Van der Westhuizen 2015 Abstract MiPschool Cape Town 2015

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Investigating mitochondrial disorders in the South African context: meeting diversity with modern-day science.


van der Westhuizen FH, Louw R, Smuts I (2015)

Event: MiPschool Cape Town 2015

Disorders of energy metabolism are the largest group of rare diseases in humans and are caused by mtDNA and nDNA mutations in more than 240 genes. Amongst these genetic and phenotypic highly diverse disorders, mitochondrial respiratory chain disease (RCD) has an estimated prevalence of ~1:5000 in populations worldwide. Although research, diagnostics and more recently also therapies receives a lot of attention in developed countries, this has not been the case in Africa. We have approached the identification and characterization of these disorders as a multidisciplinary research project since 1998, focusing on RCD in paediatric patients of predominantly the northern provinces of South Africa. Some of the key features that shaped the trajectory of this study have been the population diversity in Southern Africa, demographic, socio-economic and health system constraints, as well as limited genetic information of the indigenous African populations.

From a total patient group of of ~6000 new referrals to the paediatric neurology clinic at mainly the Steve Biko Academic Hospital (Pretoria) since 2006, a current study cohort of ~200 paediatric cases (61% African, 32% Caucasian, 7% other) with clinical scoring criteria suggestive of mitochondrial involvement had undergone a required muscle biopsy for further investigations. Over time, these cases had undergone extensive enzymology with ~65% showing a single or combined respiratory chain enzyme deficiency. Functional investigations, metabolomics and molecular genetics investigations were also conducted with the objectives of 1) accurate diagnosis, 2) identifying a urine metabolic biosignature (i.e. combination of metabolites) to improve case selection and 3) investigating the aetiology of these disorders. Within the investigations done over the past decade, we had used investigations, such as respiratory chain enzyme kinetics, respirometry and proteomics; as well as novel and high end technologies such as targeted and untargeted metabolomics, and various next generation sequencing applications for mtDNA and nuclear gene panel sequencing.

Labels: MiParea: Respiration, Instruments;methods, mtDNA;mt-genetics, mt-Medicine, Patients 

Abstract continued

From these investigations the key findings were: Firstly, looking at the phenotype, muscle involvement was more prevalent in patients of African descent, compared to Caucasian patients. Secondly, we were able to identify a metabolic biosignature in urine, which promises to greatly assist in the selection criteria for patients in line to undergo muscle biopsies. Finally, from current molecular genetic data, the prevalence of mtDNA mutations is significantly lower (<1%) compared to other population groups. Although ongoing, we have already identified a number of known and novel nuclear gene mutations, but we also foresee that other genetic and non-genetic factors may play a significant role in the aetiology of these patients.

From this, as well as other studies, we conclude that the notoriously heterogeneous and perplexing nature of mitochondrial disorders in humans is further compounded in a genetically, demographically and socio-economically diverse country such as South Africa. On the other hand, in these challenging settings, investigations into the role of mitochondrial function/dysfunction in non-communicable human diseases are, in fact, becoming progressively relevant and vital to pursue.


Biochemistry, Centre for Human Metabonomics, North-West Univ, South Africa. -