Inborn errors in the metabolism of glutathione

Abstract

Glutathione (GSH) is a tripeptide present in all mammalian cells. It takes part in several fundamental biological functions, including handling of reactive oxygen species (ROS), detoxification of xenobiotics and carcinogens, redox reactions, biosynthesis of DNA and leukotrienes, as well as neurotransmission/neuromodulation. Oxidative stress may be involved in the pathogenesis of several diseases, such as cancer, ischemia/reperfusion injury, ageing, and neurodegenerative diseases. All these conditions have also been associated with low levels of GSH. There are very few patients with inborn errors in the metabolism of GSH, but they give an opportunity to study the biological functions of GSH.

Glutathione is metabolized via the gamma-glutamyl cycle, which contains six enzymes. In man, recessively inherited defects have been described in 4 of the 6 enzymes. A large inbred Dutch kindred were investigated because of hemolytic anemia and low levels of GSH. A marked reduction in the activity of gamma-glutamylcysteine synthetase was found in two family members and a homozygous mutational defect was localized to the heavy subunit of gamma-glutamylcysteine synthetase. However, the commonest - or least unusual - defect in the gamma-glutamyl cycle is glutathione synthetase (GS) deficiency. This condition has a very wide range of disease manifestations. About 1/3 of the patients have died in the neonatal period. The clinical characteristics of patients with GS deficiency have been clarified, and a new classification based on the severity of clinical signs proposed. Patients with mild disease have only hemolytic anemia. Those with moderate GS deficiency are usually seen in the neonatal period with metabolic acidosis, 5- oxoprolinuria and hemolytic anemia. Patients with severe disease also develop progressive neurological symptoms. It is tempting to speculate that the progressive neurological symptoms are due to defective defense against oxidative stress.

A long-term follow-up study showed that an important prognostic parameter to avoid damage to the CNS in patients with GS deficiency is early supplementation with the antioxidant vitamins C and E. The fact that 2/3 of the surviving patients with GS deficiency have no neurological symptoms, may also be explained by the accumulation of gamma-glutamylcysteine in mutant cells. This dipeptide contains both reactive moieties of GSH - i.e., the gamma-glutamyl and sulthydryl residues - which may therefore replace GSH. The genetic defects have been studied in patients with deficiencies of GS and gamma-glutamylcysteine synthetase. The mutations found in patients with GS deficiency have been expressed in an E. coli system. Hitherto, no simple correlation has been found between the GS mutation and the severity of the symptoms. As the patients become older, new challenges must be considered - e.g., one woman with moderate GS deficiency became pregnant. She had a normal delivery of an apparently normal heterozygous neonate.

On the basis of our studies we conclude that low cellular levels of GSH lead to damage of the CNS by reducing the ability to withstand oxidative stress. The severity of the clinical symptoms depends on the degree of GSH deficiency, but presumably also on other genetic and environmental factors. Finally, we speculate that there are more patients with GS deficiency than with y-glutamylcysteine synthetase deficiency because they accumulate the dipeptide precursor gamma-glutamylcysteine that can at least partly replace GSH.