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A neurodegenerative perspective on mitochondrial optic neuropathies

Lookup NU author(s): Dr Patrick Yu Wai Man, Dr Florence Burte

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Yu-Wai-Man P, Votruba M, Burte F, La Morgia C, Barboni P, Carelli V

Publication type: Review

Publication status: Published

Journal: ACTA NEUROPATHOLOGICA

Year: 2016

Volume: 132

Issue: 6

Pages: 789-806

Print publication date: 01/12/2016

Online publication date: 30/09/2016

Acceptance date: 25/09/2016

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Berlin Heidelberg

URL: http://dx.doi.org/10.1007/s00401-016-1625-2

DOI: 10.1007/s00401-016-1625-2


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