eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Glutathione Synthetase Deficiency
Updated: Nov 30, 2007
Introduction
Background
Glutathione synthetase (GS) deficiency, first described in 1970, is a rare inborn error of glutathione metabolism characterized by severe metabolic acidosis, hemolytic anemia, and neurological problems. Biochemical findings include massive excretion of 5-oxoproline in the urine. In mild GS deficiency, which is characterized by hemolytic anemia, enzyme deficiency occurs primarily in erythrocytes.
Pathophysiology
Glutathione is involved in several important biologic functions, including membrane transport, detoxification of xenobiotics, and protection of cells from free radicals. Glutathione is produced from the amino acids cysteine, glycine, and glutamine via the consecutive actions of gamma-glutamylcysteine synthetase and GS. It is also widely used by RBCs, which are vulnerable to oxidative damage caused by peroxides. Reduced glutathione is required as an antioxidant in these cases.
Multiple mutations that cause GS deficiency have been described in the GS gene, GSS. The erythrocyte variant has been linked to a homozygous missense mutation that causes enzyme instability; thus, enzyme deficiency is most significant in erythrocytes and manifests as hemolytic anemia. Thirteen different missense mutations in GSS have been identified in individuals with severe GS deficiency.1 The mutations were found in 9 unrelated patients from different geographic areas. Two of these mutations were in individuals who were found to have CNS involvement. In all cases, residual enzyme activity was noted, indicating that a complete loss of enzyme function is probably lethal.
Frequency
United States
Frequency is unknown.
International
This condition is very rare. Worldwide, only approximately 40-50 cases in which the patient survived the newborn period have been published. Overall frequency is unknown.
Mortality/Morbidity
Recently, authors have recommended that 3 forms of GS deficiency be identified: mild, moderate, and severe (see History). In the severe systemic form, chronic metabolic acidosis must be managed. Long-term prognosis is guarded. With careful treatment during infancy, many patients survive, and the metabolic acidosis may become more manageable after infancy. The lack of glutathione in erythrocytes alone is apparently tolerable, as has been noted with the mild form of this condition; however, in severe GS deficiency, a progressive loss of function occurs, leading to severe mental retardation, ataxia, and seizure disorders.According to one review, the oldest reported survivor with the severe form was aged 24 years and had experienced significant neurological deterioration over the previous few years. Psychotic behavior, tremors, and dysarthria have also been reported. Patients with the moderate or mild forms have been reported to have long-term survival and little or no neurological sequelae.
Race
No race predilection is observed.
Sex
No sex predilection is known.
Age
Most individuals with systemic GS deficiency are diagnosed in the newborn period. However, with the isolated erythrocyte form, the diagnosis may not be made until adulthood, although hemolytic anemia is present at birth.
Clinical
History
The phenotypic manifestations that have been described in association with glutathione synthetase (GS) deficiency include hemolytic anemia, which occurs in mild GS deficiency, and 5-oxoprolinuria (pyroglutamicaciduria) and variable degrees of secondary neurological involvement (occurring in systemic GS deficiency). As stated in Mortality/Morbidity, authors have suggested GS deficiency be described as mild, moderate, or severe. These categories represent a continuum of disease severity that depends on the degree of enzyme function; therefore, patients can have manifestations anywhere along the continuum of mild to severe GS deficiency.- The severe phenotypic manifestation, 5-oxoprolinuria (pyroglutamicaciduria), resulting from systemic GS deficiency, is an autosomal recessive disorder. It is characterized by very large peaks of 5-oxoproline on urine organic acid analysis findings, metabolic acidosis, hemolytic anemia, and eventual CNS damage. Because of deficient enzyme activity, a decreased quantity of glutathione results, which likely causes promoter activation of the GSS gene. The large amounts of gamma-glutamylcysteine synthetase that are produced increase the pool of gamma-glutamylcysteine, which is then converted to 5-oxproline because of the inability of the defective GSS gene to produce glutathione.
- In moderate GS deficiency, neonatal acidosis and hemolytic anemia are present, but neurological involvement is not. The prognosis for the moderate form is intermediate.
- In mild GS deficiency, hemolytic anemia is the primary finding with apparently no effects outside of erythrocytes. Individuals with this form do well clinically.
Physical
Patients with GS deficiency appear healthy and do not have unusual dysmorphic features.
- In severe GS deficiency, neurological findings are the most prevalent and may include the following:
- Spasticity (spastic tetraparesis)
- Ataxia and other cerebellar findings
- Intention tremors
- Dysarthria
- Mental retardation
- Psychosis
- Seizure disorders
- Eye abnormalities, which tend to be peripheral retinal pigmentation abnormalities
- Individuals with moderate GS deficiency may have apparent respiratory distress as their bodies try to correct metabolic acidosis; however, other signs are not usually present.
- In mild GS deficiency, physical findings are not present.
Causes
Southern blot hybridizations that have been performed with a GS complementary DNA (cDNA) have revealed that only one GSS gene is present in the human genome. It is located at band 20q11.2. These findings suggest that the different phenotypic types observed in GS deficiency are part of a spectrum of disease that depends on the degree of GS function.
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| References |
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References
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Further Reading
Keywords
glutathione synthetase deficiency, GS deficiency, 5-oxoprolinemia, 5-oxoprolinuria, pyroglutamicaciduria, pyroglutamic aciduria, pyroglutamic acidemia, high anion gap metabolic acidosis, severe metabolic acidosis, chronic metabolic acidosis, hemolytic anemia, enzyme deficiency, glutathione, neutropenia, GSS, GSHS, inborn error of glutathione metabolism, ataxia, dysarthria, tremors, psychotic behavior
