Leber's Hereditary Optic Neuropathy Patients Research Articles

Analysis of Wallace mutation in patients with Leber's hereditary optic neuropathy: familial study and tissue distribution

Leber's hereditary optic neuropathy (LHON) is a disorder considered to be due to a mutation in the mitochondrial DNA (mtDNA). The authors analyzed the mtDNA genotype of peripheral blood leukocytes from two family members with LHON, and further analyzed mtDNA in various tissues originating from the separate germ layers (skin, hair, leukocyte, muscle, arachnoid, CSF cells, and buccal mucosa) in two LHON patients. A G-to-A transition of mtDNA np 11778 (Wallace mutation) was detected by the elimination of a SfaN I site and the acquisition of a Maelll site in all individuals and tissues examined.

Antibodies to human optic nerve in Leber's hereditary optic neuropathy

Mutations of mitochondrial DNA have now been identified in the majority of patients with Leber's hereditary optic neuropathy (LHON). However, these mutations do not explain all the clinical features of LHON, and other pathogenetic factors are likely to be operating. We have analysed serum from 69 LHON patients and their relatives, 58 controls and 14 patients with ischemic or compressive optic neuropathy. A significant proportion of LHON patients had circulating antibodies to tubulin protein. This finding supports the theory that autoimmunity may play some role in the pathogenesis of LHON.

Phylogenetic analysis of the mitochondrial genomes from Leber hereditary optic neuropathy pedigrees.

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well-supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.

MtDNA Mutations Associated with Leber′s Hereditary Optic Neuropathy: Studies on Cytoplasmic Hybrid (Cybrid) Cells

Leber′s hereditary optic neuropathy (LHON) has been associated with "primary" and "secondary" mtDNA missense point mutations, and a synergistic role has been proposed for secondary mutations. No previous study has investigated the effects of LHON primary or primary plus secondary mutations on the respiratory competence of cell lines. We constructed and compared cybrid cell lines obtained from two unrelated LHON patients both carrying the common 11778/ND4 primary mutation. One of the patients also carried the 13708/ND5 and 4216/ND1 secondary mutations. The cybrid clones were evaluated for growth efficiency, oxygen consumption, complexes I, III and IV enzymatic activity and mitochondrial protein synthesis. Complex activity and mitochondrial protein synthesis were not significantly changed in cybrid clones from the patients. Oxygen consumption was significantly decreased in all clones carrying the 11778/ND4 primary mutation demonstrating its pathogenic role in impairing cell respiration. Clones also carrying the secondary mutations showed an even lower oxygen consumption and a significantly higher doubling time, suggesting that the co-presence of the secondary mutations could be relevant in further reducing the cell fitness.

Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations.

The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778-positive and 30 Caucasian 11778-negative Leber's hereditary optic neuropathy (LHON) patients were PCR-amplified and subjected to high resolution restriction endonuclease analysis. Concurrently, all patient mtDNAs were screened for the common primary LHON mtDNA mutations at nucleotide pairs (nps) 3460, 11778, and 14484, the ambiguous intermediate-risk LHON mtDNA mutations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysis was performed using mtDNA haplotype data from the 47 LHON patients and 175 non-LHON Caucasian controls. The superimposition of the LHON mutation screening results upon the Caucasian mtDNA phylogeny revealed (1) 35 different LHON haplotypes, (2) that all three common primary mutations have occurred multiple times in Caucasians, (3) that while recurrent mutation is common for the primary mutations, secondary mutations tend to be lineage-specific, (4) that the np 15257 mutation was confined to a single mtDNA lineage but may be etiologically important in some LHON cases since it was found in a LHON pedigree which lacked a common primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) that the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a single mtDNA lineage and almost always in association with secondary LHON mutations. A phylogenetic approach to this genetically heterogeneous disease has thus provided key genetic data bearing on the relative pathogenicity of the LHON-associated mtDNA mutations.

Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH: ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH: ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.

Pre-excitation syndrome in Leber's hereditary optic neuropathy

Pre-excitation syndrome is common in families with Leber's hereditary optic neuropathy (LHON). 24 Finnish families with LHON were screened for the 11778 and the 3460 mitochondrial DNA mutations. 5 of 30 individuals with LHON and the 11778 mutation had the Wolff-Parkinson- White pre-excitation syndrome. None of 10 with the 3460 mutation or of 11 with “other” mutations had this syndrome. Overall, 5 of 51 LHON patients and 9 of 112 symptom-free maternal relatives had Wolff-Parkinson-White syndrome (9%). In paternal relatives, the frequency was 1·6%. Mitochondrial DNA causal for LHON may contribute to pre-excitation syndrome. Lancet 1994; 344: 857–58

Leber's hereditary optic neuropathy

Three siblings of a family affected with Leber's hereditary optic neuropathy (LHON) showed a mitochondrial DNA mutation at position 11778. The lactate response to a standardized effort was increased in only one case. Muscle biopsies and biochemistry of muscle and platelet mitochondrial enzymes were normal. All patients showed an altered energy metabolism during exercise and during recovery after exercise on phosphorus 31-magnetic resonance spectroscopy (31P-MRS) of muscle. Brain 31P-MRS showed a decreased energy reserve (decreased PCr/Pi ratio) in all patients. 31P-MRS noninvasively demonstrated an altered mitochondrial energy metabolism in muscle and, for the first time, in the brains of LHON patients.

A mutation of mitochondrial DNA in Japanese families with Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by optic nerve degeneration associated with severe bilateral visual loss in young men and occasionally in women. A mitochondrial DNA (mtDNA) replacement mutation in LHON patient, G to A transition at nucleotide position (nt) 11778 converting the 340th arginine to histidine in the NADH dehydrogenase subunit 4, was detected as SfaNI site polymorphism (Wallace et al., Science, 242: 1427-1430, 1988). To evaluate if the SfaNI site loss can be used to diagnose LHON patients, mtDNAs from peripheral blood of six affected males including five probands from five unrelated Japanese families with LHON, a pair of parents and a normal sister of one of the probands and 4 control persons were analyzed using PCR amplification method. The mutation of leukocyte mtDNA at nt 11778 was identified in all of the affected patients, the normal mother and the sister examined, while the father who is normal and 4 control persons did not show the change. These findings support that the mutation at nt 11778 is also associated with LHON in the Japanese and the test of the SfaNI site loss described here is useful for confirming the clinical diagnosis of LHON patients with the mutation at nt 11778.