Extraocular Muscle Atrophy and Central Nervous System Involvement in Chronic Progressive External Ophthalmoplegia

Cynthia Yu-Wai-Man,Stuart Guthrie,Andrew M Blamire,Robert W Taylor,Patrick F Chinnery,Philip G Griffiths,Douglass M Turnbull,Michael J Firbank,Fiona E Smith,Grainne S Gorman,Grant Guthrie,Patrick Yu-Wai-Man,Ian A Trounce

doi:10.1371/journal.pone.0075048

Abstract

BackgroundChronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction.MethodsTen age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem.ResultsThere was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes.ConclusionThe results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO.

Highlights

Chronic progressive external ophthalmoplegia (CPEO) is a slowly progressive extraocular muscle disorder characterised by bilateral, usually symmetrical, limitation of eye movements and ptosis [1]
CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, largescale mitochondrial DNA deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair [5,6]
The aim of this magnetic resonance imaging (MRI) study was to investigate whether the limitation of eye movements in CPEO is myopathic in origin or whether there is evidence of contributory brainstem dysfunction with magnetic resonance spectroscopy (MRS)

Summary

Introduction

Chronic progressive external ophthalmoplegia (CPEO) is a slowly progressive extraocular muscle disorder characterised by bilateral, usually symmetrical, limitation of eye movements and ptosis [1] This classical manifestation of mitochondrial diseases can develop either in isolation or in association with other disabling neurological features, referred to as CPEO+ [2,3]. CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction

Methods

Results

Conclusion