A neurodegenerative perspective on mitochondrial optic neuropathies

Abstract

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called "plus" phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.

Keywords: Dominant optic atrophy; Leber hereditary optic neuropathy; Mitochondrial diseases; Neurodegenerative diseases; OPA1; Retinal ganglion cell.

Fig. 1

Colour fundus and OCT findings in a patient with acute LHON compared with a healthy subject. a An 18-year-old man harbouring the m.3460G>A mtDNA mutation who was in the acute stage of LHON with onset of visual loss of 1 and 2 months in the right (OD) and left eyes (OS), respectively. There are telangiectatic microangiopathy and swelling of the peripapillary retinal nerve fibre layer (RNFL) mainly involving the superior and inferior quadrants (ONH cube 200 × 200 protocol, Cirrus HD-OCT, Carl Zeiss Meditec). The left optic disc is showing early temporal pallor consistent with the RNFL thinning observed on OCT. The bottom panel shows macular ganglion cell layer thinning that is more evident in the left eye (Macular Cube 512 × 128 protocol). b Comparative images for a healthy subject. Please refer to the Supplementary Appendix for a more detailed explanation of the OCT measurements and their anatomical correlates

Fig. 2

LHON-MS overlap syndrome. T2 MRI images from a 27-year-old woman with episodes of recurrent optic neuritis over a 10-year period associated with partial visual recovery. There are disseminated high-signal changes within the white matter regions of the brain and cervical spinal cord that are consistent with demyelination [105]

Fig. 3

Colour fundus and OCT findings in DOA. The images were obtained from a 20-year-old woman with progressive visual loss starting in early childhood and confirmed to harbour a pathogenic OPA1 mutation. There is prominent temporal optic disc pallor and marked RNFL thinning except in the nasal quadrant, which is relatively spared. The disc area analysis reveals small optic discs in both eyes. The bottom panel shows pronounced macular ganglion cell layer thinning in all sectors. Please refer to the Supplementary Appendix for a more detailed explanation of the OCT measurements and their anatomical correlates

Fig. 4

Melanopsin-expressing retinal ganglion cells and myelin ultrastructure. a Retinal cross-sections from a healthy control individual were stained with antibody against melanopsin. The inner retina shows the ganglion cell layer with retinal ganglion cells (arrows) and one melanopsin-expressing retinal ganglion cell (asterisk). b The inner retina from a patient with LHON reveals a melanopsin-expressing retinal ganglion cell (asterisk) in the complete absence of other retinal ganglion cells. c Electron micrograph of optic nerve cross-sections from a healthy control individual showing densely packed axons with variable axonal calibre and normal myelin thickness. d A representative illustration from a patient with LHON highlights the dramatic depletion of axons with a thin myelin coating around the surviving axons

Fig. 5

Dendropathy in a mouse model of dominant optic atrophy. a Flat-mounted retinas were labelled with the fluorescent marker DiI and individual RGCs were imaged with confocal microscopy. A representative RGC from a 16-month-old wild-type mouse is shown that demonstrates the extensive arborization of the dendritic tree. b An age-matched RGC from a B6;C3-Opa1 ^Q285STOP mutant mouse harbouring a nonsense mutation in the OPA1 gene. There is marked dendritic pruning characterised by a reduction in total dendritic length and field area