(mentions CMT) Mitochondrial Optic Neuropathies - Disease Mechanisms and Therape

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Prog Retin Eye Res. 2010 Nov 25

Mitochondrial Optic Neuropathies - Disease Mechanisms and Therapeutic

Strategies.

Yu-Wai-Man P, Griffiths PG, Chinnery PF.

Mitochondrial Research Group, Institute for Ageing and Health, The Medical

School, Newcastle University, UK; Department of Ophthalmology, Royal

Infirmary, Newcastle upon Tyne, UK; .Institute of Human Genetics, Newcastle

University, UK.

Abstract

Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy

(DOA) are the two most common inherited optic neuropathies in the general

population. Both disorders share striking pathological similarities, marked by

the selective loss of retinal ganglion cells (RGCs) and the early involvement of

the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations;

m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in

DOA, the majority of affected families harbour mutations in the OPA1 gene, which

codes for a mitochondrial inner membrane protein. Optic nerve degeneration in

LHON and DOA is therefore due to disturbed mitochondrial function and a

predominantly complex I respiratory chain defect has been identified using both

in vitro and in vivo biochemical assays.

However, the trigger for RGC loss is much more complex than a simple

bioenergetic crisis and other important disease mechanisms have emerged relating

to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the

involvement of the cytoskeleton in maintaining a differential mitochondrial

gradient at sites such as the lamina cribosa. The downstream consequences of

these mitochondrial disturbances are likely to be influenced by the local

cellular milieu.

The vulnerability of RGCs in LHON and DOA could derive not only from

tissue-specific, genetically-determined biological factors, but also from an

increased susceptibility to exogenous influences such as light exposure,

smoking, and pharmacological agents with putative mitochondrial toxic effects.

Our concept of inherited mitochondrial optic neuropathies has evolved over the

past decade, with the observation that patients with LHON and DOA can manifest a

much broader phenotypic spectrum than pure optic nerve involvement.

Interestingly, these phenotypes are sometimes clinically indistinguishable from

other neurodegenerative disorders such as Charcot-Marie-Tooth disease,

hereditary spastic paraplegia, and multiple sclerosis, where mitochondrial

dysfunction is also thought to be an important pathophysiological player.

A number of vertebrate and invertebrate disease models have recently been

established to circumvent the lack of human tissues, and these have already

provided considerable insight by allowing direct RGC experimentation. The

ultimate goal is to translate these research advances into clinical practice and

new treatment strategies are currently being investigated to improve the visual

prognosis for patients with mitochondrial optic neuropathies.