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

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          Abstract

          Background

          Chronic 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.

          Methods

          Ten 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.

          Results

          There 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.

          Conclusion

          The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO.

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          Most cited references17

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          A neurological perspective on mitochondrial disease.

          Disruption of the most fundamental cellular energy process, the mitochondrial respiratory chain, results in a diverse and variable group of multisystem disorders known collectively as mitochondrial disease. The frequent involvement of the brain, nerves, and muscles, often in the same patient, places neurologists at the forefront of the interesting and challenging process of diagnosing and caring for these patients. Mitochondrial diseases are among the most frequently inherited neurological disorders, and can be caused by mutations in mitochondrial or nuclear DNA. Substantial progress has been made over the past decade in understanding the genetic basis of these disorders, with important implications for the general neurologist in terms of the diagnosis, investigation, and multidisciplinary management of these patients. Copyright 2010 Elsevier Ltd. All rights reserved.
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            The neuro-ophthalmology of mitochondrial disease.

            Mitochondrial diseases frequently manifest neuro-ophthalmologic symptoms and signs. Because of the predilection of mitochondrial disorders to involve the optic nerves, extraocular muscles, retina, and even the retrochiasmal visual pathways, the ophthalmologist is often the first physician to be consulted. Disorders caused by mitochondrial dysfunction can result from abnormalities in either the mitochondrial DNA or in nuclear genes which encode mitochondrial proteins. Inheritance of these mutations will follow patterns specific to their somatic or mitochondrial genetics. Genotype-phenotype correlations are inconstant, and considerable overlap may occur among these syndromes. The diagnostic approach to the patient with suspected mitochondrial disease entails a detailed personal and family history, careful ophthalmic, neurologic, and systemic examination, directed investigations, and attention to potentially life-threatening sequelae. Although curative treatments for mitochondrial disorders are currently lacking, exciting research advances are being made, particularly in the area of gene therapy. Leber hereditary optic neuropathy, with its window of opportunity for timely intervention and its accessibility to directed therapy, offers a unique model to study future therapeutic interventions. Most patients and their relatives benefit from informed genetic counseling. Copyright 2010 Elsevier Inc. All rights reserved.
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              Cerebellar ataxia in patients with mitochondrial DNA disease: a molecular clinicopathological study.

              Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                27 September 2013
                : 8
                : 9
                : e75048
                Affiliations
                [1 ]Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
                [2 ]Institute of Cellular Medicine and Newcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom
                [3 ]Institute for Ageing and Health, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom
                [4 ]Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
                [5 ]Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom
                [6 ]Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
                Centre for Eye Research Australia, Australia
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: FES; MJF; AMB; PFC; PYWM. Performed the experiments: CYWM; FES; MJF; GG; SG. Analyzed the data: CYWM; FES; MJF; GG; SG; AMB; PFC; PYWM. Contributed reagents/materials/analysis tools: FES; MJF; RWT; AMB. Wrote the paper: CYWM; PYWM. Critical revision of the manuscipt: FES; MJF; GG; SG; GSG; RWT; DMT; PGG; AMB; PFC Obtaining funding: PGG; PFC; PYWM.

                Article
                PONE-D-13-26063
                10.1371/journal.pone.0075048
                3785524
                24086434
                bf08ab6a-d29d-4f50-a878-db6b163c0641
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 June 2013
                : 7 August 2013
                Page count
                Pages: 7
                Funding
                This work was supported by research grants from the Newcastle Joint Research Executive Scientific Committee (JRESC), the Medical Research Council (MRC, UK), and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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