Glutathione synthetase deficiency

Glutathione synthetase deficiency (GSD), also known as glutathione synthase deficiency or pyroglutamic aciduria, is a rare inborn error of metabolism caused by mutations in the GSS gene, which encodes the enzyme glutathione synthetase. This enzyme catalyzes the second step in glutathione synthesis, and its deficiency leads to reduced levels of glutathione — a critical antioxidant that protects cells from oxidative damage. The condition is classified into three forms of increasing severity: mild, moderate, and severe. The mild form is restricted to red blood cells and causes hemolytic anemia. The moderate form involves hemolytic anemia combined with metabolic acidosis due to accumulation of 5-oxoproline (pyroglutamic acid). The severe form additionally affects the central nervous system, leading to progressive neurological deterioration. Key symptoms vary by severity but commonly include chronic hemolytic anemia, recurrent metabolic acidosis (often presenting in the neonatal period), jaundice, and elevated urinary 5-oxoproline. In the severe form, patients may develop intellectual disability, seizures, spasticity, ataxia, and progressive neurological decline. Some patients are also susceptible to recurrent bacterial infections due to impaired granulocyte function resulting from low intracellular glutathione levels. Treatment is primarily supportive and aimed at managing symptoms. Correction of metabolic acidosis with bicarbonate supplementation is a cornerstone of therapy. Antioxidant supplementation, particularly with vitamins C and E, is used to help compensate for the reduced glutathione-mediated antioxidant defense. N-acetylcysteine, a glutathione precursor, has been used in some patients, though its efficacy remains variable. Blood transfusions may be necessary during severe hemolytic crises. Early diagnosis and consistent management of acidosis are important to minimize neurological damage, particularly in the severe form. There is currently no curative treatment available.

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