NORD gratefully acknowledges Agne Larsson, AL, MD & PhD, Emeritus Professor of Pediatrics, Karolinska Institute, Stockholm, Sweden, for assistance in the preparation of this report.
Glutathione synthetase deficiency may be best thought of as a spectrum of disease ranging from mild to moderate to severe expression of the disorder. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below and that each individual is unique. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The mild form of glutathione synthetase deficiency is characterized by the premature breakdown of red blood cells (hemolytic anemia). Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In affected individuals, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. The severity of the anemia is determined by the length of time that the red blood cells survive and by the rate at which the bone marrow continues to create new red blood cell production.
The primary role of red blood cells is to delivery oxygen throughout the body. Hemolytic anemia can be associated with fatigue, pale skin color, lightheadedness, irregular heartbeats, and shortness of breath. Hemolytic anemia is usually the only symptom associated with the mild form of glutathione synthetase deficiency, although some individuals may have an abnormally enlarged spleen (splenomegaly).
The moderate form may be associated with mild to moderate hemolytic anemia. Affected infants may also have severe metabolic acidosis caused by an accumulation of 5-oxoproline. Metabolic acidosis is a condition in which the chemical balance of the body is off and the body fluids contain too much acid.
The symptoms and signs of the severe form of glutathione synthetase deficiency can vary greatly from one person to another. Affected infants experience mild to moderate hemolytic anemia and metabolic acidosis in the newborn period. These infants may experience progressive cerebral and cerebellar degeneration. Affected infants may develop progressive neurological symptoms including impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation), varying degrees of intellectual disability, seizures, impaired coordination of voluntary movements (ataxia), tremors that occur when attempting to make deliberate actions (intention tremor), and increased muscle tone and stiffness of muscles (spasticity). Some infants develop recurrent bacterial infections. Severe metabolic acidosis and bacterial infections can potentially cause life-threatening complications such as widespread infection of the blood (sepsis).
Chronic and progressive disorders of vision known as retinal dystrophies have been reported in adults with glutathione synthetase deficiency.
Glutathione synthetase deficiency is caused by alterations in the GSS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The GSS gene contains instructions for making the enzyme glutathione synthetase. This enzyme is required for the body to create the small protein molecule glutathione. An alteration in the GSS gene leads to deficiency of or glutathione synthetase, which, in turn, leads to a lack of glutathione, which is a peptide molecule that plays a crucial role in many cellular processes. Cellular processes are activities that go on inside of a cell that are vital for proper health and development.
The GSS alterations that cause glutathione synthetase deficiency are inherited in an autosomal recessive manner. Most such genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Researchers believe that certain factors, in addition to alterations in the GSS gene, influence the severity of glutathione synthetase deficiency. This includes genetic and environmental factors. Modifier genes, unlike the GSS gene, affect the clinical severity of the disorder. More research is necessary to discover the various modifier genes and/or environment factors associated with glutathione synthetase deficiency and their exact role in the development of the disorder.
Glutathione synthetase deficiency affects males and females in equal numbers. More than 70 individuals from 50 families have been described in the medical literature. The exact incidence and prevalence are unknown. Because individuals may be misdiagnosed or go undiagnosed, determining the true frequency in the general population is difficult.
A diagnosis of glutathione synthetase deficiency is based upon identification of characteristic findings, a detailed patient and family history, and a variety of specialized tests.
Enzyme assays are tests that determine the activity of enzymes in certain cells of the body. These tests can demonstrate decreased activity of the enzyme glutathione synthetase in red blood cells (erythrocytes) or cultured fibroblasts. Cultured fibroblasts are connective tissue cells obtained from a skin sample and grown in a laboratory. Tests that demonstrate low levels of glutathione in red blood cells or cultured fibroblasts can also be used to support a diagnosis.
High levels of 5-oxoproline in the urine can be demonstrated through a procedure known as gas chromatography-mass spectrometry (GC-MS). In GC-MS, a sample is inserted into a machine where it is heated. The heated sample will slowly evaporate into a gas. This gas can be separated into its individual components, which can then be analyzed. Complex sample preparation and a lengthy analysis time make GC-MS testing a time-consuming technique.
Molecular genetic testing can confirm a diagnosis of glutathione synthetase deficiency. Molecular genetic testing can detect mutations in the GSS gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
In families with a known history of glutathione synthetase deficiency, a diagnosis may be obtained before birth (antenatal diagnosis). If the specific gene mutation in the family is known, then a sample of tissue taken from the placenta (chorionic villi sampling) can be studied to detect the mutation. Antenatal diagnosis is also possible through the analysis of amniotic fluid for elevated levels of 5-oxoproline or through demonstrating reduced glutathione synthetase activity in fetal cells taken from the amniotic fluid (amniocytes) or in placenta tissue.
The treatment of glutathione synthetase deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment will include sodium bicarbonate to correct the metabolic acidosis. Initially, this may require parenteral (e.g. intravenous) therapy. Eventually, affected individuals can be treated with sodium bicarbonate or citrate, delivered through the mouth (orally). Supplemental therapy with vitamins E and C, which have antioxidant properties, may also be given.
Drugs that precipitate hemolysis in glucose-6-phosphate dehydrogenase deficiency should be avoided. (For more information on this disorder and such drugs, choose “glucose 6 phosphate dehydrogenase deficiency” as your search term in the NORD Rare Disease Database.)
Genetic counseling should be offered to affected individuals and their families.
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Shi ZZ, Habib GM, Lieberman MW. Glutathione synthetase deficiency (5-oxoprolinuria). In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003: Pp. 449.
Larsson A, Anderson ME. Glutathione synthetase deficiency and other diseases of the glutamyl cycle. In: Scriver RS, AL Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001: 2205-2216.
Larsson A. Disorders of Gamma Glutamyl Cylce. In: Inborn Metabolic Diseases, 2nd ed. Fernandes J, Saudubray JM, van den Berghe G, editors. 1995 Springer-Verlag, Berlin. pp. 197-200.
Ben Ameur S, Aloulou H, Nasrallah F, et al. Hemolytic anemia and metabolic acidosis: think about glutathione synthetase deficiency. Fetal Pediatr Pathol. 2015;34:18-20. http://www.ncbi.nlm.nih.gov/pubmed/25166299
Winkler A, Njalsson R, Carlsson K, et al. Glutathione is essential for early embryogenesis – analysis of a glutathione synthetase knockout mouse. Biochem Biophys Res Commun. 2011;412:121-126. http://www.ncbi.nlm.nih.gov/pubmed/21802407
Simon E, Vogel M, Fingerhut R, et al. Diagnosis of glutathione synthetase deficiency in newborn screening. J Inherit Metab Dis. 2009;32:S269-272. http://www.ncbi.nlm.nih.gov/pubmed/19728142
Ristoff E, Larsson A. Inborn errors in the metabolism of glutathione. Orphanet J Rare Dis. 2007;2:16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852094/
Njalsson R, Ristoff E, Carlsson K, et al. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet. 2005;116:384-389. http://www.ncbi.nlm.nih.gov/pubmed/15717202
Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patient with glutathione synthetase deficiency. J Pediatr. 2001;139:79-84. http://www.ncbi.nlm.nih.gov/pubmed/11445798
Corrons JL, Alvarez R, Pujades A, et al. Hereditary non-spherocytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain. Clinical and molecular studies. Br J Haematol. 2001;112:475-82. http://www.ncbi.nlm.nih.gov/pubmed/11167850
Al-Jishi E, Meyer BF, Rashed MS, et al. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet. 1999;55:444-49. http://www.ncbi.nlm.nih.gov/pubmed/10450861
Dahl N, Pigg M, Ristoff E, et al. Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological misfunction. Hum Mol Genet. 1997;6:1147-1152. http://www.ncbi.nlm.nih.gov/pubmed/9215686
Shi ZZ, Habib GM, Rhead WJ, Gahl WA, He X, Sazer S, Lieberman MW. Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nat Genet. 1996; 13:361-365. http://www.ncbi.nlm.nih.gov/pubmed/8896573
Jain A, Buist NR, Kennaway NG et al. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatr.1994;124:229-33. http://www.ncbi.nlm.nih.gov/pubmed/8301428
FROM THE INTERNET
Larsson A, Ellinor R. Glutathione synthetase deficiency. Orphanet Encyclopedia, March 2007. Available at: http://www.orpha.net/ Accessed on: October 9, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:266130; Last Update:01/24/2013. Available at: http://omim.org/entry/266130 Accessed on: October 9, 2015.
Glader B. Disorders of the hexose monophosphate shunt and glutathione metabolism other than glucose-6-phosphate dehydrogenase deficiency. UpToDate, Inc. 2015 March 9. Available at: http://www.uptodate.com/contents/disorders-of-the-hexose-monophosphate-shunt-and-glutathione-metabolism-other-than-glucose-6-phosphate-dehydrogenase-deficiency Accessed on: October 9, 2015.
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