Inherited mitochondrial optic neuropathies

Abstract

Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common inherited optic neuropathies and they result in significant visual morbidity among young adults. Both disorders are the result of mitochondrial dysfunction: LHON from primary mitochondrial DNA (mtDNA) mutations affecting the respiratory chain complexes; and the majority of DOA families have mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein critical for mtDNA maintenance and oxidative phosphorylation. Additional genetic and environmental factors modulate the penetrance of LHON, and the same is likely to be the case for DOA which has a markedly variable clinical phenotype. The selective vulnerability of retinal ganglion cells (RGCs) is a key pathological feature and understanding the fundamental mechanisms that underlie RGC loss in these disorders is a prerequisite for the development of effective therapeutic strategies which are currently limited.

Figure 1. Acute fundal appearance in Leber hereditary optic neuropathy showing disc hyperaemia, swelling of the parapapillary retinal nerve fibre layer and retinal vascular tortuosity.

Figure 2. Secondary factors interacting with the primary mtDNA Leber hereditary optic neuropathy mutation to precipitate visual loss. ATP, adenosine triphosphate; ROS, reactive oxygen species.

Figure 3. Typical fundal appearance in dominant optic atrophy showing bilateral optic disc pallor more marked in the temporal quadrant (LE, left eye; RE, right eye; T, temporal quadrant).