Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic disease that preferentially causes blindness in young adult males, affecting about 1 in 25 000 of the British population. It is characterised by bilateral subacute loss of central vision owing to focal degeneration of the retinal ganglion cell layer and optic nerve. Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA (mtDNA) point mutations, G3460A, G11778A, and T14484C, which all involve genes encoding complex I subunits of the respiratory chain. An intriguing feature of LHON is that only approximately 50% of males and approximately 10% of females who harbour a pathogenic mtDNA mutation actually develop the optic neuropathy. This marked incomplete penetrance and gender bias imply that additional mitochondrial and/or nuclear genetic factors must be modulating the phenotypic expression of LHON. It is also likely that environmental factors contribute to the onset of visual failure. However, these secondary precipitating factors remain poorly defined at present. In this review, we describe the natural history of this optic nerve disorder and highlight issues relating to clinical diagnosis, management, and genetic counselling. We also discuss the findings of recently published studies and the light they shed on the complex aetiology and pathophysiology of LHON.

https://jmg.bmj.com/content/jmedgenet/39/3/162.full.pdf

Leber hereditary optic neuropathy

Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoid-specific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed randomly along the phylogenetic trees, without any preferential association with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that characterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This finding suggests that one ancient combination of haplogroup J-specific mutations increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.

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

During the past decade, there have been many descriptions of patients with neurological disorders due to mitochondrial DNA (mtDNA) mutations, but the extent and spectrum of mtDNA disease in the general population have not yet been defined. Adults with suspected mtDNA disease in the North East of England were referred to a single neurology center for investigation over the 10-year period from 1990 to 1999 inclusive. We defined the genetic defect in these individuals. For the midyear period of 1997, we calculated the minimum point prevalence of mtDNA disease in the adults of working age (> 16-<60 years old for female subjects and <65 years old for male subjects) and the minimum prevalence of adults and children (<60 years for female subjects, <65 years for male subjects) at risk of developing mtDNA disease. mtDNA defects caused disease in 6.57 per 100,000 individuals in the adult population of working age, and 7.59 per 100,000 unaffected adults and children were at risk of developing mtDNA disease. Overall, 12.48 per 100,000 individuals in the adult and child population either had mtDNA disease or were at risk of developing mtDNA disease. These results reflect the minimum prevalence of mtDNA disease and pathogenic mtDNA mutations and demonstrate that pathogenic mtDNA mutations are a common cause of chronic morbidity. These findings have resource implications, particularly for supportive care and genetic counseling.

The epidemiology of pathogenic mitochondrial DNA mutations.

We performed the first population-based clinical and molecular genetic study of Leber hereditary optic neuropathy (LHON) in a population of 2,173,800 individuals in the North East of England. We identified 16 genealogically unrelated families who harbor one of the three primary mitochondrial DNA (mtDNA) mutations that cause LHON. Two of these families were found to be linked genetically to a common maternal founder. A de novo mtDNA mutation (G3460A) was identified in one family. The minimum point prevalence of visual failure due to LHON within this population was 3.22 per 100,000 (95% CI 2.47–3.97 per 100,000), and the minimum point prevalence for mtDNA LHON mutations was 11.82 per 100,000 (95% CI 10.38–13.27 per 100,000). These results indicate that LHON is not rare but has a population prevalence similar to autosomally inherited neurological disorders. The majority of individuals harbored only mutant mtDNA (homoplasmy), but heteroplasmy was detected in ∼12% of individuals. Overall, however, ∼33% of families with LHON had at least one heteroplasmic individual. The high incidence of heteroplasmy in pedigrees with LHON raises the possibility that a closely related maternal relative of an index case may not harbor the mtDNA mutation, highlighting the importance of molecular genetic testing for each maternal family member seeking advice about their risks of visual failure.

G Govan

Papers

Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy.