Patients with genetic defects in the gamma-glutamyl cycle

In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.