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      Childhood-onset Leber hereditary optic neuropathy.

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          Abstract

          The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup.

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          Most cited references17

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          Gene–environment interactions in Leber hereditary optic neuropathy

          Leber hereditary optic neuropathy (LHON) is a genetic disorder primarily due to mutations of mitochondrial DNA (mtDNA). Environmental factors are thought to precipitate the visual failure and explain the marked incomplete penetrance of LHON, but previous small studies have failed to confirm this to be the case. LHON has no treatment, so identifying environmental triggers is the key to disease prevention, whilst potentially revealing new mechanisms amenable to therapeutic manipulation. To address this issue, we conducted a large, multicentre epidemiological study of 196 affected and 206 unaffected carriers from 125 LHON pedigrees known to harbour one of the three primary pathogenic mtDNA mutations: m.3460G>A, m.11778G>A and m.14484T>C. A comprehensive history of exposure to smoking, alcohol and other putative environmental insults was collected using a structured questionnaire. We identified a strong and consistent association between visual loss and smoking, independent of gender and alcohol intake, leading to a clinical penetrance of 93% in men who smoked. There was a trend towards increased visual failure with alcohol, but only with a heavy intake. Based on these findings, asymptomatic carriers of a LHON mtDNA mutation should be strongly advised not to smoke and to moderate their alcohol intake.
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            Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland.

            We have performed an entire-population-based survey of the epidemiology and penetrance of Leber hereditary optic neuropathy (LHON) in Finland - a country that is among the best-studied genetic isolates in the world. During our long-term clinical follow-up period since 1970, we have so far identified 36 LHON families in Finland, comprised of almost 1000 family members. Counting the unaffected family members has been possible thanks to accessible genealogical records, and this has improved the accuracy of our penetrance figures by minimizing the sample bias. Our results, although confirming some well-known features of LHON, indicate that the overall penetrance of LHON is lower than previously estimated, and that affected females have a higher incidence of affected offspring compared to the unaffected females. The prevalence of LHON in Finland is 1:50 000, and one in 9000 Finns is a carrier of one of the three LHON primary mutations.
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              The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.

              One hundred and seven patients from 79 families were defined as having Leber's hereditary optic neuropathy (LHON) by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Only half of the 11778 index patients had a history of similarly affected relatives; this proportion was higher with the 3460 (71%) and 14484 (100%) mutations. The ratios of affected male to female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Detailed clinical data were available for 79 patients from 55 families. Visual loss developed between the ages of 11 and 30 years in 69%, with a range of 6-62 years, and no significant differences between mutation groups or males and females. It was bilateral in all but two patients, to a median of counting fingers with a central scotoma, developing simultaneously in 22% and sequentially in 78%, with a median inter-eye delay of 8 weeks, and progressing in each eye over a period of 4-6 weeks. Nineteen patients had pain in an affected eye or on eye movements, and four experienced Uhthoff's phenomenon. Retinal microangiopathy was uncommon after 6 months from onset and was not detected in 36% of patients examined within 3 months of visual loss; the microangiopathy was particularly uncommon in the 14484 group. There was no difference in the overall visual outcome between the 11778 and 3460 groups with median final visual acuities of 1/60 and 3/60, respectively. Particularly severe visual loss occurred in one-third of women with the 11778 mutation, to vague perception of light or no perception of light in at least one eye. A multiple sclerosis-like illness was observed in 45% of females with the 11778 mutation. Prognosis was substantially better in the 14484 patients, with recovery to a final visual acuity of at least 6/24, in 71% of patients. Good visual outcome was strongly correlated with age at onset, all those with onset before 20 years having a final visual acuity better than 6/24 as opposed to only 2 out of 6 with later onset. Improvement in vision occurred as long as 4 years after onset. High alcohol and tobacco consumption, cranial or ocular trauma, young or old age at presentation, co-existing neurological disease, and recent childbirth with post-partum haemorrhage, all contributed to diagnostic difficulties in this series, usually in the absence of a family history. These problems were resolved by mtDNA analysis.
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                Author and article information

                Journal
                Br J Ophthalmol
                The British journal of ophthalmology
                BMJ
                1468-2079
                0007-1161
                November 2017
                : 101
                : 11
                Affiliations
                [1 ] UCL Institute of Ophthalmology, London, UK.
                [2 ] Moorfields Eye Hospital, London, UK.
                [3 ] Department of Ophthalmology, Helsinki University Hospital, and University of Helsinki, Helsinki, Finland.
                [4 ] Great Ormond Street Hospital, London, UK.
                [5 ] Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.
                [6 ] Department of Ophthalmology, Royal United Hospital, Bath, UK.
                [7 ] Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
                [8 ] Medical Research Council Mitochondrial Biology Unit, Cambridge, UK.
                [9 ] Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
                [10 ] School of Optometry and Vision Sciences, Cardiff University and Cardiff Eye Unit, University Hospital Wales, Cardiff, UK.
                [11 ] Ophthalmology Department, UCSF School of Medicine, San Francisco, California, USA.
                [12 ] Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
                Article
                bjophthalmol-2016-310072
                10.1136/bjophthalmol-2016-310072
                28314831
                24824ba9-ba06-4ba0-9f98-247ccb177e9d
                History

                Optic Nerve,Vision,Child health (paediatrics),Diagnostic tests/Investigation,Genetics

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