Medical management of hereditary optic neuropathies

Abstract

Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.

Keywords: DOA; LHON; OPA1; hereditary; leber; mitochondria; optic atrophy; optic nerve.

Figure 1

(A) Fundus and OCT in the acute-phase of LHON. Fundus exam shows moderate swelling of the retinal nerve fibers mainly involving the superior and inferior arcades around the optic disk associated with loss of fibers in the papillo-macular bundle (temporal pallor), retinal vessels tortuosity, and telangiectasias. Optical coherence tomography (OCT) shows retinal nerve fiber layer thinning of the temporal quadrant with thickening of all the other quadrants. (B) Fundus and OCT of a LHON carrier. Fundus examination reveals mild swelling of the superior and inferior retinal nerve fibers and microangiopathy. OCT demonstrates retinal nerve fiber layer thickening more evident in the supero-nasal (OD) and supero-inferior (OS) quadrants.

Figure 2

30° and 10° visual field pattern of recovery in LHON. (A) Example of scotoma fenestration (OS) in a LHON patient carrying the 14484/ND6 mutation (B) Example of scotoma contraction (OS) in a LHON patient carrying the 11778/ND4 mutation and (C) Example of both scotoma fenestration and contraction (OD) in a LHON patient carrying the 11778/ND4 mutation.