Objective: Organic acidaemias are inborn errors of metabolism with an unpredictable course and poorly understood pathogenesis. We hypothesised that oxidative stress due to a relative glutathione deficiency plays a role in these diseases. Glutathione is very important in the intracellular anti-oxidative defence and its synthesis could be impaired because of dietary protein restriction. Simultaneously, adverse effects of organic acids to mitochondrial function could increase free radical production leading to glutathione consumption. To test our hypothesis, we studied the redox state and amount of glutathione in patients with organic acidaemias. If decreased, glutathione levels could be augmented with pharmaceuticals.

Methods: The plasma and erythrocyte cysteine and glutathione concentrations and erythrocyte glutathione peroxidase, glutathione reductase, glutathione S-transferase and glucose-6-phosphate dehydrogenase activities were measured in 11 children with organic acidaemias (methylmalonic, propionic and isovaleric acidaemia) and 10 healthy controls. In addition, glutathione and cysteine concentrations were measured in normal human fibroblasts exposed to increasing concentrations of propionic, methylmalonic and isovaleric acid.

Results: Patients with organic acidaemias had lower plasma glutathione than the control group and a greater fraction of their plasma glutathione and cysteine was protein bound and oxidised, suggesting that both decreased glutathione synthesis and increased consumption were present. The cell culture model partly supported these findings.

Conclusions: Patients with organic acidaemias seem to have a relative glutathione deficiency, which supports the idea of oxidative stress being involved in the pathogenesis of these diseases. In the future, enhancement of glutathione synthesis could thus provide an improvement in the treatment of organic acidaemias.