Two forms of glutathione synthetase deficiency have been described; a mild form, referred to as glutathione synthetase deficiency of erythrocytes, causing hemolytic anemia, and a more severe form causing 5-oxoprolinuria with secondary neurologic involvement (266130).
Mohler et al. (1970) described a man of Scottish extraction with hemolytic anemia due to deficiency of glutathione synthetase. Four children of the proband, 1 of 3 of his sibs, and both parents had intermediate levels of enzyme. ... Mohler et al. (1970) described a man of Scottish extraction with hemolytic anemia due to deficiency of glutathione synthetase. Four children of the proband, 1 of 3 of his sibs, and both parents had intermediate levels of enzyme. Presumably, the families of Oort et al. (1961) and of Boivin et al. (1966) had the same condition. In the family reported by Prins et al. (1966), 3 of 12 sibs from second-cousin parents had absence of glutathione in the erythrocytes. The clinical picture was that of nonspherocytic hemolytic anemia. Glyoxalase activity, which is dependent on glutathione as a cofactor, was also deficient. Other enzymes were increased, presumably due to the younger average age of erythrocytes. In a later report on the kindred, 5 cases in 2 sibships, with all 4 parents traced to a common ancestral couple, were described. Glutathione (gamma-glutamyl-cysteinyl-glycine) was less than 10% of normal in presumed homozygotes. Spielberg et al. (1978) showed an enzymatic difference between 5-oxoprolinuria (pyroglutamic aciduria) and isolated hemolytic anemia due to glutathione synthetase deficiency. In the former all cell types examined have grossly deficient enzyme activity and glutathione content. In contrast, in the nonoxoprolinuric variant, red cells have reduced enzyme and glutathione, but nucleated cells are normal. The enzyme from the latter type is unstable in vitro and shows shortened survival in intact erythrocytes. Nucleated cells are apparently able to maintain sufficient enzyme activity and glutathione content to suppress overproduction of 5-oxoproline. Beutler et al. (1986) described 2 sibs with hemolytic anemia. Their red cells lacked GSH and were severely deficient in GSH-S. No neurologic abnormalities or 5-oxoprolinuria were present. A concurrent glutathione-S-transferase (GST; see 138350) deficiency was also found in red cells. The GSH-S activity was one-half normal in the parents, but GST was normal, indicating that GSH-S deficiency is the primary defect. Glutathione stabilizes GST.
In the patient with GSS deficiency reported by Mohler et al. (1970), Shi et al. (1996) identified a homozygous missense mutation in the GSS gene (601002.0007).