Glutathione synthetase (GS) deficiency, first described in 1970, is a rare inborn error of glutathione metabolism characterized by severe metabolic acidosis, hemolytic anemia, and neurological problems.  Biochemical findings include massive excretion of 5-oxoproline in the urine. In mild glutathione synthetase deficiency, which is characterized by hemolytic anemia, enzyme deficiency primarily occurs in erythrocytes. See the image below.
Glutathione is involved in several important biologic functions, including membrane transport, detoxification of xenobiotics, and protection of cells from free radicals. Glutathione is produced from the amino acids cysteine, glycine, and glutamine via the consecutive actions of gamma-glutamylcysteine synthetase and glutathione synthetase. It is also widely used by RBCs, which are vulnerable to oxidative damage caused by peroxides. Reduced glutathione is required as an antioxidant in these cases.
Multiple mutations that cause glutathione synthetase deficiency have been described in the glutathione synthetase gene, GSS. The erythrocyte variant has been linked to a homozygous missense mutation that causes enzyme instability; thus, enzyme deficiency is most significant in erythrocytes and manifests as hemolytic anemia. Thirteen different missense mutations in GSS have been identified in individuals with severe glutathione synthetase deficiency.  The mutations were found in 9 unrelated patients from different geographic areas. Two of these mutations were in individuals who were found to have CNS involvement. In all cases, residual enzyme activity was noted, indicating that a complete loss of enzyme function is probably lethal.
Frequency is unknown.
This condition is very rare. Worldwide, only approximately 40-50 cases in which the patient survived the newborn period have been published. Overall frequency is unknown.
Recently, authors have recommended that 3 forms of glutathione synthetase deficiency be identified: mild, moderate, and severe (see History). In the severe systemic form, chronic metabolic acidosis must be managed. Long-term prognosis is guarded. With careful treatment during infancy, many patients survive, and the metabolic acidosis may become more manageable after infancy. The lack of glutathione in erythrocytes alone is apparently tolerable, as has been noted with the mild form of this condition; however, in severe glutathione synthetase deficiency, a progressive loss of function occurs, leading to severe mental retardation, ataxia, and seizure disorders.
According to one review, the oldest reported survivor with the severe form was aged 24 years and had experienced significant neurological deterioration over the previous few years. Psychotic behavior, tremors, and dysarthria have also been reported. Patients with the moderate or mild forms have been reported to have long-term survival and little or no neurological sequelae.
No race predilection is observed.
No sex predilection is known.
Most individuals with systemic glutathione synthetase deficiency are diagnosed in the newborn period. However, with the isolated erythrocyte form, the diagnosis may not be made until adulthood, although hemolytic anemia is present at birth.
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