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A neurodegenerative perspective on mitochondrial optic neuropathies

Yu-Wai-Man, Patrick, Votruba, Marcela, Burté, Florence, La Morgia, Chiara, Barboni, Piero and Carelli, Valerio 2016. A neurodegenerative perspective on mitochondrial optic neuropathies. Acta Neuropathologica 132 (6) , pp. 789-806. 10.1007/s00401-016-1625-2

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Dominant optic atrophyLeber hereditary optic neuropathyMitochondrial diseasesNeurodegenerative diseasesOPA1Retinal ganglion cell
Publisher: Springer
ISSN: 0001-6322
Date of First Compliant Deposit: 2 October 2016
Date of Acceptance: 25 September 2016
Last Modified: 04 Jun 2017 09:26
URI: http://orca.cf.ac.uk/id/eprint/95033

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