Glutathione synthetase deficiency

Douglas J Lanska MD FAAN MS MSPH (

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health, the Medical College of Wisconsin, and IM Sechenov First Moscow State Medical University has no relevant financial relationships to disclose.

)
Originally released August 4, 2003; last updated October 21, 2020; October 21, 2023

Overview

Manifestations of glutathione synthetase deficiency usually include hemolytic anemia, often include metabolic acidosis, and sometimes include progressive neurologic symptoms as well as other systemic signs. At least a third of the most severely affected patients die of acidosis in the neonatal period. Among surviving patients, the most severely affected patients have intellectual disability, progressive cerebellar disease and ataxia, recurrent bacterial infections, as well as chronic metabolic acidosis and hemolytic anemia. Although there is no specific curative therapy, beneficial treatments include correction of acidosis, blood transfusion, and supplementation with antioxidants. Glutathione replacement is extremely difficult to achieve in practice.

Key points

 

• Manifestations of glutathione synthetase deficiency usually include hemolytic anemia, often include metabolic acidosis, and sometimes include progressive neurologic symptoms as well as other systemic signs (eg, respiratory distress, sepsis, hyperbilirubinemia).

 

• Although mildly affected patients manifest only a mild to moderate hemolytic anemia, at least a third of the most severely affected patients die of acidosis in the neonatal period.

 

• Among surviving patients, the most severely affected patients have intellectual disability (IQs often from 50 to 60), progressive cerebellar disease and ataxia, recurrent bacterial infections, as well as chronic metabolic acidosis and hemolytic anemia.

 

• Although there is no specific curative therapy for this disease, beneficial treatments include correction of acidosis, blood transfusion, and supplementation with antioxidants.

 

• Glutathione replacement is extremely difficult to achieve in practice.

Historical note and terminology

Glutathione synthethase deficiency is an autosomal recessive disorder that was first diagnosed in 1970 in a teenager with slowly progressive neurologic disorder and markedly elevated excretion of 5-oxoproline in the urine as well as a history of unexplained jaundice at birth and a history of chronic metabolic acidosis. Subsequently, newborns with hemolytic anemia and organic acidosis were recognized as having similar elevations in this urinary metabolite. The identification of reduced cellular glutathione levels and deficient glutathione synthetase activity established this disorder as a unique entity.

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