Gamma-Glutamylcysteine Synthetase Deficiency, Hemolytic Anemia Due To

A number sign (#) is used with this entry because the disorder is caused by mutation in the gene encoding gamma-glutamylcysteine synthetase (GCLC; 606857), the first rate-limiting enzyme in glutathione biosynthesis.

Description

Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001).

Clinical Features

Konrad et al. (1972) described a brother and sister of German descent with hemolytic anemia due to deficiency of the first enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase. There was no known consanguinity in the family. Obligatory heterozygotes had an intermediate level of enzyme. Glutathione levels of red cells were normal in heterozygotes. Both affected sibs had late-onset spinocerebellar degeneration. The same sibs were reported by Richards et al. (1974).

Beutler et al. (1990) reported the second family in which gamma-glutamylcysteine synthetase deficiency was documented, the first family being that studied by Konrad et al. (1972) and Richards et al. (1974). The second family demonstrated that neurologic symptoms are not necessarily manifestations of this enzyme defect.

Hirono et al. (1996) described the first Japanese patients with chronic nonspherocytic hemolytic anemia and marked deficiency of red blood cell glutathione. The 3 patients were unrelated; 1 patient had decreased glutathione synthetase (601002), and the other 2 had moderate deficiency of gamma-glutamylcysteine synthetase.

Inheritance

Gamma-glutamylcysteine synthetase deficiency is an autosomal recessive trait. Accordingly, first-degree relatives tend to have partial reduction of the enzyme (Larsson and Anderson, 2001).

Molecular Genetics

Beutler et al. (1999) determined the partial genomic structure of the catalytic subunit of GCLC. They identified a his370-to-leu mutation (606857.0001) in the GCLC gene in a patient with hemolytic anemia due to gamma-glutamylcysteine synthetase deficiency.

Animal Model

Using gene targeting techniques to disrupt the mouse Gclc gene, Dalton et al. (2000) observed embryonic lethality prior to embryonic day 13 (E13) in homozygous mutants. Shi et al. (2000) also reported embryonic lethality by E8.5 in mice lacking functional Gclc. Using Western immunoblot analysis, Dalton et al. (2000) detected an approximately 50% reduction in Gclc protein levels in the liver of heterozygous mutant mice, which had normal viability and fertility. They found a corresponding decrease of 45% in gamma-glutamylcysteine synthetase (Gcl) activity in heterozygous animals, but only a 20% decrease in glutathione levels. A compensatory increase of approximately 30% in hepatic ascorbate levels occurred in heterozygous animals.