Abstract
Free radical formation resulting in oxidative stress is a hallmark of mitochondrial dysfunction. Indeed, oxidative stress has been demonstrated to be an underlying pathophysiologic process in various inborn errors of metabolism. Metabolic profiling of oxidative stress may provide a non-specific measure of disease activity that may further enable physicians to monitor disease. In the present study, we investigated two markers of oxidative damage in urinary samples from IEM subjects and controls: F-2 isoprostanes, a measure of lipid peroxidation and di-tyrosine, a measure of protein oxidation. We also determined urinary antioxidant activity in these samples. Subsets of IEM patients showed significantly higher levels of the damage markers isoprostanes and di-tyrosine. Of note, patients with cobalamin disorders (i.e., CblB and CblC) consistently had the highest levels of oxidative damage markers. Lower urine antioxidant capacity was seen in all subject categories, particularly cobalamin disorders and propionic acidemia. Longitudinal studies in subjects with MSUD showed good concordance between markers of oxidative damage and acute decompensation. Overall, quantifying oxidative stress offers a unique perspective to IEM. These measures may provide a means of addressing mitochondrial function in IEM and aid in the development of therapeutic targets and clinical monitoring in this diverse set of disorders.