Propagation and Selectivity of Axonal Loss in Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a syndrome of subacute loss of central vision associated with mutations in mitochondrial DNA coding for components of complex I. LHON preferentially involves small axons in the temporal optic nerve, but the reason is unclear. We performed a Monte Carlo simulation of the spread of injury in LHON axons to better understand the predilection for small axons. Optic nerve slices were modeled as grids containing axons with sizes from reported regional distributions. The propagation of injury from a localized concentration of superoxide was simulated as the spread via passive diffusion from one axon to adjacent axons, with basal production and scavenging rate proportional to axonal area and volume, respectively. Axonal degeneration occurred when intra-axonal concentrations reached a toxic threshold. Simulations demonstrated that almost all small and medium axons degenerated by the time steady-state was reached, but about 50% of large axons were preserved. The location of initial injury affected time to steady state, with nasal injuries reaching steady state faster than temporal injuries. The pattern of axonal degeneration in the simulations mirrored both visual fields and optic nerve histology from patients with LHON. These results provide insight into the nature of axonal loss in LHON.