Glutathione synthetase deficiency is a disorder that prevents the production of an important molecule called glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

Glutathione synthetase deficiency can be classified into three types: mild, moderate, and severe. Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). In addition, affected individuals may release large amounts of a compound called 5-oxoproline in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells.

Individuals with moderate glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis).

In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); intellectual disability; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.

Glutathione synthetase deficiency is very rare. This disorder has been described in more than 70 people worldwide.

Mutations in the GSS gene cause glutathione synthetase deficiency. The GSS gene provides instructions for making an enzyme called glutathione synthetase. This enzyme is involved in a process called the gamma-glutamyl cycle, which takes place in most of the body's cells. This cycle is necessary for producing a molecule called glutathione. Glutathione protects cells from damage caused by unstable oxygen-containing molecules, which are byproducts of energy production. Glutathione is called an antioxidant because of its role in protecting cells from the damaging effects of these unstable molecules. Mutations in the GSS gene prevent cells from making adequate levels of glutathione, leading to the signs and symptoms of glutathione synthetase deficiency.

Genetic Testing Information

• Genetic Testing Registry: Glutathione synthetase deficiency with 5-oxoprolinuria
• Genetic Testing Registry: Glutathione synthetase deficiency without 5-oxoprolinuria

Genetic and Rare Diseases Information Center

• Glutathione synthetase deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• GLUTATHIONE SYNTHETASE DEFICIENCY; GSSD
• ANEMIA, CONGENITAL, NONSPHEROCYTIC HEMOLYTIC, 6; CNSHA6

Scientific Articles on PubMed

• PubMed

• Al-Jishi E, Meyer BF, Rashed MS, Al-Essa M, Al-Hamed MH, Sakati N, Sanjad S, Ozand PT, Kambouris M. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet. 1999 Jun;55(6):444-9. doi: 10.1034/j.1399-0004.1999.550608.x. Citation on PubMed
• Ben Ameur S, Aloulou H, Nasrallah F, Kamoun T, Kaabachi N, Hachicha M. Hemolytic anemia and metabolic acidosis: think about glutathione synthetase deficiency. Fetal Pediatr Pathol. 2015 Feb;34(1):18-20. doi: 10.3109/15513815.2014.947543. Epub 2014 Aug 28. Citation on PubMed
• Njalsson R, Norgren S. Physiological and pathological aspects of GSH metabolism. Acta Paediatr. 2005 Feb;94(2):132-7. doi: 10.1111/j.1651-2227.2005.tb01878.x. Citation on PubMed
• Njalsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet. 2005 Apr;116(5):384-9. doi: 10.1007/s00439-005-1255-6. Epub 2005 Feb 17. Citation on PubMed
• Njalsson R. Glutathione synthetase deficiency. Cell Mol Life Sci. 2005 Sep;62(17):1938-45. doi: 10.1007/s00018-005-5163-7. Citation on PubMed
• Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis. 2007 Mar 30;2:16. doi: 10.1186/1750-1172-2-16. Citation on PubMed or Free article on PubMed Central
• Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004 Mar;134(3):489-92. doi: 10.1093/jn/134.3.489. Citation on PubMed