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Mitochondrial diseases are caused by gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and they are among one of the most common forms of inherited disorders. It is estimated that 1 out of every 5000 individuals will develop a mitochondrial disease in their lifetime. Due to the crucial and widespread functionality of mitochondria in human cells, prolonged diseases of the mitochondria affect cells of the brain, heart, liver, muscles and kidneys and can lead to multi-organ failure in some patients. Inherited or acquired mitochondrial diseases can present at any stage of life, affecting both children and adults. Since its discovery, the mitochondrial genome has been analyzed and sequenced with increasing ease and this process has helped recognize various mitochondrial disorders as the root of genetic diseases. This paper will explore the unique properties of the mitochondrion and its genome, examine the relationship between mtDNA and some common myopathies such as Leigh syndrome (LS) or maternally inherited Leigh syndrome (MILS), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in order to explore commonalities and differences in their inheritance patterns and their effect on mitochondrial function. Although studies have shown that these conditions generally affect the process of oxidative phosphorylation in mitochondria, because of the wide variety of presentations of this disease, further research is needed to understand the different etiologies, as well as to explore novel therapies to treat them.

Mitochondrial disorders are considered to be the most common cause of metabolic abnormalities in the paediatric neurology population (Zeviani et al., 1996). These authors reported that the phenotypes observed in 25-30% of the paediatric patients in their neurology clinics were due to a mitochondrial aetiology. The genetic aetiology in an equivalently affected paediatric population in South Africa is currently unknown. This study investigated the possibility that reported mutations could account for the mitochondrial phenotypes observed in the South African population. It focussed on the most frequent paediatric mitochondrial disorders namely: Leigh Syndrome (LS), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and myoclonic epilepsy and ragged red muscle fibres (MERRF). A clinically well characterised group of 25 patients with mitochondrial disorders was included in this study. The molecular analysis of the mitochondrial genome was initially based on a restriction fragment length polymorphism (RFLP) screening strategy for the ten most common mitochondrial DNA (mtDNA) mutations associated with the above¬mentioned three disorders. However, during the study the mutation analysis strategy was modified to a sequencing strategy as this provided more information than the RFLP approach. The modified sequencing strategy extended the study to incorporate fifteen additional mtDNA mutations, associated with other mitochondrial disorders, and individuals included in the study were thus investigated for the presence of 25 mtDNA mutations. Moreover, the modified strategy provided additional information of the regions encompassing the reported mutations. A single patient was observed to harbour the reported A3243G MELAS mutation. This mutation was noted to be heteroplasmic in the proband and two of her maternal relatives. None of the other 24 reported mutations were observed in this patient population. One novel mtDNA alteration in the tRNALeu(UUR) gene was observed in a single patient, although the pathogenicity of this mutation remains to be investigated. Novel and reported polymorph isms, some of which are associated with specific haplogroups, were also observed when comparing sequencing data against the Cambridge reference sequence. The data generated during this study contributed towards the understanding of the uniqueness of the South African population in the global context. This was apparent from the fact that only one of the reported mutations was observed in our patient population who were clinically well characterised and displayed phenotypes similar to those reported internationally. Results form this study underlined the complexity of mitochondrial disorders and argues in favour of whole mitochondrial genome sequence information to be used for diagnostic purposes. Moreover, the results confer with the hypothesis that novel mitochondrial mutations may account for the majority of mitochondrial phenotypes observed in the South African population. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2007. / Genetics / unrestricted

The aim of this thesis was to assess the influence of canistherapeutic intervention on the level of fine motor skills in patients with rare diseases, namely mitochondrial encephalocardiomyopathy caused by TMEM70 gene mutation and Leigh syndrome. Canistherapeutic intervention in these patients is based on activation of motoric functions during programme reasonably designed according to the needs of specific patients. The assistance of the dog is used to achieve this activation. The dog acts as an important motivational factor and the direct contact with it contributes to development of sensomotoric skills of these patients. The thesis summarizes general information about rare diseases and focuses on one of the subgroups of mitochondrial disorders. It presents knowledge about the Leigh syndrome and mitochondrial encephalocardiomyopathy caused by TMEM70 gene mutation. Subsequently the thesis presents information about canistherapy and fine motor skills. The thesis further contains case reports of patients, data from research units and their evaluation. The aim of the thesis was to find out whether patients with mitochondrial disease show improvement of quality and effectivity of selected grasp forms and thus faster and more precise execution assigned tasks focusing on object manipulations. Partial...

Cytochrome c oxidase (COX) represents the terminal enzyme complex of respiratory chain metabolic pathway and it occurs as monomer, dimer or as a part of respiratory supercomplexes in the inner mitochondrial membrane. COX assembly process is complicated, highly regulated and depends on many ancillary proteins. Mutations in COX subunits, which are encoded by mitochondrial and nuclear DNA, or in genes encoding its assembly proteins are frequent cause of very severe mitochondrial disorders. SURF1 assembly protein participates in the first steps of COX assembly, but its exact function is not yet clarified. In humans, mutations of SURF1 gene lead to severe COX defect and fatal neurodegenerative disorder, Leigh syndrome. Knockout of SURF1 gene in mouse causes isolated COX defect as well, but less pronounced and without involvement of CNS. The aim of the thesis was detailed analysis of disturbed COX biogenesis in a condition of SURF1 gene mutations or SURF1 gene knockout, from assembly of COX monomer to interaction of COX into supercomplexes, and to the impact of isolated COX defect on other OXPHOS complexes. Mutations of SURF1 gene in patient's fibroblasts led to marked accumulation of COX assembly intermediates and to a defect in formation of functional COX monomer, which was preferentially built into an...

Cytochrome c oxidase (COX) represents the terminal enzyme complex of respiratory chain metabolic pathway and it occurs as monomer, dimer or as a part of respiratory supercomplexes in the inner mitochondrial membrane. COX assembly process is complicated, highly regulated and depends on many ancillary proteins. Mutations in COX subunits, which are encoded by mitochondrial and nuclear DNA, or in genes encoding its assembly proteins are frequent cause of very severe mitochondrial disorders. SURF1 assembly protein participates in the first steps of COX assembly, but its exact function is not yet clarified. In humans, mutations of SURF1 gene lead to severe COX defect and fatal neurodegenerative disorder, Leigh syndrome. Knockout of SURF1 gene in mouse causes isolated COX defect as well, but less pronounced and without involvement of CNS. The aim of the thesis was detailed analysis of disturbed COX biogenesis in a condition of SURF1 gene mutations or SURF1 gene knockout, from assembly of COX monomer to interaction of COX into supercomplexes, and to the impact of isolated COX defect on other OXPHOS complexes. Mutations of SURF1 gene in patient's fibroblasts led to marked accumulation of COX assembly intermediates and to a defect in formation of functional COX monomer, which was preferentially built into an...

La protéine mitochondriale LRPPRC (leucine-rich pentatricopeptide repeat motif containing), codée par le gène nucléaire du même nom, est impliquée dans la stabilisation des ARNm mitochondriaux, particulièrement les ARNm codants pour l’assemblage du complexe IV (COX) de la chaîne respiratoire mitochondriale (OXPHOS). Le syndrome de Leigh de type canadien français (LSFC) est une maladie mitochondriale neurodégénérative caractérisée par une mutation spécifique A354V du gène Lrpprc, et par une déficience de l’activité de COX. Les organes les plus affectés sont le foie et le cerveau mais, les mécanismes associés à la progression de la maladie restent encore peu compris. Un modèle murin à délétion hépato-spécifique en LRPPRC (H-LRPPRC KO) a été créé dans le but d’étudier l’aspect hépatique du LSFC caractérisé par des dommages et une stéatose hépatique. Représentant l’objectif 1 de ce mémoire, le modèle H-LRPPRC KO a été utilisé pour une étude de caractérisation de la stéatose hépatique non-alcoolique (SHNA) sans obésité dans laquelle nous avons pu mettre en évidence une progression plus avancée de la pathologie hépatique chez les souris mâles associée à la présence d’une dysfonction cardiaque diastolique. L’objectif 2 de ce mémoire a pour but la caractérisation d’un nouveau modèle murin plus représentatif du LSFC pour ultimement trouver de nouvelles signatures/approches thérapeutiques. Nous utilisons cette fois un modèle murin développé par nos collaborateurs, à délétion inductible (KI), par le tamoxifène, de Lrpprc sur un allèle tandis que le deuxième exprime la mutation A354V spécifique au LSFC pour ainsi caractériser la maladie d’un point de vue biochimique et moléculaire. Nos premiers résultats montrent des signatures et caractéristiques comparables à celles observées chez les patient(e)s LSFC et dans le modèle H-LRPPRC KO avec une perte de poids drastique, une diminution des niveaux de la protéine LRPPRC et de COX et plusieurs perturbations du profil lipidomique dans le foie, le plasma et le cerveau. Ces résultats posent les bases biochimiques et moléculaires de ce modèle pour justifier son utilisation ultérieure pour l’évaluation des manifestations cliniques comme les atteintes musculaires et encore cognitives tel qu’observé chez les personnes atteintes de LSFC. / The mitochondrial protein LRPPRC (leucine-rich pentatricopeptide repeat motif containing), encoded by the nuclear gene of the same name, is involved in the stabilization of mitochondrial mRNAs, particularly those coding for the assembly of complex IV (COX) of the mitochondrial respiratory chain (OXPHOS). Leigh syndrome French Canadian type (LSFC) is a mitochondrial neurodegenerative disease characterized by a specific A354V mutation in the Lrpprc gene as well as a deficiency in COX activity. The most affected organs are the liver and brain, but the mechanisms associated with disease progression remain poorly understood. A hepato-specific knockout of LRPPRC mouse model (H-LRPPRC KO) was created to study the hepatic aspect of LSFC which includes liver damage and steatosis. Defined as the first objective of this master’s thesis, the H-LRPPRC KO model was used for the characterization of non-alcoholic hepatic steatosis (NAHS) without obesity in which we were able to highlight a more advanced progression of liver pathology in male mice associated with the presence of cardiac diastolic dysfunction. Furthermore, the second objective of this master’s thesis aims to characterize a new mouse model more representative of LSFC to ultimately find new therapeutic signatures/approaches. Here, we use a mouse model developed by our collaborators with tamoxifen-inducible deletion (KI) of Lrpprc on one allele, while the second one expresses the LSFC-specific A354V mutation, to characterize the disease from a biochemical and molecular perspective. Our initial results show signatures and characteristics comparable to those observed in LSFC patients as well as in the H-LRPPRC KO model, with drastic weight loss, reduced protein levels of LRPPRC and COX, and several disturbances of the lipidomic profile in liver, plasma and brain. These results lay the biochemical and molecular foundations of this model, justifying its future use in the evaluation of clinical manifestations such as muscular and cognitive impairment as observed in LSFC patients.