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Pierre Rustin - One of the best experts on this subject based on the ideXlab platform.
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Respiratory Chain alternative enzymes as tools to better understand and counteract Respiratory Chain deficiencies in human cells and animals
Physiologia plantarum, 2009Co-Authors: Pierre Rustin, Howard T. JacobsAbstract:Mitochondrial Respiratory Chain defects are now recognized to underlie a large number of human diseases with a spectacular variety in their phenotypic presentations. Despite progress made in the elucidation of their molecular basis, these diseases remain essentially untreatable. To date, most strategies to counteract these diseases, either in vitro or in vivo have proven unsuccessful. In humans, the Respiratory Chain lacks several redox active proteins long known in many micro-organisms, as well as in plants, and, as found recently, even in some metazoans. These alternative enzymes, e.g. the cyanide-insensitive alternative oxidase and the internal rotenone-insensitive NADH dehydrogenase, confer a significant flexibility to the Respiratory Chain, allowing it to overcome potential constraints exerted by the cell phosphorylation potential or by environmental xenobiotics. In plants, these alternative enzymes, activated by a subset of keto-acids, including pyruvate, are essentially engaged under highly reducing conditions. Because these are conditions observed in patients with Respiratory Chain dysfunction, we made the hypothesis that expression of these proteins might be of benefit in such situations. The observation that a functional alternative oxidase from Ciona intestinalis could be expressed in mammalian cells without obvious detrimental effect has provided a basis to develop a research programme to test the hypothesis, within an ad hoc international consortium, that this paper aims to describe. Combining research on human cells, flies and mice, the project aims, firstly, to verify that expressing these alternative enzymes is physiologically benign, useful as a tool to delineate the mechanisms of Respiratory Chain dysfunction and, finally, test their potential therapeutic benefit.
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Respiratory Chain diseases related to complex iii deficiency
Biochimica et Biophysica Acta, 2009Co-Authors: Paule Benit, Pierre Rustin, Sophie LebonAbstract:Complex III deficiencies are among the least common Respiratory-Chain abnormalities identified to date in humans. Nevertheless, their unexplained tissue specificity and broad clinical spectrum make them a valuable model for investigating Respiratory-Chain diseases. In this review, we briefly discuss the properties of complex III and the assay conditions relevant to the screening of high-risk patients. We then review the most recent advances in the field, which include the characterization of several disease genes and of the corresponding clinical presentations. Finally, we discuss genetic and biochemical aspects that may help to understand complex III-associated diseases.
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Mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency.
Methods in enzymology, 2004Co-Authors: Pierre Rustin, Arnold Munnich, Agnès RötigAbstract:Publisher Summary This chapter analyzes mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency. CoQ10 plays a pivotal role in the mitochondrial Respiratory Chain, distributing the electrons between the various dehydrogenases and the cytochrome segments of the Respiratory Chain. Being in large excess compared to any other component of the Respiratory Chain (RC), it forms a kinetically compartmentalized pool. Depending on its redox and protonation status, CoQ10 can react with molecular oxygen to produce superoxides. In particular, the full reduction of b-type cytochromes and the increased formation of unstable ubisemiquinone ensures maximal superoxide production. Besides the pro-oxidant effect of CoQ10, the fully reduced species (ubiquinol) can reduce a number of radical species, including superoxides, therefore acting as an antioxidant. The chapter presents an overview of Respiratory Chain and ubiquinone. Cellular consequences of CoQ 10 depletion along with clinical presentation of coenzyme Q 10 depletion are also discussed in the chapter. The chapter elaborates the detection of CoQ 10 deficiency and presents the details of supplementation therapy.
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Animal models for Respiratory Chain disease
Trends in molecular medicine, 2001Co-Authors: Nils-göran Larsson, Pierre RustinAbstract:Elucidation of the pathogenesis in Respiratory Chain diseases is of great importance for developing specific treatments. The limitations inherent to the use of patient material make studies of human tissues often difficult and the mouse has therefore emerged as a suitable model organism for studies of Respiratory Chain diseases. In this review, we present an overview of the field and discuss in depth a few examples of animal models reproducing pathology of human disease with primary and secondary Respiratory Chain involvement.
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Respiratory Chain deficiency in Alpers syndrome.
Neuropediatrics, 2001Co-Authors: Marion Gauthier-villars, Pierre Rustin, Agnès Rötig, Arnold Munnich, P. Landrieu, Valérie Cormier-daire, Emmanuel Jacquemin, D Chretien, Pascale De LonlayAbstract:Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on Respiratory Chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to Respiratory Chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the Respiratory Chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for Respiratory Chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.
Agnès Rötig - One of the best experts on this subject based on the ideXlab platform.
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Respiratory Chain deficiencies.
Handbook of clinical neurology, 2013Co-Authors: Pascale Delonlay, Agnès Rötig, Harvey B. SarnatAbstract:Mitochondrial functions are intimately associated with neurological symptoms. Various clinical and biological features are suggestive of energy depletion diseases, such as Leigh syndrome, Alpers syndrome, epilepsy (including myoclonic seizures and status epilepticus), stroke-like episodes, and acute cerebellar ataxia with high lactate peaks on magnetic resonance spectroscopy. Magnetic resonance imaging (MRI) discloses abnormalities in over 90% of the cases presenting with neurological symptoms. Basal ganglionic involvement, the most frequent imaging sign, can be isolated or combined with subtentorial atrophy of both the cerebellum and brainstem. MRS monovoxel proton spectroscopy is useful to reveal high lactate spikes if placed in the putamen and the cerebellar dentate nucleus. Lactate and pyruvate levels are required to exclude pyruvate dehydrogenase deficiency. However, lactate may be normal in the CSF. Clinical and biochemical investigations guide molecular studies, with two major heredities: mtDNA point mutations and autosomal recessive defects that program the majority of Respiratory Chain subunits. Muscle biopsy is the first test demonstrating the histochemical and ultrastructural alterations in mitochondria, even in diseases in which myopathy is not clinically prominent, and is also a good tissue for biochemical analysis, as the biopsy is not dangerous for the patient. Negative results in skeletal muscle do not exclude Respiratory Chain deficiency, and a liver biopsy may be necessary whatever the blood AST and ALT levels, to perform biochemical and molecular investigations. Only the identification of nuclear or mitochondrial mutation confirms the diagnosis.
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Mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency.
Methods in enzymology, 2004Co-Authors: Pierre Rustin, Arnold Munnich, Agnès RötigAbstract:Publisher Summary This chapter analyzes mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency. CoQ10 plays a pivotal role in the mitochondrial Respiratory Chain, distributing the electrons between the various dehydrogenases and the cytochrome segments of the Respiratory Chain. Being in large excess compared to any other component of the Respiratory Chain (RC), it forms a kinetically compartmentalized pool. Depending on its redox and protonation status, CoQ10 can react with molecular oxygen to produce superoxides. In particular, the full reduction of b-type cytochromes and the increased formation of unstable ubisemiquinone ensures maximal superoxide production. Besides the pro-oxidant effect of CoQ10, the fully reduced species (ubiquinol) can reduce a number of radical species, including superoxides, therefore acting as an antioxidant. The chapter presents an overview of Respiratory Chain and ubiquinone. Cellular consequences of CoQ 10 depletion along with clinical presentation of coenzyme Q 10 depletion are also discussed in the chapter. The chapter elaborates the detection of CoQ 10 deficiency and presents the details of supplementation therapy.
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Respiratory Chain deficiency in Alpers syndrome.
Neuropediatrics, 2001Co-Authors: Marion Gauthier-villars, Pierre Rustin, Agnès Rötig, Arnold Munnich, P. Landrieu, Valérie Cormier-daire, Emmanuel Jacquemin, D Chretien, Pascale De LonlayAbstract:Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on Respiratory Chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to Respiratory Chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the Respiratory Chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for Respiratory Chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.
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Quinone-responsive multiple Respiratory-Chain dysfunction due to widespread coenzyme Q10 deficiency
The Lancet, 2000Co-Authors: Agnès Rötig, Vanna Geromel, Marc Lebideau, Noman Kadhom, Dominique Chretien, Eeva-liisa Appelkvist, Patrick Edery, Arnold Munnich, Gustav Dallner, Lars ErnsterAbstract:Summary Background The Respiratory-Chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q 10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. Methods We assessed Respiratory-Chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q 10 content. Clinical follow-up and detailed biochemical investigations of Respiratory Chain activity were carried out over the 3 years of oral quinone administration. Findings Deficiency of coenzyme Q 10 -dependent Respiratory-Chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q 10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q 10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. Interpretation Particular attention should be paid to multiple quinone-responsive Respiratory-Chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.
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Respiratory Chain deficiency presenting as recurrent myoglobinuria in childhood
Neuropediatrics, 1999Co-Authors: P De Lonlaydebeney, Beatrice Parfait, Dominique Chretien, Norma B Romero, Valerie Cormierdaire, Agnès Rötig, Patrick Edery, Arnold Munnich, Jean-marie Saudubray, Pierre RustinAbstract:: Myoglobinuria is an abnormal urinary excretion of myoglobin due to an acute destruction of skeletal muscle fibres. Several metabolic diseases are known to account for myoglobinuria including defects of glycolysis and fatty acid oxidation. Here, we report on Respiratory Chain enzyme deficiency in three unrelated children with recurrent episodes of myoglobinuria and muscle weakness (complex I: one patient, complex IV: two patients). All three patients had generalized hyporeflexia during attacks, a feature which is not commonly reported in other causes of rhabdomyolysis. Studying Respiratory Chain enzyme activities in cultured skin fibroblasts might help diagnosing this condition, especially when acute rhabdomyolysis precludes skeletal muscle biopsy during and immediately after episodes of myoglobinuria.
Arnold Munnich - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency.
Methods in enzymology, 2004Co-Authors: Pierre Rustin, Arnold Munnich, Agnès RötigAbstract:Publisher Summary This chapter analyzes mitochondrial Respiratory Chain dysfunction caused by coenzyme Q deficiency. CoQ10 plays a pivotal role in the mitochondrial Respiratory Chain, distributing the electrons between the various dehydrogenases and the cytochrome segments of the Respiratory Chain. Being in large excess compared to any other component of the Respiratory Chain (RC), it forms a kinetically compartmentalized pool. Depending on its redox and protonation status, CoQ10 can react with molecular oxygen to produce superoxides. In particular, the full reduction of b-type cytochromes and the increased formation of unstable ubisemiquinone ensures maximal superoxide production. Besides the pro-oxidant effect of CoQ10, the fully reduced species (ubiquinol) can reduce a number of radical species, including superoxides, therefore acting as an antioxidant. The chapter presents an overview of Respiratory Chain and ubiquinone. Cellular consequences of CoQ 10 depletion along with clinical presentation of coenzyme Q 10 depletion are also discussed in the chapter. The chapter elaborates the detection of CoQ 10 deficiency and presents the details of supplementation therapy.
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Respiratory Chain deficiency in Alpers syndrome.
Neuropediatrics, 2001Co-Authors: Marion Gauthier-villars, Pierre Rustin, Agnès Rötig, Arnold Munnich, P. Landrieu, Valérie Cormier-daire, Emmanuel Jacquemin, D Chretien, Pascale De LonlayAbstract:Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on Respiratory Chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to Respiratory Chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the Respiratory Chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for Respiratory Chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.
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Quinone-responsive multiple Respiratory-Chain dysfunction due to widespread coenzyme Q10 deficiency
The Lancet, 2000Co-Authors: Agnès Rötig, Vanna Geromel, Marc Lebideau, Noman Kadhom, Dominique Chretien, Eeva-liisa Appelkvist, Patrick Edery, Arnold Munnich, Gustav Dallner, Lars ErnsterAbstract:Summary Background The Respiratory-Chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q 10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. Methods We assessed Respiratory-Chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q 10 content. Clinical follow-up and detailed biochemical investigations of Respiratory Chain activity were carried out over the 3 years of oral quinone administration. Findings Deficiency of coenzyme Q 10 -dependent Respiratory-Chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q 10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q 10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. Interpretation Particular attention should be paid to multiple quinone-responsive Respiratory-Chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.
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Defects of the Respiratory Chain
2000Co-Authors: Arnold MunnichAbstract:Respiratory Chain deficiencies have long been regarded as neuromuscular diseases. However, oxidative phosphorylation (i.e., ATP synthesis by the Respiratory Chain) is not restricted to the neuromuscular system but proceeds in all cells that contain mitochondria (Fig. 13.1). Most non-neuromuscular organs and tissues are, therefore, also dependent upon mitochondrial energy supply. Therefore, due to the twofold genetic origin of Respiratory enzymes [nuclear DNA and mitochondrial (mtDNA)] a Respiratory Chain deficiency can theoretically give rise to any symptom in any organ or tissue at any age and with any mode of inheritance.
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Respiratory Chain deficiency presenting as recurrent myoglobinuria in childhood
Neuropediatrics, 1999Co-Authors: P De Lonlaydebeney, Beatrice Parfait, Dominique Chretien, Norma B Romero, Valerie Cormierdaire, Agnès Rötig, Patrick Edery, Arnold Munnich, Jean-marie Saudubray, Pierre RustinAbstract:: Myoglobinuria is an abnormal urinary excretion of myoglobin due to an acute destruction of skeletal muscle fibres. Several metabolic diseases are known to account for myoglobinuria including defects of glycolysis and fatty acid oxidation. Here, we report on Respiratory Chain enzyme deficiency in three unrelated children with recurrent episodes of myoglobinuria and muscle weakness (complex I: one patient, complex IV: two patients). All three patients had generalized hyporeflexia during attacks, a feature which is not commonly reported in other causes of rhabdomyolysis. Studying Respiratory Chain enzyme activities in cultured skin fibroblasts might help diagnosing this condition, especially when acute rhabdomyolysis precludes skeletal muscle biopsy during and immediately after episodes of myoglobinuria.
David R. Thorburn - One of the best experts on this subject based on the ideXlab platform.
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The importance of liver biopsy in the investigation of possible mitochondrial Respiratory Chain disease
Neuropediatrics, 2005Co-Authors: J. Panetta, David R. Thorburn, Denise M Kirby, Kate Gibson, Avihu BonehAbstract:The diagnosis of mitochondrial Respiratory Chain deficiency is usually made by analysis of mitochondrial Respiratory Chain activity in muscle biopsy. We describe 4 patients in whom the diagnosis was based on mitochondrial Respiratory Chain deficiency in liver alone. In 3 patients, liver complex IV activity was deficient, and the 4th patient had liver complex I deficiency (relative to citrate synthase and complex II activity). The enzyme activities in skeletal muscle biopsies from these patients were normal or equivocal. The age at presentation and the neurological symptoms differed from one patient to another. All 3 patients with complex IV deficiency had non-specific white matter changes on brain MRI. None of the patients had clinical or biochemical evidence of liver disease. These findings illustrate the wide variety of presentations associated with liver mitochondrial Respiratory Chain deficiency. They also demonstrate the importance of mitochondrial Respiratory Chain enzyme analysis in liver, in addition to muscle, even in cases where the primary clinical deficit is neurological and there is no liver disease.
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Minimum birth prevalence of mitochondrial Respiratory Chain disorders in children
Brain, 2003Co-Authors: Daniela Skladal, Jane Halliday, David R. ThorburnAbstract:Mitochondrial Respiratory Chain disorders comprise a group of perhaps several hundred different genetic diseases. Each individual disorder is rare, but collectively they account for substantial use of health care resources. However, few accurate data on prevalence are available due to problems such as variation in clinical presentation, age of onset, referral practices and limitations of diagnostic methodologies. With this retrospective study, we aimed to determine the minimum birth prevalence of Respiratory Chain disorders that have onset in childhood, that is the proportion of births that will have onset of symptoms caused by a Respiratory Chain defect by 16 years of age. Of the 1 706 694 children born in the three south-eastern states of Australia (New South Wales, Victoria and South Australia) between January 1st 1987 and December 31st 1996, samples from 430 were referred for investigation of a Respiratory Chain disorder. Definite diagnosis of a Respiratory Chain disorder was made in 86 cases based on defined clinical, pathological, enzyme and molecular criteria. Age at presentation ranged from 0 to 129 months (median 4 months). The total data set predicts a minimum birth prevalence for Respiratory Chain disorders in children of 5.0/100 000 [95% confidence interval (CI) 4.0-6.2]. A significantly higher figure of 58.6/100 000 (95% CI 34.7-92.6) was noted for Australian families of Lebanese origin. Clinical awareness of Respiratory Chain disorders and investigation methods have improved since 1987, but not all affected children would have been recognized as such from the more recent years. The minimum birth prevalence of 6.2/100 000 (95% CI 4.5-8.4) for the 43 patients born between 1991 and 1994 is thought to be a more accurate estimate for Respiratory Chain disorders presenting in childhood. Combining our data with a previous study on prevalence of adult-onset Respiratory Chain disorders predicts a minimum birth prevalence of 13.1/100 000 or 1/7634 for Respiratory Chain disorders with onset at any age.
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Respiratory Chain complex i deficiency an underdiagnosed energy generation disorder
Neurology, 1999Co-Authors: Denise M Kirby, M Crawford, M A Cleary, H H M Dahl, X Dennett, David R. ThorburnAbstract:Objective: To define the spectrum of clinical and biochemical features in 51 children with isolated complex I deficiency. Background: Mitochondrial Respiratory Chain defects are one of the most commonly diagnosed inborn errors of metabolism. Until recently there have been technical problems with the diagnosis of Respiratory Chain complex I defects, and there is a lack of information about this underreported cause of Respiratory Chain dysfunction. Methods: A retrospective review of clinical features and laboratory findings was undertaken in all diagnosed patients who had samples referred over a 22-year period. Results: Presentations were heterogeneous, ranging from severe multisystem disease with neonatal death to isolated myopathy. Classic indicators of Respiratory Chain disease were not present in 16 of 42 patients in whom blood lactate levels were normal on at least one occasion, and in 23 of 37 patients in whom muscle morphology was normal or nonspecific. Ragged red fibers were present in only five patients. Tissue specificity was observed in 19 of 41 patients in whom multiple tissues were examined, thus the diagnosis may be missed if the affected tissue is not analyzed. Nine patients had only skin fibroblasts available, the diagnosis being based on enzyme assay and functional tests. Modes of inheritance include autosomal recessive (suggested in five consanguineous families), maternal (mitochondrial DNA point mutations in eight patients), and possibly X-linked (slight male predominance of 30:21). Recurrence risk was estimated as 20 to 25%. Conclusion: Heterogeneous clinical features, tissue specificity, and absence of lactic acidosis or abnormal mitochondrial morphology in many patients have resulted in underdiagnosis of Respiratory Chain complex I deficiency.
Anthony H. V. Schapira - One of the best experts on this subject based on the ideXlab platform.
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Current Understanding of Mitochondrial Respiratory-Chain Diseases
NEJM Journal Watch, 2003Co-Authors: Anthony H. V. Schapira, FrcpAbstract:Mitochondrial disorders reflect the ubiquity of mitochondria by encompassing a huge array of diseases spanning virtually every specialty in medicine. DiMauro and Schon provide an excellent, up-to-date overview of mitochondrial Respiratory-Chain diseases. Since the 1980s, well over 100 different mitochondrial DNA (mtDNA) mutations have been identified and associated with human disease. In recent years, attention has shifted from mtDNA mutations to the much more complex involvement in disease pathogenesis of nuclear-encoded subunits of the Respiratory Chain and nuclear-encoded, mitochondrial-located proteins. The authors discuss research …
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Primary and secondary defects of the mitochondrial Respiratory Chain.
Journal of inherited metabolic disease, 2002Co-Authors: Anthony H. V. SchapiraAbstract:Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the Respiratory Chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the Respiratory Chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the Respiratory Chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the Respiratory Chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve Respiratory Chain function may ameliorate the progression of these disorders.
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Primary and secondary deficiencies of the mitochondrial Respiratory Chain
The Neurologist, 1998Co-Authors: Sarah J. Tabrizi, Anthony H. V. SchapiraAbstract:The first observation of mitochondrial Respiratory Chain dysfunction was made in 1959 with the report of a biochemical defect in the skeletal muscle of a euthyroid patient with hypermetabolism. Since then, numerous disorders have been found to be associated with mitochondrial Respiratory Chain dysfunction, the nervous system being particularly affected. In 1988, the discovery of large-scale deletions of mitochondrial UNA (mtDNA) in mitochondrial myopathies and a point mutation associated with Leber's hereditary optic neuropathy marked the beginning of a new era of mitochondrial research with the identification of many more pathogenic mutations. More recently, there has been great interest in the role of mitochondrial dysfunction in neurodegenerative diseases and aging. In this review, we discuss inborn and acquired mitochondrial abnormalities and the relationship of mitochondrial Respiratory Chain dysfunction to neurological disorders.
