Breaking down long-chain fatty acid oxidation disorders From pathophysiology to better treatment

In long-chain fatty acid ß-oxidation disorders (lcFAODs) the (mitochondrial) oxidation of long-chain fatty acids is not working properly due to an inherited defect in one of the enzymes involved in the carnitine cycle or in the ß-oxidation cascade. While lcFAODs have been studied extensively during the past decades, there are still several unmet needs in the diagnosis and treatment of this group of patients. Implementation of lcFAODs in newborn screening programs worldwide led to a generally improved outcome and decrease in mortality, but an early diagnosis and timely initiation of treatment is not sufficient to prevent all symptoms. Many patients still suffer from intermittent episodes of rhabdomyolysis, leading to frequent hospitalizations and inability to participate in normal daily life. Furthermore, in some patients the severe cardiac complications, including cardiomyopathy and arrhythmia, cannot be prevented by early start of (dietary) treatment, and may still be fatal. This thesis contains a number of studies that aim to (1) further unravel the pathophysiology in lcFAODs, with focus on cardiac disease; (2) improve the diagnostic and disease severity stratification process; and finally (3) optimize treatment options, in order to provide better care for patients.