Leber hereditary optic neuropathy: Potential opportunities potential pitfalls for drug therapy of optic nerve degenerative disorders

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiologic event is a mutation in the mit ochondrial genome. The primary mitochondrial mutation is necessary-but not sufficient-for manifestation of the optic neuropathy, and secondary genetic and/or epigenetic risk factors are also involved. There is broad agreement that mutations at mtDNA nucleotides 3460, 11778, and 14484 are primary LHO N mutations and that they account for 95% of the classic LHON cases in Cauc asians of northern European descent. It appears that these three primary LH ON mutations are associated with respiratory-chain dysfunction, but the der angement may be relatively subtle and/or vary among different tissues. The optic neuropathy involves a toss of central vision due to degeneration of t he retinal ganglion cells and optic nerve axons that subserve central visio n. The specific pattern of neurodegeneration in LHON may arise from a mitoc hondrial "chokepoint" in the region of the optic nerve that spans the nerve head and lamina cribosa. It is hypothesized that in the acute phase, a res piratory-chain dysfunction "crisis" leads to axoplasmic stasis and swelling , initially in the chokepoint, thereby blocking ganglion cell function and causing loss of vision. in some LHON patients, this toss of function is rev ersible in a subset of ganglion cells and a substantial recovery of vision occurs. However, in other patients, a cell death pathway (probably apoptoti c) is activated, with subsequent extensive degeneration of the retinal gang lion cell layer and optic nerve with an irreversible loss of vision. The co mplex etiology of LHON may allow therapeutic intervention at any one of sev eral steps, but there are also potential pitfalls. (C) 1999 Wiley-Liss, Inc .