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.