Exploring the mechanisms underlying the phenotype of MCAD deficiency with Systems Medicine: from computational model to mice to man

Martines, A-C., 2019, [Groningen]: Rijksuniversiteit Groningen. 275 p.

Research output: ThesisThesis fully internal (DIV)Academic

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  • Title and contents

    Final publisher's version, 271 KB, PDF document

  • Chapter 1

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  • Chapter 2

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  • Chapter 3

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  • Chapter 4

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  • Chapter 5

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  • Chapter 6

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  • Chapter 7

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  • Appendices

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  • Complete thesis

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  • Propositions

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  • Anne-Claire Martines
The deficiency of the enzyme Medium-Chain Acyl-CoA Dehydrogenase (MCAD) is the most prevalent inborn error of mitochondrial fatty acid oxidation (mFAO). During fasting or high fever, when a lot of energy is needed, the liver vividly oxidizes fat to support the production of glucose for other organs. Untreated MCAD-deficient children may suddenly develop life-threatening low blood-glucose levels. However, inexplicably, some untreated individuals never develop any symptoms. MCAD-deficiency is currently detected at birth by newborn screening. Children are treated indiscriminately by avoidance of fasting and frequent carbohydrate-enriched meals. This results in overweight and consequent detrimental health risks.
In this thesis, the question was addressed which molecular factors affect the functioning of the mFAO pathway in healthy and MCAD-deficient liver. The underlying hypothesis was that asymptomatic MCAD-deficient children may have adaptation in such factors. The research project entailed a combination of computational modelling and experimental research. The computational model showed how the mFAO can easily become overloaded and accumulate toxic intermediates, particularly when MCAD is deficient. Vitamin B–derived coenzymes alleviated this risk. Genome-wide analysis of gene expression confirmed an important role of these coenzymes. In MCAD-deficient mice exposed to cold, as well as in skin cells of asymptomatic MCAD-deficient people, further molecular adaptations were found. To evaluate the impact of various adaptations, the computational model was extended with potential protective pathways. This led to identification of a number of protective enzymes and coenzymes, which should eventually provide a basis for a more personalized diagnosis and risk assessment.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Award date10-Jul-2019
Place of Publication[Groningen]
Print ISBNs978-94-034-1799-8
Electronic ISBNs978-94-034-1798-1
Publication statusPublished - 2019

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