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      Leber Hereditary Optic Neuropathy in 2 of 4 Siblings with 11778 mtDNA Mutation: Clinical Variability or Effect of Toxic Environmental Exposure?

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          Although mitochondrial (mt) DNA mutation at nucleotide position 11778 accounts for most cases of Leber’s hereditary optic neuropathy (LHON), the phenotypic expression may vary greatly even in different members of the same family. The possible influence of exogenous toxicity on phenotypic expression is still debated in LHON. Here we describe 4 siblings carrying the 11778 mtDNA mutation with a different phenotype. The index case developed an atypical optic neuropathy at the age of 60 years after a long history of occupational exposure to polycyclic aromatic hydrocarbons (PAHs). This report underlines a number of unanswered questions about phenotypic variability of LHON including the possible influence of PAH toxicity.

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          Most cited references 9

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          Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies.

          Selective degeneration of the smallest fibers (papillo-macular bundle) of the human optic nerve occurs in a large number of optic neuropathies characterized primarily by loss of central vision. The pathophysiology that underlies this peculiar pattern of cell involvement probably reflects different forms of genetic and acquired mitochondrial dysfunction. Maternally inherited Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (Kjer disease), the optic atrophy of Leigh's syndrome, Friedreich ataxia and a variety of other conditions are examples of inherited mitochondrial disorders with different etiologies. Tobacco-alcohol amblyopia (TAA), the Cuban epidemic of optic neuropathy (CEON) and other dietary (Vitamins B, folate deficiencies) optic neuropathies, as well as toxic optic neuropathies such as due to chloramphenicol, ethambutol, or more rarely to carbon monoxide, methanol and cyanide are probably all related forms of acquired mitochondrial dysfunction. Biochemical and cellular studies in LHON point to a partial defect of respiratory chain function that may generate either an ATP synthesis defect and/or a chronic increase of oxidative stress. Histopathological studies in LHON cases and a rat model mimicking CEON revealed a selective loss of retinal ganglion cells (RGCs) and the corresponding axons, particularly in the temporal-central part of the optic nerve. Anatomical peculiarities of optic nerve axons, such as the asymmetric pattern of myelination, may have functional implications on energy dependence and distribution of mitochondrial populations in the different sections of the nerve. Histological evidence suggests impaired axonal transport of mitochondria in LHON and in the CEON-like rat model, indicating a possible common pathophysiology for this category of optic neuropathies. Histological evidence of myelin pathology in LHON also suggests a role for oxidative stress, possibly affecting the oligodendrocytes of the optic nerves.
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            Titrating the effects of mitochondrial complex I impairment in the cell physiology.

            The mitochondrial oxidative phosphorylation system consists of five multimeric enzymes (complexes I-V). NADH dehydrogenase or complex I (CI) is affected in most of the mitochondrial diseases and in some neurodegenerative disorders. We have studied the physiological consequences of a partial CI inhibition at the cellular level. We used a genetic model (40% CI-inhibited human-ape xenomitochondrial cybrids) and a drug-induced model (0-100% CI-inhibited cells using different concentrations of rotenone). We observed a quantitative correlation between the level of CI impairment and cell respiration, cell growth, free radical production, lipid peroxidation, mitochondrial membrane potential, and apoptosis. We showed that cell death was quantitatively associated with free radical production rather than with a decrease in respiratory chain function. The results obtained with human xenomitochondrial cybrid cells were compatible with those observed in rotenone-induced 40% CI-inhibited cells. At high concentrations (5-6-fold higher than the concentration necessary for 100% CI inhibition), rotenone showed a second toxic effect at the level of microtubule assembly, which also led to apoptosis. The correlation found among all the parameters studied helped clarify the physiological consequences of partial CI inhibitions at the cellular level.
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              Occupationally related cancer risk among coke oven workers: 30 years of follow-up.

              This study concerns the update of cause-specific mortality among coke oven workers. Updated information provides 3 decades of work history and vital status follow-up on 15,818 workers. Mortality patterns are summarized by race, cumulative exposure, and period of follow-up. The findings are consistent with those from earlier assessments, indicating that occupational exposure to coke oven emissions is associated with significant excess mortality from cancer of the respiratory system and of the prostate. Depending on the segment of the population considered, the respiratory cancer risk for coke oven workers ranged as high as 4.45 times that for non-oven workers. Relative risk values for cancer of the prostate ranged as high as 1.93. Rates of respiratory cancer across period of follow-up are declining, suggesting that the implementation of emissions control and occupational exposure limits has been beneficial.

                Author and article information

                Eur Neurol
                European Neurology
                S. Karger AG
                March 2005
                27 December 2004
                : 53
                : 1
                : 32-34
                Department of Neurological and Behavioral Sciences, Medical School, University of Siena, Siena, Italy
                83927 Eur Neurol 2005;53:32–34
                © 2005 S. Karger AG, Basel

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                Figures: 1, References: 15, Pages: 3
                Original Paper


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