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      Leber hereditary optic neuropathy: bridging the translational gap

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          Abstract

          Purpose of review

          Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments.

          Recent findings

          LHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations.

          Summary

          LHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.

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          Most cited references41

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          Induced pluripotent stem cell technology: a decade of progress

          Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.
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            Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.

            Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.
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              The epidemiology of Leber hereditary optic neuropathy in the North East of England.

              We performed the first population-based clinical and molecular genetic study of Leber hereditary optic neuropathy (LHON) in a population of 2,173,800 individuals in the North East of England. We identified 16 genealogically unrelated families who harbor one of the three primary mitochondrial DNA (mtDNA) mutations that cause LHON. Two of these families were found to be linked genetically to a common maternal founder. A de novo mtDNA mutation (G3460A) was identified in one family. The minimum point prevalence of visual failure due to LHON within this population was 3.22 per 100,000 (95% CI 2.47-3.97 per 100,000), and the minimum point prevalence for mtDNA LHON mutations was 11.82 per 100,000 (95% CI 10.38-13.27 per 100,000). These results indicate that LHON is not rare but has a population prevalence similar to autosomally inherited neurological disorders. The majority of individuals harbored only mutant mtDNA (homoplasmy), but heteroplasmy was detected in approximately 12% of individuals. Overall, however, approximately 33% of families with LHON had at least one heteroplasmic individual. The high incidence of heteroplasmy in pedigrees with LHON raises the possibility that a closely related maternal relative of an index case may not harbor the mtDNA mutation, highlighting the importance of molecular genetic testing for each maternal family member seeking advice about their risks of visual failure.
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                Author and article information

                Journal
                Curr Opin Ophthalmol
                Curr Opin Ophthalmol
                COOPH
                Current Opinion in Ophthalmology
                Lippincott Williams & Wilkins
                1040-8738
                1531-7021
                September 2017
                10 August 2017
                : 28
                : 5
                : 403-409
                Affiliations
                [a ]NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London
                [b ]Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University
                [c ]Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne
                [d ]Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK
                Author notes
                Correspondence to Patrick Yu-Wai-Man, BMedSci, MBBS, PhD, FRCPath, FRCOphth, Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK. E-mail: py237@ 123456cam.ac.uk
                Article
                280519 00002
                10.1097/ICU.0000000000000410
                5562441
                28650878
                f7e115eb-c9cd-452c-88cc-0a2f76b91c41
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                History
                Categories
                OCULAR GENETICS: Edited by Alex V. Levin
                Custom metadata
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                gene therapy,leber hereditary optic neuropathy,mitochondrial diseases,mitochondrial replacement,optical coherence tomography

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