11 1 General Introduction On the other end of the spectrum, there are also monogenic diseases where a single mutation can lead to disturbances in fatty acid metabolism. These genetic diseases, which lead to a deficiency of a single enzyme of any metabolic pathway related to the metabolism of carbohydrates, fats or protein are known as inborn errors of metabolism (IEM)41. Some examples of inborn errors of metabolism affecting mitochondrial β-oxidation are deficiencies in any of the dehydrogenases involved in the first step of the pathway (SCADD, MCADD and VLCADD)42. IEMs often present during childhood, and they can lead to the development of life-threating symptoms. Despite the fact that extensive research is currently being done, the fact remains that these diseases are commonly only managed palliatively as no cure is known for most of them. This thesis focuses on two diseases affecting lipid metabolism on both ends of the spectrum: one caused by an imbalance of the diet (severe malnutrition) and the other by a genetic mutation in the ACADM gene (MCADD). SEVERE MALNUTRITION The first disease central to the thesis is Severe malnutrition (SM). Malnutrition refers to an imbalance or deficit in the intake of energy and nutrients required to maintain homeostasis. Malnutrition can be caused by either a deficiency or an excess of nutrients, undernutrition and overnutrition respectively43. In this thesis, the term malnutrition is used to refer to undernutrition. Severe malnutrition is known as the most severe form of macronutrient deficiency. In the case of children, this can hamper optimal growth and development44. There are different types of malnutrition, namely stunting, wasting, underweight and deficiencies of vitamins and minerals. Stunting refers to children who are too short for their age. Wasting is used to describe children who are too thin for their height. Finally, the term undernutrition engulfs both stunting and wasting. Severe malnutrition is a highly challenging global health problem: in 2023 approximately 45 million children were wasted, of whom 13.7 million were severely wasted45. Severe malnutrition is common in low-income countries, where diets are often high in carbohydrates and contain low amounts of protein46. Children suffering from malnutrition present with a wide spectrum of symptoms affecting the liver and the intestine amongst other organs47. Severely malnourished children often suffer from intestinal dysfunction, including diarrhea and increased permeability of the intestinal barrier. These factors can contribute to increased risk of dehydration and sepsis respectively48.
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