Leber Optic Atrophy, Susceptibility To

In 95% of cases worldwide, Leber hereditary optic atrophy (LHON) is due to 1 of 3 point mutations of mitochondrial DNA in genes that code for complex I of the respiratory chain: 3460G-A in MTND1 (516000.0001), 11778G-A in MTND4 (516003.0001), and 14484T-C in MTND6 (516006.0001). That only approximately 50% of male and 10% of female mutation carriers develop symptoms (Newman, 2002) indicates a requirement for additional genetic or environmental factors for phenotypic expression of LHON. Epidemiologic studies failed to substantiate anecdotal reports of a link with excess alcohol and tobacco (Kerrison et al., 2000).

Bu and Rotter (1991) concluded that available pedigree data on LHON are most consistent with a 2-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. They demonstrated that a proportion of affected females are probably heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female was 0.11 +/- 0.02. The calculated frequency of the X chromosome-linked gene for LHON was 0.08. Among affected females, 60% are expected to be heterozygous and the remainder are expected to be homozygous at the responsible X chromosome-linked locus.

Sweeney et al. (1992) presented evidence against an X-linked susceptibility locus near DXS7: linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately, excluded the presence of such a locus from an interval of about 30 cM around DXS7, with a total lod score of -26.51 at a recombination fraction of 0.0. Assuming that the optic tissue is the primary site of action of the mutant gene(s), Bu and Rotter (1992) further proposed that there should be no fewer than 6 embryonic precursor cells for the involved optic tissue at the stage in early development when X-chromosome inactivation occurs. They also estimated that the disease threshold (i.e., proportion of cells with abnormal X chromosome active in the responsible tissue at the time of X-chromosome inactivation) for a heterozygous female is in the range of 0.60 to 0.83.

On the basis of families with Leber optic atrophy observed in Australia, Mackey (1993) analyzed the frequency of blindness in the offspring of affected blind women. The frequency of blindness in women was much too high if the susceptibility gene on the X chromosome is dominant. Furthermore, since most of the blind females would be heterozygous, half of their sons and half of their daughters should be blind, also far from the observed figures. If recessive, blindness in women would be predicted to be almost exactly what is observed to be the case in LHON families. However, recessive inheritance of susceptibility would predict that all sons and no daughters of blind females would be affected, also far from the observed figures. On the basis of this analysis, Mackey (1993) concluded that it is unlikely that an X-linked factor is involved in the expression of LHON; some other sex-variable factor must be involved.

Nakamura et al. (1993) pursued the 2-locus mitochondrial and X-linked nuclear gene model for Leber optic atrophy, which proposes that an affected female is either a homozygote at the X-linked locus or a heterozygote with biased inactivation of a normal allele on an X chromosome. In Japanese families, Nakamura et al. (1993) found an excellent fit for the predicted 1:1 segregation of a putative X-linked gene. When male sibship data with a presumed heterozygous mother from maternal lines was investigated, the calculated frequency of the X-linked gene was 0.10, which may not be different from that estimated in Caucasians, 0.08. On the other hand, the estimated penetrance for a heterozygous female was about twice as high in the Japanese (0.196) as in Caucasians (0.111). In Japanese LHON pedigrees, more females are affected than in Caucasian pedigrees. The mtDNA 11778 mutation (516003.0001) accounts for about 92% of Japanese cases but perhaps only 50 to 70% of Caucasian cases.

If a nuclear X-linked modifier gene influences the expression of the mitochondrial mutant gene responsible for LHON, then the affected females should be homozygous for the nuclear determinant or, if heterozygous, lyonization should favor the mutant X. With this in mind, Pegoraro et al. (1996) studied X-inactivation patterns in 35 females with known mitochondrial DNA mutations from 10 LHON pedigrees. The results did not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers.

Chalmers et al. (1996) presented evidence from linkage analysis in British and Italian families with genetically proven LHON that excluded the presence of an X-linked visual loss susceptibility locus (VLSL) involved in the pathogenesis of LHON. VLSL was excluded over 169 cM of the X chromosome when all families were analyzed together and when only families with the nucleotide 11778 mutation in the MTND4 gene (516003.0001) were studied. Furthermore, there was no excess skewing of X inactivation in affected females, a finding supported also by Oostra et al. (1996). Chalmers et al. (1996) found no evidence for close linkage to 3 markers in the pseudoautosomal region of the sex chromosomes. The authors concluded that the mechanism of incomplete penetrance and male predominance in LHON remained unclear.

According to the 2-locus model for LHON, females would be affected only if they were homozygous for the X-linked recessive susceptibility gene or had skewed X inactivation. Pegoraro et al. (2003) noted that previous attempts to localize the putative LHON-modifying gene by linkage analysis and to find an excess of skewed X inactivation in affected females had been unsuccessful, although the inactivation pattern had been studied only in DNA isolated from blood cells. They analyzed a wide range of tissues, including the optic nerves and the retina, at autopsy in 2 female LHON patients. They found no evidence of skewed X inactivation in the affected tissues, thus further weakening the hypothesized involvement of a specific X chromosome locus in the pathophysiologic expression of LHON. One patient was from an Italian pedigree and carried the MTND1 3460 mutation (516000.0001). The onset of optic neuropathy and an extrapyramidal syndrome occurred at 22 years of age, and she died at 75 years of age of heart failure after a 10-year course of progressive dementia. All tissues showed homoplasmic mutant mtDNA. The second patient was heteroplasmic for the MTND4 11778 mutation (516003.0001). This woman was affected with optic neuropathy at 38 years of age and died at 68 years of age of chronic obstructive pulmonary disease.

Large multigenerational pedigrees with LHON are well recognized, with affected individuals present in as many as 10 generations. It is therefore unlikely that a nuclear modifier locus would be strictly coinherited with the primary mtDNA mutation throughout the whole pedigree. Given the relative rarity of the primary mtDNA mutation, it is far more likely that the nuclear modifier is common in the general population and moves in and out of the maternal pedigree through random mating between mothers who transmit the LHON mtDNA mutation (who largely remain unaffected) and unrelated male partners not harboring the LHON mtDNA mutation. The nuclear modifier, as reasoned by Hudson et al. (2005) is likely to be 1 or more ancient genetic variants that may be present at a high frequency in the population. Following this reasoning, they used a nonparametric complex disease mapping strategy to identify the modifier locus. They collected a total of 389 DNA samples from affected and unaffected individuals from 100 families with LHON in 6 different countries. The percentage with heteroplasmy was determined, and only samples with more than 70% mutated mtDNA were included in the linkage study because this level of mutated mtDNA is associated with the same penetrance as homoplasmic mutated mtDNA (Chinnery et al., 2001). They initially performed nonparametric linkage (NPL) analysis in 6 Finnish families, since linkage disequilibrium blocks in young, geographically isolated populations are generally larger than average, facilitating low density linkage mapping of complex traits (Wright et al., 1999). They then turned to independent European cohorts with LHON. Thus they defined an X-chromosomal haplotype bounded by markers in the proximal half of the short arm of the X chromosome at DXS8090 and DXS1068, located in Xp11. The effect of the modulating haplotype was independent of the mtDNA genetic background and appeared to explain the incomplete penetrance and sex bias that characterizes LHON.

Using 15 X-chromosome markers for linkage analysis of Leber disease families, Chen et al. (1989) excluded the involvement of a gene located almost anywhere on the X chromosome. Although the strong male bias for Leber optic atrophy might suggest an interaction between an X-linked gene and a mitochondrial DNA defect, the experience of this study made this unlikely.

Findings from genealogic data suggest that more males than females in the maternal lineages have optic atrophy, thus raising the possibility of an X-chromosomal gene that renders susceptible to optic atrophy those individuals who have mtDNA mutations for Leber hereditary optic neuropathy (LHON; see 535000). Vilkki et al. (1991) presented data suggesting linkage of a susceptibility locus to DXS7 in several Finnish LHON families; maximum lod = 2.32 at theta = 0.0. Chen and Denton (1991) questioned this conclusion on the basis of their data.

Hudson et al. (2005) remarked that early attempts to map a susceptibility locus were inconclusive because the studies used widely spaced, often noninformative markers and failed to account for mtDNA heteroplasmy. Later studies were more comprehensive, but exclusion mapping was based on an X-linked recessive model, which cannot explain the segregation pattern in all pedigrees (Mackey, 1993), and study size limited the power to exclude a substantial portion of the X chromosome (Juvonen et al., 1993; Chalmers et al., 1996).