Key words: organic academia, oxysterol, maple syrup urine disease, methylmalonicacidemia, propionic acidemia, isovaleric acidemia, glutaric aciduria type 1, LCMS/MS

Eraslan Y. Investigation of Oxysterols in Patients with Various Organic Acidurias by LC-MS/MS. Hacettepe University, Faculty of Medicine, Thesis on Department of Pediatrics. Ankara 2018. Organic acidemias are a group of inborn errors of metabolism (IEM) caused mostly by a deficient enzyme in the catabolic pathways of amino acids, carbohydrates or lipids and characterized by abnormal urinary excretion of organic acids. The pathophysiology of these diseases is poorly known and this prevents the development of appropriate treatment strategies. The main factors responsible for the pathophysiology of these diseases are thought to be the accumulation of toxic metabolites and the deficiency of essential metabolic intermediates. Recent studies have shown that accumulating toxic metabolites increases oxidative stress in these disease. It is also thought that the restricted diets which have an important role in the treatment of these patients may lead to a decrease in the antioxidant capacity of tissues due to the lack of certain essential substances in the antioxidant defense systems. In this study, oxysterols (7-keto cholesterol and cholestane-3β,5α,6β-triol) were studied as oxidative stress biomarkers in patients with various organic acidurias (maple syrup urine disease, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, glutaric aciduria type 1) followed at Hacettepe University Department of Pediatrics Metabolism Unit were studied by LC-MS/MS. Plasma oxysterol levels in organic acidemia patients were found to be significantly higher than the control group. No statistically significant difference was found between organic acidemia patient subgroups with respect to oxysterols. There was no statistically significant difference in plasma oxysterol levels of the patients between who were coming for routine clinic visits and who were brought to emergency department. There was no strong correlation between plasma oxysterol levels and age, LDL, triglyceride, total cholesterol, ESR, CRP, blood pH value, urine ketone, urine ketoacid level, plasma free carnitine level in organic acidemia patients; plasma oxysterol levels and leucine levels in patients with MSUD. Based on these findings, it is suggested that oxysterols, free radical-mediated oxidation product of cholesterol, in organic acidemia patients are increased and cause oxidative stress by inducing toxic metabolite stimulation, independent of serum total cholesterol and LDL levels. Increased oxidative stress in these patients is not an acute but chronic process and plays a role in the long-term pathophysiology and prognosis of these diseases and oxysterols can be used in the long-term follow-up of these patients. The use of antioxidants as an adjuvant in the treatment of these patients may be considered. To our knowledge, this is the first study to determine plasma levels of oxysterols in organic acidemia patients. Further studies are required to understand the underlying mechanisms of oxysterol production in depth and their clinical implications in patients with organic acidemia. Key words: organic academia, oxysterol, maple syrup urine disease, methylmalonic acidemia, propionic acidemia, isovaleric acidemia, glutaric aciduria type 1, LC-MS/MS