A neurodegenerative perspective on mitochondrial optic neuropathies.
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.
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK. Patrick.Yu-Wai-Man@ncl.ac.uk.|Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. Patrick.Yu-Wai-Man@ncl.ac.uk.|NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, EC1V 2PD, UK. Patrick.Yu-Wai-Man@ncl.ac.uk.
Patrick
P
Yu-Wai-Man
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK.|Cardiff Eye Unit, University Hospital of Wales, Cardiff, UK.
Marcela
M
Votruba
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Florence
F
Burté
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
Chiara
C
La Morgia
Studio Oculistico d'Azeglio, Bologna, Italy.|San Raffaele Scientific Institute, Milan, Italy.
Piero
P
Barboni
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Unit of Neurology, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
Valerio
V
Carelli
D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*
D004272:DNA, Mitochondrial
Dominant optic atrophy; Leber hereditary optic neuropathy; Mitochondrial diseases; Neurodegenerative diseases; OPA1; Retinal ganglion cell
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