I., Poulton J., Mackey D., Taylor L., Turnbull D. M. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet. 1991 Nov;49(5):939–950. [PMC free article] [PubMed] [Google Scholar]
  11. Howell N. Human mitochondrial diseases: answering questions and questioning answers. Int Rev Cytol. 1999;186:49–116. doi: 10.1016/s0074-7696(08)61051-7. [DOI] [PubMed] [Google Scholar]
  12. Huoponen K., Vilkki J., Aula P., Nikoskelainen E. K., Savontaus M. L. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1991 Jun;48(6):1147–1153. [PMC free article] [PubMed] [Google Scholar]
  13. Johns D. R., Neufeld M. J., Park R. D. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1551–1557. doi: 10.1016/0006-291x(92)90479-5. [DOI] [PubMed] [Google Scholar]
  14. Kerrison J. B., Howell N., Miller N. R., Hirst L., Green W. R. Leber hereditary optic neuropathy. Electron microscopy and molecular genetic analysis of a case. Ophthalmology. 1995 Oct;102(10):1509–1516. doi: 10.1016/s0161-6420(95)30838-x. [DOI] [PubMed] [Google Scholar]
  15. Kerrison J. B., Miller N. R., Hsu F., Beaty T. H., Maumenee I. H., Smith K. H., Savino P. J., Stone E. M., Newman N. J. A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy. Am J Ophthalmol. 2000 Dec;130(6):803–812. doi: 10.1016/s0002-9394(00)00603-6. [DOI] [PubMed] [Google Scholar]
  16. Klivenyi P., Karg E., Rozsa C., Horvath R., Komoly S., Nemeth I., Turi S., Vecsei L. 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 Mar;70(3):359–362. doi: 10.1136/jnnp.70.3.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mackey D., 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 Dec;51(6):1218–1228. [PMC free article] [PubMed] [Google Scholar]
  18. Murakami T., Mita S., Tokunaga M., Maeda H., Ueyama H., Kumamoto T., Uchino M., Ando M. Hereditary cerebellar ataxia with Leber's hereditary optic neuropathy mitochondrial DNA 11778 mutation. J Neurol Sci. 1996 Oct;142(1-2):111–113. doi: 10.1016/0022-510x(96)00165-7. [DOI] [PubMed] [Google Scholar]
  19. Sadun A. A. Mitochondrial optic neuropathies. J Neurol Neurosurg Psychiatry. 2002 Apr;72(4):423–425. doi: 10.1136/jnnp.72.4.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sadun A. A., Win P. H., Ross-Cisneros F. N., Walker S. O., Carelli V. Leber's hereditary optic neuropathy differentially affects smaller axons in the optic nerve. Trans Am Ophthalmol Soc. 2000;98:223–235. [PMC free article] [PubMed] [Google Scholar]
  21. Sadun A. Acquired mitochondrial impairment as a cause of optic nerve disease. Trans Am Ophthalmol Soc. 1998;96:881–923. [PMC free article] [PubMed] [Google Scholar]
  22. Simon D. K., Pulst S. M., Sutton J. P., Browne S. E., Beal M. F., Johns D. R. Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation. Neurology. 1999 Nov 10;53(8):1787–1793. doi: 10.1212/wnl.53.8.1787. [DOI] [PubMed] [Google Scholar]
  23. Wallace D. C., Singh G., Lott M. T., Hodge J. A., Schurr T. G., Lezza A. M., Elsas L. J., 2nd, Nikoskelainen E. K. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427–1430. doi: 10.1126/science.3201231. [DOI] [PubMed] [Google Scholar]
  24. Wong A., Cortopassi G. mtDNA mutations confer cellular sensitivity to oxidant stress that is partially rescued by calcium depletion and cyclosporin A. Biochem Biophys Res Commun. 1997 Oct 9;239(1):139–145. doi: 10.1006/bbrc.1997.7443. [DOI] [PubMed] [Google Scholar]

Articles from Transactions of the American Ophthalmological Society are provided here courtesy of American Ophthalmological Society

RESOURCES