Leber Hereditary Optic Neuropathy (LHON)

Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disease, caused by maternally inherited point mutations in mitochondrial DNA (mtDNA), most commonly m.11778G>A (MT-ND4, 70% of cases), m.14484T>C (MT-ND6, 14%), and m.3460G>A (MT-ND1, 13%). These mutations affect complex I (NADH dehydrogenase) of the electron transport chain, causing reactive oxygen species accumulation and apoptosis of retinal ganglion cells, particularly in the papillomacular bundle.

LHON typically presents in males in their second to third decade (mean age 24, though variable from childhood to elderly) with sequential bilateral painless central or centrocecal scotomas. The fellow eye is usually involved within weeks to months. Penetrance is incomplete (50% in male carriers, 10-15% in female carriers), suggesting nuclear modifier genes and environmental triggers (smoking, alcohol, certain medications). Vision typically declines to 20/200 to count fingers within months.

Idebenone (Raxone, 900 mg/day in three divided doses), a synthetic short-chain quinone, is approved in Europe for LHON to enhance mitochondrial electron transport. Recovery may occur in some patients (especially m.14484 mutation, 50% recover; m.11778 has only 4% spontaneous recovery). Gene therapy with intravitreal AAV2 vector encoding wild-type ND4 (lenadogene nolparvovec/GS010) is in advanced clinical trials with promising results. Avoid mitochondrial toxins (smoking, alcohol, certain antibiotics).