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Disease Profile

Glutathione synthetase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Neonatal

ICD-10

D55.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

5-Oxoprolinuria; Oxoprolinase deficiency; Pyroglutamic aciduria;

Categories

Metabolic disorders

Summary

Glutathione synthetase deficiency is a genetic metabolic disorder that affects the body’s ability to produce an important substance called glutathione. People with glutathione synthetase deficiency do not have enough of the molecule called glutathione synthetase, which helps the body produce glutathione. People with glutathione synthetase deficiency can have mild, moderate, or severe disease. The signs and symptoms of the deficiency may include anemia, the buildup of too much acid in the body (metabolic acidosis), frequent infections, and symptoms caused by problems in the brain including seizuresintellectual disability, and loss of coordination (ataxia).[1]

Glutathione synthetase deficiency is caused by genetic changes (pathogenic variants or mutations) in the GSS gene. The deficiency is inherited in an autosomal recessive manner.[1] Diagnosis of a metabolic disorder such as glutathione synthetase deficiency may be suspected when a doctor observes signs of the deficiency including metabolic acidosis. A doctor may order tests to confirm the diagnosis including enzyme assaysurine analysis, and genetic testing.[2] Treatment for glutathione synthetase deficiency may include sodium bicarbonate to treat metabolic acidosis and taking vitamin supplements.[2]

Symptoms

The signs and symptoms of glutathione synthetase deficiency depend on whether a person has mild, moderate, or severe disease. The primary symptom of mild glutathione synthetase deficiency affects the red blood cells. People with the mild form of the deficiency may have red blood cells that are broken down too quickly, and new red blood cells are not made quickly enough to replace them. This is called hemolytic anemia. Symptoms of hemolytic anemia may include fatigue, pale skin color, lightheadedness, and shortness of breath.[1][2] Some people with the mild form of the deficiency may also have a larger spleen than expected (splenomegaly).[2]

Symptoms of moderate glutathione synthetase deficiency may include hemolytic anemia as well as a buildup of a substance called 5-oxoproline in the urine (5-oxoprolinuria). The build up of certain substances in the body can also cause metabolic acidosis, which happens when there is too much acid in the body. Signs of metabolic acidosis may include nausea, vomiting, and fatigue.[3]

The severe form of glutathione synthetase deficiency usually causes the same signs and symptoms seen in the milder forms of the deficiency, but can also affect the brain, which causes neurological problems. Neurological problems may include seizuresintellectual disability, and trouble coordinating movements (ataxia). Children with the severe form of the deficiency may not meet milestones such as sitting up or walking as would be expected (developmental delay), and they may have difficulty learning to talk (speech delay). Some children with the severe form have very stiff muscles (spasticity). The severe form of glutathione synthetase deficiency can increase the risk of repeated bacterial infections.[1][2] Adults with the severe form of the deficiency may have problems affecting the eyes, including retinal dystrophy.[2]

In many cases, signs of moderate or severe deficiency are apparent during infancy. Symptoms of mild deficiency may not be recognized until later in life.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of immune system physiology
0010978
Abnormality of the nervous system
Neurologic abnormalities
Neurological abnormality

[ more ]

0000707
Chronic metabolic acidosis
0001996
Hemolytic anemia
0001878
Reduced glutathione synthetase level
0003343
Percent of people who have these symptoms is not available through HPO
Ataxia
0001251
Autosomal recessive inheritance
0000007
Dysarthria
Difficulty articulating speech
0001260
Increased level of L-pyroglutamic acid in urine
0410132
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Intention tremor
0002080
Neutropenia
Low blood neutrophil count
Low neutrophil count

[ more ]

0001875
Pigmentary retinopathy
0000580
Psychotic mentation
0001345
Seizure
0001250
Spastic tetraparesis
0001285

Cause

Glutathione synthetase deficiency is caused by changes (pathogenic variants or mutations) in the GSS gene. This gene provides instructions to the body for making an enzyme called glutathione synthetase. Glutathione synthetase is one of the enzymes that helps the body make a molecule called glutathione. Glutathione is important because it is an antioxidant, meaning it helps prevent damage in the cells of the body. Many normal processes in the cells can create substances that cause damage to the cell if the substances are not removed. Glutathione helps change (neutralize) these damaging substances into harmless substances. It also neutralizes other substances that can cause damage to cells such as medications.[1] Glutathione is also part of the process that helps break down a substance called 5-oxoproline.[4]

People with pathogenic variants in the GSS gene do not have enough working glutathione synthetase, and therefore their cells do not have enough glutathione to neutralize harmful substances or to break down 5-oxoproline. This causes 5-oxoproline to build up in the body. When 5-oxoproline builds up in the body, it causes the symptoms of glutathione synthetase deficiency.[1][4] 

Because there are mild, moderate, and severe forms of glutathione synthetase deficiency, it is thought that there may be other environmental and genetic factors that may impact the severity of symptoms associated with the deficiency.[2]

Diagnosis

A diagnosis of glutathione synthetase deficiency may be suspected when a person has problems associated with the deficiency such as metabolic acidosis. Metabolic acidosis is suggestive of a metabolic disorder including glutathione synthetase deficiency. A doctor may then order tests to determine the exact cause of the medical problems. These tests may include an enzyme assay, which is a test that determines if the enzymes of the body are working as they should. A doctor may also order a blood test and urinalysis to determine if the levels of certain substances in the blood and urine are within the normal range. If these tests suggest glutathione synthetase deficiency, a doctor may order genetic testing of the GSS gene to confirm the diagnosis.[2]

Treatment

Unfortunately, there is no cure for glutathione synthetase deficiency. Treatment typically includes managing the medical problems associated with the deficiency. For example, if a person with glutathione synthetase deficiency develops metabolic acidosissodium bicarbonate can be used to treat the symptoms. Sodium bicarbonate may be given through an injection in the veins (intravenously). People with glutathione synthetase deficiency may also be recommended to take supplements for vitamin E and vitamin C. These vitamins are known as antioxidants. Antioxidants help the body neutralize some of the byproducts of chemical reactions that can be damaging to cells of the body, which is one of the roles of glutathione. In some cases, doctors may recommend a combination of sodium citrate and citric acid as medication to help treat people with glutathione synthetase deficiency.[5] People with the deficiency may be recommended to avoid medications that can cause a more rapid breakdown of red blood cells (hemolytic anemia).[6]

People with glutathione synthetase deficiency require close follow-up by doctors who are familiar with the deficiency. Therefore, a consultation with genetics specialists such as a biochemical geneticist, metabolic disorders specialist, and genetic counselor, are recommended for the parents of children with glutathione synthetase deficiency.[5]

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • The Organic Acidemia Association provides further information on this topic. Click on Organic Acidemia Association to view this information page.
    • The Merck Manual provides information on metabolic acidosis. Click on Merck Manual to view this information page.
    • Genetics Home Reference (GHR) contains information on Glutathione synthetase deficiency. This website is maintained by the National Library of Medicine.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • MeSH® (Medical Subject Headings) is a terminology tool used by the National Library of Medicine. Click on the link to view information on this topic.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Glutathione synthetase deficiency. Click on the link to view a sample search on this topic.

        Selected Full-Text Journal Articles

        • The Orphanet Journal of Rare Diseases has published an article with information on this condition. This journal is affiliated with the Orphanet reference portal for information on rare diseases and orphan drugs.

          References

          1. Glutathione synthetase deficiency. Genetics Home Reference. May 2015; https://ghr.nlm.nih.gov/condition/glutathione-synthetase-deficiency.
          2. Larsson A. Glutathione Synthetase Deficiency. National Organization for Rare Disorders. 2015; https://rarediseases.org/rare-diseases/glutathione-synthetase-deficiency/.
          3. Lewis, III JL. Metabolic Acidosis. Merck Manual. March 2018; https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/acid-base-regulation-and-disorders/metabolic-acidosis.
          4. GSS gene. Genetics Home Reference. March 2015; https://ghr.nlm.nih.gov/gene/GSS.
          5. Saadeh-Haddad R. Glutathione Synthetase Deficiency. Medscape. May 18, 2017; https://emedicine.medscape.com/article/944368-overview.
          6. Larsson A and Ristoff E. Glutathione synthetase deficiency. Orphanet. March 2007; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=32.
          7. Atwal PS, Medina CR, Burrage LC, and Sutton VR. Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency. Journal of Human Genetics. July 2016; 61(7):668-672. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/26984560/.

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