Last updated:
9/11/2024
Years published: 1988, 1989, 1990, 1999, 2002, 2015, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Agne Larsson, AL, MD & PhD, Emeritus Professor of Pediatrics, Karolinska Institute, Stockholm, Sweden, for assistance in the preparation of this report.
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Glutathione synthetase deficiency is a very rare condition that affects the body’s ability to produce an important protein called glutathione. Glutathione plays a key role in many processes inside our cells, helping protect them from damage and ensuring they function properly.
Glutathione synthetase deficiency can vary widely in how it presents, ranging from mild to severe forms:
The mild form affects only the red blood cells, which are responsible for carrying oxygen throughout the body. It is characterized by the premature breakdown of red blood cells (hemolytic anemia). Symptoms are often less severe and may be easier to manage.
The moderate form has effects that are more widespread than the mild form but not as severe as the generalized form and impacts more types of cells in the body.
The severe form or generalized form affects many different cells throughout the body. It is characterized by hemolytic anemia and metabolic acidosis, progressive neurological symptoms, intellectual disability, seizures and in some cases, recurrent infections that can be very severe.
GSD is caused by changes (pathogenic variants) in a specific gene called the GSS gene. Inheritance is autosomal recessive.
There is no cure for glutathione synthetase deficiency, so effective supportive care is crucial. Metabolic acidosis can be treated with sodium bicarbonate or citric acid, especially during infections. To protect tissues from oxidative stress, supplementing with vitamins C and E is recommended to improve neurological outcomes.
Glutathione synthetase deficiency (GSD) 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 known, mainly because there are only a few cases reported. Therefore, it is important to note that affected people may not have all the symptoms discussed below and that each individual is unique.
The mild form of glutathione synthetase deficiency is characterized by:
The moderate form may include the following signs and symptoms:
The severe form can vary greatly from one person to another, but symptoms can start in babies and may include:
Some babies and young children may develop severe life-threatening complications due to:
Chronic and progressive disorders of vision known as retinal dystrophies have been reported in adults with glutathione synthetase deficiency.
Glutathione synthetase deficiency (GSD) is caused by variants in the GSS gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene variant occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the 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.
Multiple variants that cause glutathione synthetase deficiency have been described in the GSS gene. The erythrocyte variant has been linked to a variant that causes enzyme instability; thus, enzyme deficiency is most important in erythrocytes and manifests as hemolytic anemia. Thirteen different missense variants in GSS have been identified in individuals with severe glutathione synthetase deficiency leading to different levels of enzyme activity. However, in all cases, residual enzyme activity was noted, indicating that a complete loss of enzyme function is probably lethal.
Other factors may influence the severity of glutathione synthetase deficiency. This includes genetic and environmental factors.
The GSS variants that cause glutathione synthetase deficiency are inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having 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.
Glutathione synthetase deficiency (GSD) affects males and females in equal numbers. As of 2024, more than 80 cases in 50 families have been reported 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 (GSD) 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.
Moderate and severe forms cannot be differentiated based on enzyme activity, which suggests that other factors, as commented above are involved in the specific presentation of the disease.
Genetic testing detecting variants in the GSS gene known to cause the disorder can confirm the diagnosis.
In families with a known history of glutathione synthetase deficiency, a diagnosis may be obtained before birth (prenatal diagnosis). If the specific gene variant in the family is known, then a sample of tissue taken from the placenta (chorionic villi sampling) can be studied to detect the gene variant. Prenatal 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.
For people diagnosed with glutathione synthetase deficiency (GSD), managing the condition is a long-term commitment, even though there are no specific clinical guidelines currently in place. Treatment is personalized and generally focuses on three main goals: correcting metabolic acidosis (a condition where the body produces too much acid), preventing damage from oxidative stress (which is when harmful molecules cause cell damage) and addressing any symptoms that arise.
One of the key steps in treatment is correcting metabolic acidosis. This usually starts with intravenous sodium bicarbonate, and once the patient is stable, it can often be managed with oral sodium bicarbonate or citrate, like Bicitra. Sometimes, larger doses may be needed. Alongside this, supplementing with antioxidants like vitamins E and C is recommended because they help protect cells from damage.
People with GSD should avoid certain medications that can cause their red blood cells to break down, especially if they also have glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition that can sometimes occur alongside GS deficiency. It’s also a good idea for patients and their families to consider genetic counseling to fully understand the condition and its implications.
The outlook for GSD can vary widely, but early treatment with sodium citrate, citric acid, or other buffers, along with vitamins C and E, can help support normal development. Some research has looked into using lipoic acid, an antioxidant, to prevent learning disabilities by protecting the brain. However, because glutathione is crucial for producing certain stress-related chemicals (like leukotrienes) and neurotransmitters (which are chemical messengers in the body), lipoic acid might not address all symptoms effectively.
Another supplement that may be helpful is Selenium, because it aids in forming protective proteins called selenoproteins, which help reduce oxidative stress— a condition that may occur when there are too many unstable molecules called free radicals in the body and not enough antioxidants to get rid of them. This can lead to cell and tissue damage.
N-acetylcysteine (NAC) is another treatment that can boost glutathione levels, an important antioxidant in the body. However, NAC isn’t suitable for everyone, especially those with high levels of cysteine, as too much cysteine can harm the nervous system. Therefore, NAC is not recommended for patients who already have elevated cysteine levels.
It’s also crucial for people with GS deficiency to avoid certain medications. For instance, acetaminophen, commonly used to treat pain and fever, has been linked to liver damage in GS deficiency patients, even at regular doses. Additionally, medications like phenobarbital, sulfonamides and aspirin should be avoided because they can cause a dangerous reaction where red blood cells are rapidly destroyed.
By understanding these treatment options and working closely with healthcare providers, patients with GS deficiency can manage their condition more effectively and improve their quality of life.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
TEXTBOOKS
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.
JOURNAL ARTICLES
Ekuni S, Hirayama K, Nagasaka M, Osumi K, Kondo H, Nakahara E, Shimojima Yamamoto K, Kanno H, Katayama Y. Severe hemolytic anemia and metabolic acidosis at birth with glutathione synthetase deficiency and progressive neurological symptoms on follow-up. Am J Case Rep. 2023 Apr 13;24:e938396. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10106969/
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. https://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. https://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. https://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. https://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. https://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. https://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. https://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. https://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. https://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. https://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. https://www.ncbi.nlm.nih.gov/pubmed/8301428
INTERNET
Larsson A, Ellinor R. Glutathione synthetase deficiency. Orphanet. March 2007. Available at: Orphanet: Glutathione synthetase deficiency Accessed Sept 11, 2024.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:266130; Last Update: 07/09/2016. Available at: https://omim.org/entry/266130 Accessed Sept 11, 2024.
Glader B.Rare RBC enzyme disorders. UpToDate, Inc. Sep 28, 2023. Available at: https://www.uptodate.com/contents/disorders-of-the-hexose-monophosphate-shunt-and-glutathione-metabolism-other-than-glucose-6-phosphate-dehydrogenase-deficiency Accessed Sept 11, 2024.
Defendi GL. Glutathione Synthetase Deficiency. Medscape Reference. Feb 12, 2024. https://emedicine.medscape.com/article/944368-overview Accessed Sept 11, 2024.
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