AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Distal renal tubular acidosis, autosomal dominant
Cobalamin C disease
Cobalamin D disease

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Electrolyte and blood gas determinations indicate high anion gap metabolic acidosis. The CBC count demonstrates hemolytic anemia. Diagnosis of glutathione synthetase (GS) deficiency is confirmed by the presence of a large peak of 5-oxoproline in the urine. Concentrations of this metabolite are also increased in the cerebrospinal fluid (CSF) and blood. Diagnosis can be confirmed through enzyme analysis of GS (which is found to be deficient) in cultured skin fibroblasts. Upon routine testing, in addition to a hemolytic anemia, episodic neutropenia may occur. Additional findings include the following:
• • Neutrophil bactericidal and iodination defects, which are corrected with vitamin E therapy
  • Pyroglutamic aciduria
  • Pyroglutamic acidemia
  • Decreased glutathione in erythrocytes
  • Increased gamma-glutamylcysteine synthetase
• Moderate and severe forms cannot be differentiated based on enzyme activity, which suggests that other factors are involved in the final phenotypic presentation.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Treatment of individuals who have been diagnosed with glutathione synthetase (GS) deficiency involves providing supplements to correct the metabolic acidosis and supplying antioxidants such as vitamin E and vitamin C. A combination of sodium citrate and citric acid (Bicitra) may be used as an oral medication and can maintain plasma bicarbonate levels within the reference range. Alternatively, bicarbonate may be used; however, very large doses may be needed.

• The prognosis for GS deficiency widely varies. In some cases, early use of sodium citrate and citric acid (Bicitra) or other buffers, vitamin C, and vitamin E may allow normal development to occur.
• Experiments using lipoic acid as an intracerebral antioxidant have been performed in animal models. Lipoic acid penetrates the blood-brain barrier well and may prevent the onset of learning disabilities in children with GS deficiency. However, individuals may have an absolute requirement of glutathione for the production of certain leukotrienes and possibly even neurotransmitters. If this is the case, lipoic acid may not effectively correct the problem.
• N-acetylcysteine (NAC) has been used in patients with GS deficiency because it is thought to increase the low intracellular glutathione concentrations and cysteine availability in the leukocytes of these patients. Whether these findings in leukocytes may result in similar changes in neurons is not yet known.

Consultations

Consultations with a clinical biochemical geneticist, metabolic diseases specialist, or hematologist may be indicated.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Treatment of individuals who have been diagnosed with glutathione synthetase (GS) deficiency involves providing supplements to correct the metabolic acidosis and supplying antioxidants such as vitamin E and vitamin C. NAC has been used in patients with GS deficiency because it is thought to increase the low intracellular glutathione concentrations and cysteine availability in the leukocytes of patients with this disorder. Use of sodium citrate and citric acid (Bicitra), vitamin C and vitamin E, thioctic acid (ie, lipoic acid), and NAC are included here.

Drug Category: Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs. Citric acid mixtures may also be used. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.

Drug Category: Vitamins and antioxidants

These are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are used clinically for the prevention and treatment of specific vitamin deficiency states.

Drug Category: Amino acids

NAC is the N-acetyl derivative of the amino acid cysteine. NAC enhances the levels of glutathione in the liver, plasma, and bronchioalveolar lavage fluid. It is used to treat various diseases with the underlying etiology of decreased glutathione.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Outpatient Care

• Glutathione synthetase (GS) deficiency is a chronic life-threatening disorder. Regular follow-up with a metabolic diseases specialist may be indicated. All patients should be encouraged to wear a medical alert bracelet or necklace.

Transfer

• Transfer to a center where metabolic diseases specialists are available may be indicated.

Deterrence/Prevention

• Because accumulation of 5-oxoproline occurs in all body fluids, especially the urine, of affected individuals, the possibility of prenatal diagnosis with amniotic fluid was realized; most of this fluid is from fetal urine after the first trimester.
• In 1994, 2 pregnancies of 2 at-risk couples were studied at 16 weeks' gestation.² In both cases, the levels of 5-oxoproline were 25-30 times reference range values. Both pregnancies were terminated, and the diagnosis was confirmed in one case by cultured fetal fibroblast enzyme analysis.

Prognosis

• In the systemic form, chronic metabolic acidosis must be treated, but long-term prognosis is guarded. The lack of glutathione in erythrocytes alone is apparently tolerable, as has been noted with the peripheral form of this condition; however, in severe GS, a progressive loss of function occurs, leading to severe mental retardation, ataxia, and seizure disorders.
• The oldest reported survivor of severe GS was aged 24 years and had experienced significant neurological deterioration over the previous few years. Older children with mild and moderate forms who are doing well have been reported.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Severe high anion gap metabolic acidosis may be attributed to poisoning. The laboratory diagnosis of this condition is nontrivial and requires ordering the correct test (ie, urine organic acids). Laboratory personnel with experience in detecting 5-oxoproline should perform this test.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Biochemical pathway of glutathione synthetase.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. 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 dysfunction. Hum Mol Genet. Jul 1997;6(7):1147-52. [Medline].
2. Manning NJ, Davies NP, Olpin SE, et al. Prenatal diagnosis of glutathione synthase deficiency. Prenat Diagn. Jun 1994;14(6):475-8. [Medline].
3. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. Aug 2007;7(4):355-9. [Medline].
4. Boxer LA, Oliver JM, Spielberg SP, et al. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. N Engl J Med. Oct 25 1979;301(17):901-5. [Medline].
5. Bruggemann LW, Groenendaal F, Ristoff E, et al. Glutathione synthetase deficiency associated with antenatal cerebral bleeding. J Inherit Metab Dis. 2004;27(2):275-6. [Medline].
6. Divry P, Roulaud-Parrot F, Dorche C, et al. 5-Oxoprolinuria (glutathione synthetase deficiency): a case with neonatal presentation and rapid fatal outcome. J Inherit Metab Dis. 1991;14(3):341-4. [Medline].
7. Erasmus E, Mienie LJ, de Vries WN, et al. Prenatal analysis in two suspected cases of glutathione synthetase deficiency. J Inherit Metab Dis. 1993;16(5):837-43. [Medline].
8. Fily A, Vaillant C, Truffert P. [Gluthathion synthetase deficit in a newborn infant.]. Arch Pediatr. Nov 2004;11(11):1339-41. [Medline].
9. Jellum E, Kluge T, Borresen HC, et al. Pyroglutamic aciduria--a new inborn error of metabolism. Scand J Clin Lab Invest. Dec 1970;26(4):327-35. [Medline].
10. Larsson A, Zetterstrom R, Hagenfeldt L, et al. Pyroglutamic aciduria (5-oxoprolinuria), an inborn error in glutathione metabolism. Pediatr Res. Oct 1974;8(10):852-6. [Medline].
11. Marstein S, Jellum E, Halpern B. Biochemical studies of erythrocytes in a patient with pyroglutamic acidemia (5-oxoprolinemia). New Engl J Med. 1976;295.
12. Martensson J, Gustafsson J, Larsson A. A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5-oxoprolinuria). J Inherit Metab Dis. 1989;12(2):120-30. [Medline].
13. Meister A, Anderson ME. Glutathione. Annu Rev Biochem. 1983;52:711-60. [Medline].
14. Mohler DN, Majerus PW, Minnich V, et al. Glutathione synthetase deficiency as a cause of hereditary hemolytic disease. N Engl J Med. Dec 3 1970;283(23):1253-7. [Medline].
15. Njalsson R, Carlsson K, Winkler A, et al. Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene. Hum Mutat. Dec 2003;22(6):497. [Medline].
16. Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr. Jul 2001;139(1):79-84. [Medline].
17. Robertson PL, Buchanan DN, Muenzer J. 5-Oxoprolinuria in an adolescent with chronic metabolic acidosis, mental retardation, and psychosis. J Pediatr. Jan 1991;118(1):92-5. [Medline].
18. Shi ZZ, Habib GM, Rhead WJ, et al. Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nat Genet. Nov 1996;14(3):361-5. [Medline].
19. Spielberg SP, Boxer LA, Oliver JM, et al. Oxidative damage to neutrophils in glutathione synthetase deficiency. Br J Haematol. Jun 1979;42(2):215-23. [Medline].
20. Uhlig S, Wendel A. The physiological consequences of glutathione variations. Life Sci. 1992;51(14):1083-94. [Medline].
21. Webb GC, Vaska VL, Gali RR, et al. The gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2. Genomics. Dec 10 1995;30(3):617-9. [Medline].
22. Yapicioaylu H, Satar M, Tutak E. A newborn infant with generalized glutathione synthetase deficiency. Turk J Pediatr. Jan-Mar 2004;46(1):72-5. [Medline].

Article Last Updated: Nov 30, 2007