Profiling of oxidative stress in patients with inborn errors of metabolism

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 nonspecific 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 dityrosine. 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.

Pathogenic Mutations Differentially Affect the Catalytic Activities of the Human B12-processing Chaperone CblC and Increase Futile Redox Cycling

“…Arg-161 is highly conserved, and disease severity and age of onset are correlated with whether it is mutated to glutamine or glycine. Furthermore, cblC patients exhibit high levels of oxidative damage biomarkers, and human cblC fibroblasts have elevated levels of ROS (26,38). Furthermore, an imbalance in GSH metabolism with a significant decrease in GSH and an increase in GSSG concentration has been reported in CblC-deficient individuals (40).…”

Noncompaction of the Ventricular Myocardium and Hydrops Fetalis in Cobalamin C Disease

“…The role of MMACHC in development is unknown but given that MMADHC, a related enzyme in the pathway and a MMACHC binding partner (Plesa et al 2011), was not expressed in the same temporal/spatial pattern may indicate a unique role for MMACHC in cardiac physiology and/or development (Pupavac et al 2011). Other factors related to the biology of MMACHC may be contributory: MMACHC can localize to mitochondria (Pagliarini et al 2008) and cblC patients and their fibroblasts have increased markers of oxidative stress suggesting underlying mitochondrial dysfunction (Richard et al 2009;Mc Guire et al 2009). In addition, patient-derived cells display global dysregulation of cytoskeletal proteins, such as actin, lamin A/C, and collagen VI (Hannibal et al 2011).…”

Vitamin B12 and Redox Homeostasis: Cob(II)alamin Reacts with Superoxide at Rates Approaching Superoxide Dismutase (SOD)

“…Cbl likely acts as a second line of defense when O 2 •-levels overwhelm the SOD protection system, perhaps accounting for the significantly increased oxidative damage markers in patients with inherited disorders of intracellular Cbl metabolism. 19 Given that B 12 is nontoxic even at high doses and that a significant proportion of the elderly are B 12 deficient, our results provide a compelling argument for clinical trials studying the pharmacological effects of B 12 in the treatment and prevention of diseases associated with chronic inflammation and aging. •-levels in HAEC.…”