Disorders of mitochondrial fatty acid oxidation

Fatty acid oxidation disorders (FAODs) are inheritable metabolic diseases (IMD) that disrupt the breakdown of fat into energy, potentially leading to problems in the  liver, heart, brain and muscle, as well as life-threatening metabolic crises. While clinical symptoms vary among individuals affected by FAODs, the underlying mechanisms remain incompletely understood. In this thesis, various challenges in the screening, diagnostics, and management of mitochondrial fatty acid oxidation disorders (FAODs) are addressed, with a focus on medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

The thesis initially centres on prevention and evaluates the Dutch newborn screening program for MCADD. It also discusses the development of a perinatal protocol to expedite the diagnosis of neonates at high risk of an IMD. Subsequently, the thesis delves into predicting disease severity of MCADD. This involves the use of personalised computational models of fatty acid oxidation in the livers of MCADD patients. Additionally, it explores fasting tolerance in infants with MCADD through an explorative, clinical study and identifies risk factors for metabolic decompensation in children with MCADD via a retrospective cohort study.

The thesis also examines personalization of management, including a study on the effects of carnitine deficiency and supplementation in persons with MCADD, as well as by an international systematic analysis of the efficacy and safety of D,L-3-beta-hydroxybutyrate as a potential treatment for individuals with FAODs. Overall, the thesis emphasizes the potential of transitioning toward "P4" medicine —  preventive, predictive, personalised, and participatory—in FAOD research and healthcare.

Dissertation: https://hdl.handle.net/11370/7f260c38-9c29-4c32-ba86-35110ad86c27