Vulnerability to Oxidative Stress In Vitro in Pathophysiology of Mitochondrial Short-Chain Acyl-CoA Dehydrogenase Deficiency: Response to AntioxidantsReport as inadecuate




Vulnerability to Oxidative Stress In Vitro in Pathophysiology of Mitochondrial Short-Chain Acyl-CoA Dehydrogenase Deficiency: Response to Antioxidants - Download this document for free, or read online. Document in PDF available to download.

Objective

To elucidate the pathophysiology of SCAD deficient patients who have aunique neurological phenotype, among fatty acid oxidation disorders, withearly developmental delay, CNS malformations, intractable seizures, myopathyand clinical signs suggesting oxidative stress.

Methods

We studied skin fibroblast cultures from patients homozygous for ACADScommon variant c.625G>A n = 10, compound heterozygousfor c.625G>A-c.319C>T n = 3 or homozygous forpathogenic c.319C>T n = 2 and c.1138C>T n = 2mutations compared to fibroblasts from patients with carnitine palmitoyltransferase2 CPT2 n = 5, mitochondrial trifunctional proteinMTP-long-chain L-3-hydroxyacyl-CoA dehydrogenase LCHAD n = 7,and medium-chain acyl-CoA dehydrogenase MCAD deficiencies n = 4and normal controls n = 9. All were exposed to 50 µMmenadione at 37°C. Additonal conditions included exposure to 39°Cand-or hypoglycemia. Time to 100% cell death was confirmed with trypanblue dye exclusion. Experiments were repeated with antioxidants VitaminsC and E or N-acetylcysteine, Bezafibrate or glucose and temperature rescue.

Results

The most significant risk factor for vulnerability to menadione-inducedoxidative stress was the presence of a FAO defect. SCADD fibroblasts werethe most vulnerable compared to other FAO disorders and controls, and weresimilarly affected, independent of genotype. Cell death was exacerbated byhyperthermia and-or hypoglycemia. Hyperthermia was a more significant independentrisk factor than hypoglycemia. Rescue significantly prolonged survival. Incubationwith antioxidants and Bezafibrate significantly increased viability of SCADDfibroblasts.

Interpretation

Vulnerability to oxidative stress likely contributes to neurotoxicity ofSCADD regardless of ACADS genotype and is significantly exacerbatedby hyperthermia. We recommend rigorous temperature control in SCADD patientsduring acute illness. Antioxidants and Bezafibrate may also prove instrumentalin their management.



Author: Zarazuela Zolkipli, Christina B. Pedersen, Anne-Marie Lamhonwah, Niels Gregersen, Ingrid Tein

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents