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      A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy

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          Abstract

          Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

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          Most cited references23

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          Resolving the clinical acuity categories "hand motion" and "counting fingers" using the Freiburg Visual Acuity Test (FrACT).

          The Freiburg Visual Acuity Test (FrACT) has been suggested as a promising test for quantifying the visual acuity (VA) of patients with very low vision, a condition often classified using the semi-quantitative clinical scale "counting fingers" (CF), "hand motion" (HM), "light perception" (LP) and "no light perception". The present study was designed to assess FrACT performance in a sizable number of CF, HM, and LP patients in order to generate a setting for future clinical studies in the low vision range. We examined a total of 41 patients (LP, n = 11; CF, n = 15; HM, n = 15) with various eye diseases (e.g., diabetic retinopathy, ARMD), covering the clinical VA scale from LP to CF. The FrACT optotypes were presented at a distance of 50 cm on a 17-inch LCD monitor with four random orientations. After training, two FrACT measurements (test and retest) were taken, each comprising 30 trials. FrACT measures reproducibly the VA of CF and HM patients. In CF patients, FrACT resulted in a mean logMAR = 1.98 +/- 0.24 (corresponding to a decimal VA of 0.010), for HM in a mean logMAR = 2.28 +/- 0.15 (corresponding to a decimal VA of 0.0052). In all LP patients the FrACT values were close to what would be obtained by random guessing. The mean test-retest 95% confidence interval was 0.21 logMAR for CF patients and 0.31 logMAR for HM respectively. Test-retest variability declined from 24 to 30 trials, showing that at least 30 trials are necessary. FrACT can reproducibly quantify VA in the CF and HM range. We observed a floor effect for LP, and it was not quantifiable further. Quantitative VA measures are thus obtainable in the very low-vision range using FrACT.
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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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              The epidemiology of mitochondrial disorders--past, present and future.

              A number of epidemiological studies of mitochondrial disease have been carried out over the last decade, clearly demonstrating that mitochondrial disorders are far more common than was previously accepted. This review summarizes current knowledge of the prevalence of human mitochondrial disorders--data that has important implications for the provision of health care and adequate resources for research into the pathogenesis and treatment of these disorders.
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                Author and article information

                Journal
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                September 2011
                23 July 2011
                23 July 2011
                : 134
                : 9
                : 2677-2686
                Affiliations
                1 Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany
                2 Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospital, NE1 4LP, NHS Trust, UK
                3 Department of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospital, NE1 4LP NHS Trust, UK
                4 Mitochondrial Research Group, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
                5 Ophthalmology Department, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec H2L 4M1, Canada
                6 Department of Ophthalmology, Ludwig-Maximilians-University, Munich, 80336 Germany
                7 Santhera Pharmaceuticals, 4410 Liestal, Switzerland
                8 4Pharma, Stockholm, 16440 Kista, Sweden
                Author notes
                Correspondence to: Patrick F. Chinnery, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK E-mail: p.f.chinnery@ 123456newcastle.ac.uk
                Correspondence may also be addressed to: Thomas Klopstock, Dept. of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, Munich, Germany E-mail: thomas.klopstock@ 123456med.uni-muenchen.de
                Article
                awr170
                10.1093/brain/awr170
                3170530
                21788663
                3c6758ff-3f82-43f9-b9f8-148f2f973a70
                © The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 May 2011
                : 9 June 2011
                : 11 June 2011
                Page count
                Pages: 10
                Categories
                Original Articles

                Neurosciences
                idebenone,mitochondrial encephalomyopathy,lhon,optic atrophy,mitochondrial dna,optic neuropathy,mitochondrial disease

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