The Experts below are selected from a list of 11967 Experts worldwide ranked by ideXlab platform
Salvatore Dimauro - One of the best experts on this subject based on the ideXlab platform.
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The clinical maze of Mitochondrial neurology
Nature Reviews Neurology, 2013Co-Authors: Salvatore Dimauro, Eric A. Schon, Valerio Carelli, Michio HiranoAbstract:Mitochondrial diseases are a complex and clinically heterogeneous group of disorders, which— together with our poor understanding of the underlying pathology—makes their diagnosis difficult. Here, DiMauro et al . review current knowledge of defects of the Mitochondrial respiratory complex that lead to neurological Mitochondrial disorders, outlining diagnostic clues for each disorder, and discussing current therapeutic approaches for these often devastating diseases. Few neurological disorders are as phenotypically heterogeneous and diagnostically challenging as Mitochondrial encephalomyopathies The clinical heterogeneity of Mitochondrial disorders can be explained by both the unique rules of Mitochondrial Genetics and the dependence of most Mitochondrial functions on a wide variety of nuclear genes Despite advances in understanding the molecular aetiology of Mitochondrial diseases, their pathogenesis is still largely unknown Through whole-exome or mito-exome sequencing, novel mutant genes and novel disease mechanisms of Mitochondrial disease are being revealed Promising areas of investigation for neurological mitochondria-associated disorders include defects in lipid composition of the Mitochondrial membrane and defects of the mitochondria-associated membrane Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and Mitochondrial DNA (mtDNA). The complexity of Mitochondrial Genetics provides one explanation for the clinical heterogeneity of Mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian Mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical Mitochondrial disease phenotypes. Mendelian Mitochondrial defects can affect five components of Mitochondrial biology: subunits of respiratory chain complexes (direct hits); Mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner Mitochondrial membrane; or Mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and Mitochondrial Genetics. Genetic defects in Mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the Genetics and pathogenesis of the six categories of Mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of Mitochondrial disease, as well as potential therapeutic strategies, is also discussed.
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The clinical maze of Mitochondrial neurology
Nature Reviews Neurology, 2013Co-Authors: Salvatore Dimauro, Eric A. Schon, Valerio Carelli, Michio HiranoAbstract:Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and Mitochondrial DNA (mtDNA). The complexity of Mitochondrial Genetics provides one explanation for the clinical heterogeneity of Mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian Mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical Mitochondrial disease phenotypes. Mendelian Mitochondrial defects can affect five components of Mitochondrial biology: subunits of respiratory chain complexes (direct hits); Mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner Mitochondrial membrane; or Mitochondrial dynamics. A sixth category-defects of mtDNA maintenance-combines features of Mendelian and Mitochondrial Genetics. Genetic defects in Mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot-Marie-Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the Genetics and pathogenesis of the six categories of Mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of Mitochondrial disease, as well as potential therapeutic strategies, is also discussed.
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Mitochondrial DNA Medicine
Bioscience Reports, 2007Co-Authors: Salvatore DimauroAbstract:The small, maternally inherited Mitochondrial DNA (mtDNA) has turned out to be a hotbed of pathogenic mutations: 15 years into the era of ‘Mitochondrial medicine’, over 150 pathogenic point mutations and countless rearrangements have been associated with a variety of multisystemic or tissue-specific human diseases. MtDNA-related disorders can be divided into two major groups: those due to mutations in genes affecting Mitochondrial protein synthesis in toto and those due to mutations in specific protein-coding genes. Here we review the Mitochondrial Genetics and the clinical features of the mtDNA-related diseases.
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Mutations in mtDNA: are we scraping the bottom of the barrel?
Brain Pathology, 2006Co-Authors: Salvatore Dimauro, Antoni L. AndreuAbstract:The small, maternally inherited mtDNA has turned out to be a Pandora's box of pathogenic mutations: 12 years into the era of “Mitochondrial medicine,” about 100 pathogenic point mutations and innumerable rearrangements have been associated with a bewildering variety of multisystemic as well as tissue-specific human diseases. After reviewing the principles of Mitochondrial Genetics, we compare and contrast the clinical and pathological features of disorders due to mutations in genes affecting Mitochondrial protein synthesis with those of mutations in protein-coding genes. In contrast to the striking progress in our understanding of etiology, pathogenesis is only partially explained by the rules of Mitochondrial Genetics and remains largely terra incognita. We review recent progress in prenatal diagnosis and epidemiology. Therapy is still woefully inadequate, but a number of promising approaches are being developed.
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Mitochondrial DNA mutations in human disease.
American Journal of Medical Genetics, 2001Co-Authors: Salvatore Dimauro, Eric A. SchonAbstract:The small, maternally inherited Mitochondrial DNA (mtDNA) has turned out to be a Pandora's box of pathogenic mutations: 13 years into the era of "molecular Mitochondrial medicine," more than 100 pathogenic point mutations and innumerable rearrangements have been associated with a striking variety of multisystemic as well as tissue-specific human diseases. After reviewing the principles of Mitochondrial Genetics, we consider disorders due to mutations in genes affecting Mitochondrial protein synthesis and disorders due to mutations in protein-coding genes. In contrast to the remarkable progress in our understanding of etiology, pathogenesis is only partially explained by the rules of Mitochondrial Genetics and remains largely unclear. We review recent progress in prenatal diagnosis, epidemiology, and in the development of animal models harboring mtDNA mutations.
Robert W. Taylor - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial DNA mutations and human disease
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010Co-Authors: Helen A.l. Tuppen, Douglass M. Turnbull, Emma L. Blakely, Robert W. TaylorAbstract:Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological Mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in Mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of Mitochondrial Genetics, an inability to manipulate the Mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of Mitochondrial Genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances.
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Experimental Strategies Towards Treating Mitochondrial DNA Disorders
Bioscience Reports, 2007Co-Authors: Julie L. Gardner, Douglass M. Turnbull, Lyndsey Craven, Robert W. TaylorAbstract:An extensive range of molecular defects have been identified in the human Mitochondrial genome (mtDNA), causing a range of clinical phenotypes characterized by Mitochondrial respiratory chain dysfunction. Sadly, given the complexities of Mitochondrial Genetics, there are no available cures for mtDNA disorders. In this review, we consider experimental, genetic-based strategies that have been or are being explored towards developing treatments, focussing on two specific areas which we are actively pursuing—assessing the benefit of exercise training for patients with mtDNA defects, and the prevention of mtDNA disease transmission.
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Mitochondrial DNA mutations in human disease
Nature Reviews Genetics, 2005Co-Authors: Robert W. Taylor, Doug M. TurnbullAbstract:The human Mitochondrial genome is extremely small compared with the nuclear genome, and Mitochondrial Genetics presents unique clinical and experimental challenges. Despite the diminutive size of the Mitochondrial genome, Mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic Mitochondrial Genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely. Mutations in the maternally inherited Mitochondrial genome (mtDNA), which contributes essential protein subunits to the enzyme complexes of oxidative phosphorylation, are an important cause of genetic disease. The clinical manifestations of mtDNA disorders are extremely variable; onset of symptoms might occur in infancy or in adulthood and can involve either a single organ or multiple tissues. Multiple copies (several hundreds or thousands) of the Mitochondrial genome are present in individual cells. Many pathogenic mutations only affect a subset of mtDNA molecules, and there are differences in the mutation load between tissues that contribute to the observed clinical heterogeneity. Treatment options for mtDNA disorders are extremely limited, although several new approaches are being considered, including methods to prevent the transmission of pathogenic mutations from mother to offspring. Somatic mtDNA mutations in both human tumours and tissues from ageing individuals are increasingly being described. Recent data from a mouse model engineered to lose mtDNA sequence integrity supports a causal link between mtDNA mutations and the ageing process.
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Gene Therapy for the Treatment of Mitochondrial DNA Disorders
Expert Opinion on Biological Therapy, 2005Co-Authors: Robert W. TaylorAbstract:Despite recent epidemiological studies confirming that Mitochondrial respiratory chain disorders due to mutations in either the Mitochondrial or nuclear genome are amongst the most common inherited human diseases, realistic therapeutic strategies for these patients remain limited. The disappointing response to various vitamins, cofactors and electron acceptors that have been administered to patients in an attempt to bypass the underlying respiratory chain defect, coupled with the complexities of human Mitochondrial Genetics, means that novel and innovative means are required to offer realistic treatments. Several ‘gene therapy’ strategies have therefore been proposed to treat patients with pathogenic Mitochondrial DNA mutations, and although these are not without their own inherent problems, several exciting approaches promise much in the near future. This review will provide a basic background to Mitochondrial Genetics and Mitochondrial DNA disorders before introducing the various strategies being tested...
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Mitochondrial DNA MUTATIONS IN HUMAN DISEASE
Nature Reviews Genetics, 2005Co-Authors: Robert W. Taylor, Douglass M. TurnbullAbstract:The human Mitochondrial genome is extremely small compared with the nuclear genome, and Mitochondrial Genetics presents unique clinical and experimental challenges. Despite the diminutive size of the Mitochondrial genome, Mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic Mitochondrial Genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely.
Eric A. Schon - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Genetics and Disease
Journal of Child Neurology, 2014Co-Authors: Estela Area-gomez, Eric A. SchonAbstract:Mitochondrial disease resulting in reduced bioenergetic output can be due to mutations in either nuclear DNA–encoded or Mitochondrial DNA–encoded gene products. We summarize some of the underlying principles of Mitochondrial Genetics that impact the diagnosis and pathogenesis of Mitochondrial disorders. In addition, we present a brief overview of a new frontier in the field, namely, Mitochondrial “dynamics,” which controls organellar fusion, fission, trafficking, and positioning, and exerts Mitochondrial “quality control” by maintaining organellar integrity and viability. Analysis of mutations in gene products associated with this latter area has opened up new vistas in the study of disorders associated with compromised energy production.
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The clinical maze of Mitochondrial neurology
Nature Reviews Neurology, 2013Co-Authors: Salvatore Dimauro, Eric A. Schon, Valerio Carelli, Michio HiranoAbstract:Mitochondrial diseases are a complex and clinically heterogeneous group of disorders, which— together with our poor understanding of the underlying pathology—makes their diagnosis difficult. Here, DiMauro et al . review current knowledge of defects of the Mitochondrial respiratory complex that lead to neurological Mitochondrial disorders, outlining diagnostic clues for each disorder, and discussing current therapeutic approaches for these often devastating diseases. Few neurological disorders are as phenotypically heterogeneous and diagnostically challenging as Mitochondrial encephalomyopathies The clinical heterogeneity of Mitochondrial disorders can be explained by both the unique rules of Mitochondrial Genetics and the dependence of most Mitochondrial functions on a wide variety of nuclear genes Despite advances in understanding the molecular aetiology of Mitochondrial diseases, their pathogenesis is still largely unknown Through whole-exome or mito-exome sequencing, novel mutant genes and novel disease mechanisms of Mitochondrial disease are being revealed Promising areas of investigation for neurological mitochondria-associated disorders include defects in lipid composition of the Mitochondrial membrane and defects of the mitochondria-associated membrane Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and Mitochondrial DNA (mtDNA). The complexity of Mitochondrial Genetics provides one explanation for the clinical heterogeneity of Mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian Mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical Mitochondrial disease phenotypes. Mendelian Mitochondrial defects can affect five components of Mitochondrial biology: subunits of respiratory chain complexes (direct hits); Mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner Mitochondrial membrane; or Mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and Mitochondrial Genetics. Genetic defects in Mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the Genetics and pathogenesis of the six categories of Mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of Mitochondrial disease, as well as potential therapeutic strategies, is also discussed.
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The clinical maze of Mitochondrial neurology
Nature Reviews Neurology, 2013Co-Authors: Salvatore Dimauro, Eric A. Schon, Valerio Carelli, Michio HiranoAbstract:Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and Mitochondrial DNA (mtDNA). The complexity of Mitochondrial Genetics provides one explanation for the clinical heterogeneity of Mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian Mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical Mitochondrial disease phenotypes. Mendelian Mitochondrial defects can affect five components of Mitochondrial biology: subunits of respiratory chain complexes (direct hits); Mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner Mitochondrial membrane; or Mitochondrial dynamics. A sixth category-defects of mtDNA maintenance-combines features of Mendelian and Mitochondrial Genetics. Genetic defects in Mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot-Marie-Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the Genetics and pathogenesis of the six categories of Mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of Mitochondrial disease, as well as potential therapeutic strategies, is also discussed.
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Functional complementation of Mitochondrial DNAs: mobilizing Mitochondrial Genetics against dysfunction.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2010Co-Authors: Eric A. Schon, Robert GilkersonAbstract:Human Mitochondrial DNA (mtDNA) is a 16.6-kb circular genome that is typically found in approximately 1000 copies per cell. Frequently, one or more forms of mtDNA (i.e. wildtype (WT) and one or more mutant variants) will co-exist within an individual cell, a situation termed heteroplasmy; however, it has been unclear how different mitochondria and mtDNA populations interact functionally in a heteroplasmic cell system. Using sequence-specific microscopic methods to examine mtDNA at suborganellar resolution, we examined the subMitochondrial organization of mtDNA heteroplasmy in nucleoids, the DNA-protein complexes that organize and package mtDNA. Our recent results reveal that, while heterologous mtDNAs are generally maintained stably in separate nucleoid populations, the two mtDNAs transcomplement each other to restore WT-like levels of Mitochondrial function and morphology. These findings reveal that the diffusion of mtDNA-derived transcripts through the Mitochondrial matrix allows for transcomplementation, despite the apparent genetic autonomy of nucleoids. The fundamental ability of mtDNAs to complement each other within the matrix of the Mitochondrial network provides a mechanistic basis for therapeutic strategies designed to restore Mitochondrial function in heteroplasmic cells by increasing WT mtDNA content, particularly in light of the emerging connection between the processes of Mitochondrial fission/fusion and mtDNA nucleoid organization.
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Nucleoid autonomy: An underlying mechanism of Mitochondrial Genetics with therapeutic potential.
Communicative & Integrative Biology, 2008Co-Authors: Robert Gilkerson, Eric A. SchonAbstract:Emerging research shows that the packaging of Mitochondrial DNA (mtDNA) into protein-DNA assemblies called nucleoids confers higher-order organization to the Mitochondrial genome. Studies of nucleoid composition, structure and dynamics reveal the Mitochondrial nucleoid to be tightly regulated in its genetic autonomy, macromolecular organization and distribution throughout the cell. Our recent research shows that Mitochondrial nucleoids are self-contained genetic entities that do not exchange mtDNAs with each other frequently. This suggests that the genetic composition of a cell's nucleoids will be the key determinant of the cell's mtDNA dynamics, and provides a mechanistic basis for therapeutic methods to rescue dysfunction due to mutations in mtDNA.
Doug M. Turnbull - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial disease: Genetics and management
Journal of Neurology, 2016Co-Authors: Yi Shiau Ng, Doug M. TurnbullAbstract:Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the Mitochondrial and nuclear genome make Mitochondrial disease particularly challenging for the clinician. In this review article we cover Mitochondrial Genetics and common neurological presentations associated with adult Mitochondrial disease. In addition, specific and supportive treatments are discussed.
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Mitochondrial DNA mutations in human disease
Nature Reviews Genetics, 2005Co-Authors: Robert W. Taylor, Doug M. TurnbullAbstract:The human Mitochondrial genome is extremely small compared with the nuclear genome, and Mitochondrial Genetics presents unique clinical and experimental challenges. Despite the diminutive size of the Mitochondrial genome, Mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic Mitochondrial Genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely. Mutations in the maternally inherited Mitochondrial genome (mtDNA), which contributes essential protein subunits to the enzyme complexes of oxidative phosphorylation, are an important cause of genetic disease. The clinical manifestations of mtDNA disorders are extremely variable; onset of symptoms might occur in infancy or in adulthood and can involve either a single organ or multiple tissues. Multiple copies (several hundreds or thousands) of the Mitochondrial genome are present in individual cells. Many pathogenic mutations only affect a subset of mtDNA molecules, and there are differences in the mutation load between tissues that contribute to the observed clinical heterogeneity. Treatment options for mtDNA disorders are extremely limited, although several new approaches are being considered, including methods to prevent the transmission of pathogenic mutations from mother to offspring. Somatic mtDNA mutations in both human tumours and tissues from ageing individuals are increasingly being described. Recent data from a mouse model engineered to lose mtDNA sequence integrity supports a causal link between mtDNA mutations and the ageing process.
Douglass M. Turnbull - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial DNA mutations and human disease
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010Co-Authors: Helen A.l. Tuppen, Douglass M. Turnbull, Emma L. Blakely, Robert W. TaylorAbstract:Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by a lack of cellular energy due to oxidative phosphorylation (OXPHOS) defects. Since the identification of the first human pathological Mitochondrial DNA (mtDNA) mutations in 1988, significant efforts have been spent in cataloguing the vast array of causative genetic defects of these disorders. Currently, more than 250 pathogenic mtDNA mutations have been identified. An ever-increasing number of nuclear DNA mutations are also being reported as the majority of proteins involved in Mitochondrial metabolism and maintenance are nuclear-encoded. Understanding the phenotypic diversity and elucidating the molecular mechanisms at the basis of these diseases has however proved challenging. Progress has been hampered by the peculiar features of Mitochondrial Genetics, an inability to manipulate the Mitochondrial genome, and difficulties in obtaining suitable models of disease. In this review, we will first outline the unique features of Mitochondrial Genetics before detailing the diseases and their genetic causes, focusing specifically on primary mtDNA genetic defects. The functional consequences of mtDNA mutations that have been characterised to date will also be discussed, along with current and potential future diagnostic and therapeutic advances.
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Experimental Strategies Towards Treating Mitochondrial DNA Disorders
Bioscience Reports, 2007Co-Authors: Julie L. Gardner, Douglass M. Turnbull, Lyndsey Craven, Robert W. TaylorAbstract:An extensive range of molecular defects have been identified in the human Mitochondrial genome (mtDNA), causing a range of clinical phenotypes characterized by Mitochondrial respiratory chain dysfunction. Sadly, given the complexities of Mitochondrial Genetics, there are no available cures for mtDNA disorders. In this review, we consider experimental, genetic-based strategies that have been or are being explored towards developing treatments, focussing on two specific areas which we are actively pursuing—assessing the benefit of exercise training for patients with mtDNA defects, and the prevention of mtDNA disease transmission.
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Mitochondrial DNA MUTATIONS IN HUMAN DISEASE
Nature Reviews Genetics, 2005Co-Authors: Robert W. Taylor, Douglass M. TurnbullAbstract:The human Mitochondrial genome is extremely small compared with the nuclear genome, and Mitochondrial Genetics presents unique clinical and experimental challenges. Despite the diminutive size of the Mitochondrial genome, Mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease. Recent years have witnessed considerable progress in understanding basic Mitochondrial Genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer. However, many challenges remain, including the prevention and treatment of these diseases. This review explores the advances that have been made and the areas in which future progress is likely.
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Genotypes from patients indicate no paternal Mitochondrial DNA contribution.
Annals of Neurology, 2003Co-Authors: Robert W. Taylor, Patrick F. Chinnery, Neil Howell, Emma L. Blakely, Martina T. Mcdonnell, Geoffrey A. Taylor, Massimo Zeviani, Egill Briem, Franco Carrara, Douglass M. TurnbullAbstract:A cornerstone of Mitochondrial Genetics, strict maternal inheritance, has been challenged recently by the study of a patient with Mitochondrial myopathy due to a sporadic 2bp deletion. The Mitochondrial DNA (mtDNA) harboring the mutation was paternal in origin, whereas the patient's blood was identical to the maternal genotype. To determine whether this is a common phenomenon, we studied mtDNA sequence variation between muscle and blood from 35 patients with sporadic Mitochondrial myopathies, but detected no evidence of paternal mtDNA transmission. Our findings suggest that paternal transmission of mtDNA is rare and should not alter our genetic advice to families.
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The inheritance of Mitochondrial DNA heteroplasmy: random drift, selection or both?
Trends in Genetics, 2000Co-Authors: Patrick F. Chinnery, Robert N. Lightowlers, Douglass M. Turnbull, David R. Thorburn, David C. Samuels, Sarah L. White, Hans-heinrik M Dahl, Neil HowellAbstract:The mammalian Mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of Mitochondrial Genetics.