Chapter 96

## Abstract

Abstract  Hereditary defects have been described for four of the six enzymes of the γ-glutamyl cycle:

1. Glutathione synthetase deficiency (OMIM 266130) is associated in its severe form with decreased cellular levels of glutathione, massive urinary excretion of 5-oxoproline, elevated levels of 5-oxoproline in the blood and cerebrospinal fluid, severe metabolic acidosis, increased rate of hemolysis, central nervous system symptoms, and defective granulocyte function. Glutathione normally regulates its own biosynthesis by inhibiting γ-glutamylcysteine synthetase, the enzyme that catalyzes the first step in the γ-glutamyl cycle. Therefore, marked reduction of glutathione levels caused by glutathione synthetase deficiency leads to a modified γ-glutamyl cycle, and γ-glutamylcysteine is formed in increased amounts. This dipeptide is converted to 5-oxoproline and cysteine by the action of γ-glutamyl cyclotransferase. The overproduction of 5-oxoproline exceeds the capacity of 5-oxoprolinase to convert this substrate to glutamate, and some of the 5-oxoproline formed is therefore excreted in the urine. More than 65 patients in about 55 families have been described with glutathione synthetase deficiency. Several mutations in the glutathione synthetase gene (OMIM 601002) have been identified.

Previously, two forms of glutathione synthetase deficiency were described on the basis of clinical findings: generalized glutathione synthetase deficiency and erythrocyte glutathione synthetase deficiency. The two forms suggested that there might be several genes involved. Glutathione synthetase is a homodimer with a subunit with a molecular mass of 52 kDa consisting of 474 amino acids. Today, we know that the human genome contains only one glutathione synthetase gene that has been localized to chromosome 20 q 11.2. A new classification of glutathione synthetase deficiency based on the severity of clinical signs--i.e., mild, moderate, and severe glutathione synthetase deficiency--is more appropriate. The mild form of glutathione synthetase deficiency (OMIM 231900) is associated with decreased erythrocyte glutathione levels and well-compensated hemolytic disease. This mild disorder has been identified in 7 patients and seems to be less prevalent than the moderate and severe forms of glutathione synthetase deficiency; it usually does not lead to 5-oxoprolinuria. This inborn error (mild glutathione synthetase deficiency) is probably associated with synthesis of an unstable glutathione synthetase. Turnover of the defective but active enzyme is sufficiently rapid in most tissues to compensate for the defect; however, this is not true for erythrocytes in which protein synthesis does not take place. The moderate form of glutathione synthetase deficiency is associated with hemolytic anemia and metabolic acidosis, while patients with the severe form additionally have progressive neurologic symptoms.

2. Deficiency of γ-glutamylcysteine synthetase (OMIM 230450) has been described in eight patients in six different families. A consistent clinical finding is an increased rate of hemolysis. In addition, two sibs also had spinocerebellar degeneration, peripheral neuropathy, myopathy, and aminoaciduria. The patients had generalized glutathione deficiency and marked deficiency in the synthesis of γ-glutamylcysteine.

3. Five patients with hereditary deficiency of γ-glutamyl transpeptidase (OMIM 231950) have been reported in four families. They exhibit central nervous system involvement, glutathionemia, and urinary excretion of substantial amounts of glutathione, as well as of γ-glutamylcysteine and cysteine moieties. Animal models indicate that this enzyme deficiency is associated with central nervous system dysfunction and growth retardation.

4. Eight individuals in six families with inborn deficiency of 5-oxoprolinase (OMIM 260005) have been reported. They excrete increased amounts of 5-oxoproline in their urine and also have elevated plasma levels of 5-oxoproline. The patients do not have chronic acidosis or other symptoms clearly related to the biochemical defect. The patients have normal activity of glutathione synthetase.

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