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Unravelling Leber hereditary optic neuropathy

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One in 10 young women, but around half of young men, carrying the genetic mutation for Leber hereditary optic neuropathy (LHON) will become blind. The reasons for this are unclear, but other secondary genetic and environmental factors are likely to be involved.

The disease is transmitted though the mother. And most cases are caused by one of three MtDNA genetic mitochondrial point mutations—G346OA, G11778A, and T14484C. But the frequency varies enormously. G11778A seems to be the most prevalent in Europe, Australia, and South East Asia. Relatively rare, T14484C is the most common mutation among French Canadians. How likely a patient is to regain his or her sight depends on the mutation. G11778A carries the worst prognosis, while those with T14484C are more likely to improve if eyesight fails before the age of 20.

A significant minority of carriers, especially women with the G11778A mutation, will have features that are identical with multiple sclerosis. But the evidence for the “autoimmunity hypothesis” is inconclusive, although accompanying neurological problems have been linked to other mtDNA mutations.

In most LHON pedigrees, every mtDNA molecule harbours the mutation. But not all, and preliminary research suggests that this might explain the incomplete penetrance, with a minimal risk of blindness if the mutations are below 60 per cent. The male bias might be attributable to a recessive X linked susceptibility gene which strengthens the mtDNA mutation. Twin studies point to environmental factors, and there is some evidence to suggest that diet, stress, acute illness, smoking and alcohol intake can all precipitate the blindness.