[A review of the molecular mechanism of development of Leber hereditary optic neuropathy].

BACKGROUND

Leber hereditary optic neuropathy (LHON) is a maternally transmitted, bilateral optic neuropathy. Although mitochondrial (mt) DNA mutations are known to be associated with the maternal inheritance, there are few reviews on how they lead to optic neuropathy. In addition, low penetrance and male preponderance cannot be accounted for by mtDNA mutations alone.

METHODS

Presumable molecular mechanisms of LHON due to mtDNA mutations were reviewed based on cellular and molecular studies. Environmental factors regulating LHON expression were also extracted from pedigree analyses.

RESULT: Histopathologically, LHON, comprises apoptosis of retinal ganglion cells and chronic inflammation of the retrobulbar optic nerve. Trans-mitochondrial cybrid studies demonstrated that mtDNA mutations cause an increase in the production of reactive oxygen species. Over the last 50 years, the penetrance in females has been greatly reduced in both Japanese and Caucasian pedigrees. Smoking, over-consumption of alcohol, and sex hormones may control LHON expression.

CONCLUSIONS

These findings indicate that LHON is not a monogenetic disease, but that LHON transmits a predisposition to develop optic neuropathy and requires additional factors triggering phenotypic expression. Therapeutic intervention including gene therapy should be further investigated.