16 Chapter 1 MEDIUM CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY The second disease studied in this thesis is a monogenic disease known as Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD). Medium-chain Acyl-CoA dehydrogenase (MCAD) is a flavoprotein containing a flavin adenine nucleotide (FAD). It catalyzes the oxidation of an acyl-CoA with the simultaneous reduction of the flavin, which then needs to be reoxidized85. MCAD is involved in the oxidation of medium chain fatty acids in the mitochondrial β-oxidation. Prior to being metabolized, fatty acids need to be activated into their CoA ester form. The acyl-CoA esters can then be oxidized to acetyl-CoA in order to produce NADH and FADH2. This pathway is of special importance during fasting or situations of high energy demand (cold exposure, infection, etc.) when gluconeogenic precursors are low and we depend on our fat reserves. Medium Chain Acyl-CoA Dehydrogenase Deficiency is the most common fatty acid oxidation disorder with a prevalence of 1:8000 in the Netherlands86. Biochemically, MCADD is characterized by the accumulation of medium-chain monocarboxylic acids and acyl-carnitines. Fatty acids of more than 12 carbons (C12) are often considered to be long while those between 10 and 6 carbons (C10-C6) are referred to as medium-chain fatty acids. Given the lack of efficient oxidation of medium-chain fatty acids, MCADD is also characterized by a high ratio C8 over C10 acylcarnitines87–89. Clinically, MCADD patients are at risk of suffering hypoketotic hypoglycemia (low levels of blood glucose and ketone bodies) which can be fatal2. Interestingly, heterogeneity in symptomatology in MCADD patients is high. While some patients present with severe symptoms, other patients never develop any symptoms, even when carrying the same mutation and without surveillance90–92. While MCADD patients present as healthy under most conditions, they are insufficiently able to oxidize medium-chain fatty acids when they rely on fatty acid reserves such as fasting, illness or long bouts of exercise93. Current methods for the study of MCADD include animal models (rodents)94,95 and artificial KO cell lines. While these models have shed some light onto the pathophysiology of MCADD, both have their own limitations. Although animal models are wholistic systems that allow for a physiologically accurate picture, rodents express a long-chain acyl-CoA dehydrogenase isoform in charge of oxidizing long-chain acyl-CoAs96. LCAD shares substrate specificity with MCAD which might alleviate the phenotype. On the other hand, KO human cell lines allow us to study the disease without expression of LCAD but are limited in terms of cell functionality and lack interaction with other organs. Moreover,
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