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Human mitochondrial disease: from pathogenesis to therapeutic intervention.

Hart, P.E.; (2005) Human mitochondrial disease: from pathogenesis to therapeutic intervention. Doctoral thesis , University of London. Green open access

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The spectrum of diseases caused by mitochondrial dysfunction is very broad and encompasses the archetypal mtDNA mutation diseases, mutations of nuclear genesencoding mitochondrial proteins (including those of the oxidative phosphorylation system), and a variety predominantly neurodegenerative diseases in which the primary cause of mitochondrial dysfunction remains undefined. The last two decades have seen an explosion in our understanding of the archetypal i mitochondrial disorders. Attention has now focused on the nuclear encoded mitochondrial disorders. Furthermore, nuclear factors may be of significance in the pathogenesis of the archetypal disorders associated with mitochondrial DNA mutations. These conditions are typified by their clinical diversity and poor phenotype-genotype correlation. One of several potential explanations for this is that nuclear genes determine the fate of mtDNA mutations, or that secondary mtDNA mutations have a modulating effect upon the expression of the primary mutation. In this thesis I have sought to address several aspects of the biochemical and clinical features of mitochondrial diseases. In chapter 3 cell cybrids have been used to study the role of the nuclear genome on the biochemical expression of mtDNA mutations in an attempt to understand potential influences on phenotypic expression. An extension of this was the use of xenomitochondrial cybrids to analyse nuclear-mitochondrial interactions and the function of the respiratory chain. At the biochemical/clinical interface, skeletal muscle from patients with focal dystonia has been used as a model to investigate the role that mitochondrial dysfunction might play in this movement disorder. Finally, the clinical role of therapy for mitochondrial disorders has been investigated in the context of Friedreich's ataxia (FRDA). Existing rating scales have been assessed and new ones developed to lay a firm foundation for evaluating disease-modifying therapies. These have been piloted in a long term intervention trial for FRDA.

Type: Thesis (Doctoral)
Title: Human mitochondrial disease: from pathogenesis to therapeutic intervention.
Identifier: PQ ETD:592091
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School
URI: https://discovery.ucl.ac.uk/id/eprint/1444782
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