Long-chain fatty acid oxidation disorders: biochemical, pathophysiological and clinical aspects

While newborn screening in lcFAO deficient patients is performed using bloodspot acylcarnitine analysis, the follow-up of patients with a lcFAO disorder is usually done by plasma acylcarnitine analysis. In chapter 2, the differences between acylcarnitine profiles in plasma and bloodspots are described. Although bloodspot acylcarnitine analysis is a good way to determine very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, patients were missed. In chapter 3 a new marker that enhanced the sensitivity to detect VLCAD deficiency are described. A major challenge in VLCAD deficiency is however to predict disease severity based on biochemical and molecular testing. In chapter 4, the best predictor for clinical outcome of VLCAD deficient patients was investigated. Fatty acid oxidation flux in cultured fibroblasts appeared to be the best predictor. Many clinical studies in the past have focused on disease presentations. In chapter 5, cardiac function of lcFAO deficient children that have been diagnosed years before is described. Normal cardiac function with only a minimal decrease in myocardial contractility was observed. In chapter 6, the consequences of rhabdomyolysis on muscle of patients with lcFAO disorders have been visualized. Specific abnormalities are observed on MRI, which may reflect lipid accumulation secondary to lcFAO deficiency or due to accumulating muscle damage. To investigate the cause of rhabdomyolysis of which the pathogenic basis has been poorly understood, MRS during prolonged exercise of the vastus lateralis muscle was performed. In chapter 7, impaired ATP homeostasis during prolonged exercise in VLCADD patients was are described. Mouse models are crucial to gain mechanistic insight in disease symptoms. In chapter 8, a new mouse model for lcFAO deficiency was studied. Fasting lowers energy expenditure and induces inactivity in these mice. Surgical procedures in patients with lcFAO disorders require specific measures to improve energy homeostasis and reduce long-chain fatty acid load to prevent symptoms such as rhabdomyolysis. Hence, a specific perioperative regimen in patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is discussed in chapter 9. Newborn screening does not discriminate between isolated LCHAD deficiency, isolated long-chain keto acyl-CoA (LCKAT) deficiency and general mitochondrial trifunctional protein (MTP) deficiency. In chapter 10 a classification system to discriminate between these disorders based on enzymatic measurements is described and applied to two new cases. One of whom presented with necrotizing enterocolitis, a symptom previously not associated with MTP deficiency. Finally, in chapter 11, all the findings are discussed and future research directions are provided.