Glutathione Synthetase Deficiency

A number sign (#) is used with this entry because glutathione synthetase deficiency, or 5-oxoprolinuria, is caused by homozygous or compound heterozygous mutation in the gene encoding glutathione synthetase (GSS; 601002) on chromosome 20q11. The same gene is mutant in hemolytic anemia due to glutathione synthetase deficiency of erythrocytes (231900).

Also see 5-oxoprolinuria due to oxoprolinase deficiency (260005).

Description

Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and central nervous system damage. The metabolic defect results in decreased levels of cellular glutathione, which overstimulates the synthesis of gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline (Larsson and Anderson, 2001).

Clinical Features

Jellum et al. (1970) discovered large amounts of pyroglutamic acid in the urine and plasma of a 19-year-old retarded Norwegian male. The chemical search was initiated because of unexplained chronic metabolic acidosis. Pyroglutamic acid was isolated by gas chromatography and identified by mass spectrometry; it is ninhydrin-negative. The patient showed spastic tetraparesis and a cerebellar disorder with intention tremor and dysarthria. Deficiency of 5-oxoprolinase in the kidney was suspected but not proved. Larsson et al. (1974) described 2 sisters, a neonate and a 3 year old, with pyroglutamic aciduria. Both had chronic metabolic acidosis requiring therapy with bicarbonate. Both showed increased hemolysis and marked decrease in glutathione in erythrocytes. Psychologic and somatic development of the 3 year old was normal, and she had no signs of neurologic damage. Marstein et al. (1976) studied a 24-year-old mentally retarded man who had demonstrated neurologic deterioration during the previous few years. Ataxia prevented his walking unaided. He developed epileptic seizures. Erythrocytes contained no detectable glutathione, and his glutathione synthetase activity was less than 2% of normal. The overproduction of pyroglutamate is probably caused by increased in vivo activity of gamma-glutamyl-cysteine synthetase, which in turn is caused by absence of normal feedback inhibition by glutathione with resulting superabundance of substrates available for gamma-glutamyl cyclotransferase. Lack of glutathione in the erythrocytes is apparently tolerable, but in nonrenewable neurons leads to serious neurologic problems of progressive nature.

Because of the observation of several episodes of neutropenia in a child with 5-oxoprolinuria, Spielberg et al. (1979) examined the response of neutrophils to oxidative stress associated with phagocytosis. Following ingestion of particles, the cells accumulated excess hydrogen peroxide compared with normal cells and showed impaired protein iodination and bacterial killing.

Robertson et al. (1991) described a 12-year-old girl with chronic metabolic acidosis, mental retardation, and psychotic behavior, as well as mild hemolytic anemia and peripheral retinal pigmentation abnormalities. A urine metabolic screen demonstrated 5-oxoprolinuria and further studies showed glutathione synthetase deficiency. The acidosis in the newborn period had been labeled renal tubular acidosis and treated with bicarbonate.

Divry et al. (1991) described a patient with a very severe neurologic presentation leading to fatal outcome in the first hours of life.

Manning et al. (1994) stated that approximately 20 cases of glutathione synthase deficiency had been reported and another 10 were known. The usual presentation had been neonatal acidosis and hemolysis with or without signs of neurologic damage. Some cases had not been diagnosed until adult life, however, reflecting a less severe form of the condition.

Clinical Management

Boxer et al. (1979) reported that vitamin E (alpha-tocopherol), 400 IU/day, increased red cell survival, corrected both the bactericidal and the iodination defects, and eliminated the neutropenia that accompanied intercurrent illnesses.

Martensson et al. (1989) concluded that N-acetylcysteine may be of value in increasing the low intracellular glutathione concentrations and cysteine availability in patients with this disorder.

Ristoff et al. (2001) studied 28 patients with glutathione synthetase deficiency, which they classified into 3 types based on severity of clinical signs: mild (hemolytic anemia only), moderate (neonatal acidosis), and severe (neurologic involvement). They concluded that early supplementation with vitamins C and E may improve the long-term clinical outcome of these patients.

Diagnosis

Prenatal Diagnosis

Erasmus et al. (1993) described a family in which an affected girl died at the age of 6 weeks. Both parents and the maternal grandmother had erythrocyte glutathione synthetase activity in the heterozygote range. Two later pregnancies were monitored with the measurement of 5-oxoproline in the amniotic fluid and in the latter of the 2 pregnancies by glutathione synthetase activity measurements. Both tests suggested that the infants were not affected and such was proved to be the case after delivery. Since accumulation of 5-oxoproline in body fluids, including urine, is characteristic of this disorder and since the amniotic fluid from the second trimester consists mostly of fetal urine, prenatal diagnosis by amniocentesis should be possible.

Manning et al. (1994) studied 2 pregnancies of an at-risk couple at 16 weeks' gestation. The levels of 5-oxoproline in both pregnancies was 25 to 30 times normal. The pregnancies were terminated and the diagnosis in one case was subsequently confirmed by assay of glutathione synthase in cultured fetal fibroblasts. In the other case, postmortem tissue samples failed to grow.

Molecular Genetics

In 3 families with glutathione synthetase deficiency, Shi et al. (1996) identified 7 mutations in the GSS gene on 6 alleles (601002.0001-601002.0006).

In 41 patients (33 previously reported) with glutathione synthetase deficiency from 33 families, Njalsson et al. (2005) evaluated genotype, enzyme activity, metabolite levels, and clinical phenotype. They identified 27 different mutations; 23 patients were homozygotes and 18 were compound heterozygotes. The moderate and severe clinical phenotypes could not be distinguished based on enzyme activity or glutathione or gamma-glutamylcysteine levels in cultured fibroblasts. All mutations causing frameshifts, premature stop codons, or aberrant splicing were associated with moderate or severe clinical phenotypes. Njalsson et al. (2005) concluded that additional genetic or environmental factors modify at least the moderate and severe phenotypes and that the clinical classification given to patients may be influenced by variation in follow-up.