The Elusive Pathophysiology of Leber's Hereditary Optic Neuropathy

Leber’s Hereditary Optic Neuropathy (LHON) is a mitochondrially inherited disorder characterized by rapid, subacute vision loss. LHON has historically been a difficult disease to study due to its low incidence. Many questions concerning its pathophysiology have remained unanswered. A significant enigma concerns LHON’s gender bias as represented by the male-to-female ratio of about 4:1. Another source of confusion includes the variable penetrance, since the mitochondrial mutation is necessary, but not sufficient, to cause conversion. A third challenge involves the tissue specificity, since typically only the optic nerve is involved with a specific pattern of optic atrophy due to primary loss of the papillomacular bundle (PMB) in affected individuals. The fourth remaining complexity is the pattern of rapid, subacute vision loss observed in nearly all affected individuals. Several clinical genetic studies, cybrid experiments, and histochemical studies have been conducted to address the three enigmas of gender bias, variable penetrance, and tissue specificity. Despite elucidation of these three aspects of the pathophysiology, the mechanism behind the rapid, significant vision loss remains a mystery.