What Is Glutathione?
Glutathione is a strong antioxidant commonly found in plants, animals, fungi, and certain bacteria. Glycine, cysteine, and glutamic acid are the three amino acids that constitute glutathione. It is synthesized by the liver and is required for numerous functions in the body. The production of chemicals and proteins required by the body and immune system function are all aided by glutathione. It also helps in tissue growth and repair.
What Is Glutathione Synthetase Deficiency?
Glutathione synthetase deficiency is a condition that prevents the synthesis of glutathione. It is a rare disorder characterized by a deficiency of glutathione synthetase enzyme in the body. The glutathione synthetase enzyme is crucial for the production of glutathione. Glutathione is a substance that protects cells by neutralizing potentially harmful chemicals produced during energy production in the body. In addition to processing drugs and carcinogens, glutathione helps synthesize DNA, proteins, and other vital components.
Glutathione synthetase deficiency is typically divided into three categories; mild, moderate, or severe. The mild form of glutathione synthetase deficiency often only impacts red blood cells. The severity and specific symptoms can differ substantially from person to person.
What Are the Types of Glutathione Synthetase Deficiency?
Glutathione synthetase deficiency is classified as the following:
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Mild: Red blood cells typically get destroyed due to mild glutathione synthetase deficiency. Additionally, persons who are affected may produce a lot of the chemical 5-oxo proline in their urine. This substance accumulates in the cells when glutathione is not processed properly.
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Moderate: Hemolytic anemia (decreased red blood cells due to hemolysis), 5-oxoprolinuria (release of 5-oxo proline in the urine), and increased acidity in the blood and tissues are the common symptoms that people with moderate glutathione synthetase deficiency may report. These symptoms may start manifesting shortly after birth.
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Severe: The severe form of glutathione synthetase deficiency may cause neurological symptoms in addition to the symptoms of moderate glutathione synthetase deficiency. Seizures, psychomotor retardation, intellectual impairment, and ataxia (loss of coordination) are a few of the symptoms that may arise. Recurrent bacterial infections can also occur in individuals with severe glutathione synthetase deficiency.
Is Glutathione Synthetase Deficiency a Common Condition?
Glutathione synthetase deficiency is an extremely rare condition, and it has been reported in only about 70 people from 50 families globally. The prevalence of glutathione synthetase insufficiency is equal in men and women. Moreover, the exact prevalence of the disorder in the general population is unknown. Determining the exact prevalence in the general population is challenging since most cases go undetected or are misdiagnosed.
What Causes Glutathione Synthetase Deficiency?
Glutathione synthetase deficiency occurs due to mutations in the GSS gene. The GSS gene is responsible for giving instructions for the synthesis of glutathione synthetase enzymes. This enzyme is a part of the gamma-glutamyl cycle, which occurs in most of the body's cells. This cycle is required for the synthesis of the glutathione molecule.
Is Glutathione Synthetase Deficiency Hereditary?
Yes, glutathione synthetase deficiency is an inherited condition. An inherited condition or disorder refers to a condition that is genetically passed down from parents to their children. Glutathione synthetase deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when a person receives two copies of a mutated gene for the same trait from each parent.
The degree of glutathione synthetase deficiency depends on several variables and changes in the GSS gene. Environmental and genetic factors are included in this.
What Are the Symptoms of Glutathione Synthetase Deficiency?
Although experts have identified a distinct syndrome with characteristic symptoms, many aspects of glutathione synthetase deficiency remain poorly understood. Physicians cannot build a comprehensive picture of related symptoms and prognosis because of several variables, including the limited number of documented cases, the lack of significant clinical research, and the potential influence of other genes (apart from the GSS gene) on the condition. The commonly reported symptoms of glutathione synthetase deficiency may include the following:
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Premature red blood cell breakdown (hemolytic anemia) is a hallmark of the mild form of glutathione synthetase deficiency. Typically, the red blood cells live for about 120 days; after that, the spleen destroys the RBCs. In individuals with glutathione synthetase deficiency, the red blood cells die prematurely. The rate of new cell production in the bone marrow fails to compensate for the premature loss of RBCs.
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The main function of red blood cells is to transport oxygen throughout the body. Fatigue, pale skin, dizziness, irregular heartbeats, and dyspnea (shortness of breath) are all symptoms of hemolytic anemia associated with glutathione synthetase deficiency.
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Splenomegaly (spleen enlargement) may also be reported in certain individuals with mild glutathione synthetase deficiency.
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Infants affected may also have severe metabolic acidosis caused by an accumulation of 5-oxo proline. Metabolic acidosis occurs when the body's chemical balance is wrong and too much acid is present in the body fluids.
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Those with severe glutathione synthetase deficiency may experience various symptoms and indications. In the newborn stage, affected infants have mild to moderate hemolytic anemia and metabolic acidosis. These newborns could develop progressive cerebral and cerebellar atrophy.
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Infants who are affected may experience progressive neurological symptoms such as difficulty learning skills that require the coordination of mental and physical activities, intellectual disability in varying degrees, seizures, poor coordination, tremors that appear when trying to perform deliberate movements, etc.
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Recurrent bacterial infections are another common symptom of severe glutathione synthetase deficiency.
How Is Glutathione Synthetase Deficiency Diagnosed?
A thorough patient and family history, several tests, and identifying distinctive symptoms all contribute to the diagnosis of glutathione synthetase deficiency. The following tests may be done:
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Enzyme Assay: Enzyme assays are used to identify the activity of the enzymes in specific body cells. These tests can show that the glutathione synthase enzyme is less active in RBCs (red blood cells) or fibroblasts.
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Gas Chromatography-Mass Spectrometry (GC-MS): This is a specialized test used to determine increased levels of 5-oxo proline in the urine. During GC-MS, a sample is collected and placed inside a machine, where this sample is heated. The sample will gradually turn into a gas when it gets heated. This gas can be broken down into its constituent parts, which can then be examined separately. However, GC-MS is a complex and time-taking method.
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Genetic Testing: A diagnosis of glutathione synthetase deficiency can be confirmed using molecular genetic testing. Molecular genetic testing, which is only offered at very few laboratories, can identify variations in the GSS gene (the gene that causes glutathione synthetase deficiency).
How Is Glutathione Synthetase Deficiency Treated?
There is no standard treatment for glutathione synthetase deficiency, and the treatment is generally symptomatic for each individual. The treatment may include the following:
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Sodium bicarbonate is used to address the metabolic acidosis associated with glutathione synthetase deficiency. Parenteral (intravenous) treatment may be necessary at first. Later, affected people can be treated with oral sodium bicarbonate or citrate.
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Vitamin E and vitamin C supplements are also advised.
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It is important to provide affected people and their families with genetic counseling.
Conclusion:
Glutathione synthetase deficiency is an uncommon disorder characterized by the deficiency of the glutathione synthetase enzyme, which is crucial for glutathione production. The condition is classified into mild, moderate, and severe. The symptoms are variable depending upon the severity of the deficiency. The diagnosis is primarily based on the individual’s symptoms, family history, and specialized laboratory tests. The treatment of glutathione synthetase deficiency is mostly symptomatic.
