INTRODUCTION:
Leber’s hereditary optic neuropathy (LHON) is one of the most prevalent inherited mitochondrial disorders and of these, the most common mitochondrial optic neuropathy.The condition has been reported to be held as a carrier gene mutation in up to 1 in 9000 people and affect as many as 1 in 30,000 individuals of European ancestry. It exhibits a heavy male predominance with 80-90% of those affected being male.The disorder typically presents within the second and third decade of life and is characterised by progressive optic neuropathy which can result in irreversible bilateral central vision loss. Therapies for LHON are limited with only one treatment registered for use (Idebenone) and ongoing clinical trials for other disease modifying treatments including gene therapy.
The disorder is most commonly caused by mutations on nucleotide positions 3460, 11778, and 14484 of mitochondrial DNA.These mutations predominantly affect genes encoding the subunit proteins of NADH dehydrogenase or complex I in the mitochondrial respiratory chain. This is thought to result in dysfunction of oxidative phosphorylation with reduced adenosine triphosphate production and an increase in reactive oxygen species. Cybrid experimentation on cell lines transmutated with mitochondrial DNA (mtDNA) possessing these LHON associated mutations have demonstrated greater susceptibility to apoptotic cell death via the fatty acid synthesis (FAS) and apoptosis inducing factor pathways.These changes are thought to subsequently result in retinal ganglion cell degeneration and consequent optic neuropathy.
Environmental exposures including toxic medications, smoking and significant alcohol intake have been associated with activation of disease in carriers resulting in vision loss. For this reason, LHON patients with malignancy have presented a therapeutic dilemma, balancing a fear of chemotherapy induced vision loss against the threat of the malignancy requiring treatment.