Glutathione Synthetase Deficiency: An Inborn Error of the Gamma-Glutamyl Cycle

Year 2011, Volume: 3 Issue: 1, 1 - 9, 01.01.2011

Andrea Schlune , Ertan Mayatepek

Abstract

Glutathione (GSH) is a tripetptide consisting of the amino acids glutamate, cysteine and glycine. It is ubiquitous in the eukaryotic organism and plays a role in many fundamental cellular processes. GSH is metabolized in the gamma-glutamyl cycle in which six enzymes take part in its synthesis and turnover. The most common disorder of the gamma-glutamyl cycle is glutathione synthetase (GSS) deficiency. About 70 patients have been described worldwide. GSS deficiency is inherited in an autosomal recessive manner resulting in decreased levels of cellular glutathione and subsequent overproduction of 5-oxoproline which accumulates in body fluids and is excreted in urine. GSS deficiency is a heterogeneous condition with varying clinical severity. Based on the severity of the clinical symptoms it is classified into three groups. The most severe form is mainly associated with metabolic acidosis, usually present in the neonatal period, haemolytic anemia, 5-oxoprolinuria and central nervous system (CNS) damage. Diagnosis is established by measurement of enzyme activity and mutation analysis. Antenatal diagnosis is possible. Treatment is symptomatic and aims at correction of metabolic acidosis, prevention of haemolysis and support of endogenous defence against reactive oxygen species (ROS). The prognosis is difficult to predict, as the number of patients is limited and the clinical condition varies widely.

Keywords

gamma-glutamyl cycle, glutathione, haemolytic anemia, metabolic acidosis, 5-oxoprolinuria

References

• Meister A. On the discovery of glutathione. Trends Biochem Sci 1988; 13: 185-8.
• Kosower NS, Kosower EM. The glutathione status of cells. Int Rev Cytol 1978; 54: 109-60.
• Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983; 52: 711-60.
• Meister A. Glutathione metabolism and its selective modification. J Biol Chem 1988; 263: 17205-8.
• Spielberg SP. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc 1984; 43; 230813.
• Rinaldi R, Eliasson E, Swedmark S, Morgenstern R. reactive intermediates and the dynamics of glutathione transferases. Drug Metab Dispos 2002; 30: 1053-8
• Cai J, Chen Y, Seth S, Furukawa S, Compans RW, Jones DP. Inhibition of Influenza Infection by Glutathione. Free Radic Biol Med 2003; 34: 92836.
• Mayatepek E, Hoffmann GF, Carlsson B, Larsson A, Becker K. Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency. Pediatr Res 1994; 35: 307-10.
• Watson WH, Chen Y, Jones DP. Redox state of glutathione and thioredoxin in differentiation and apoptosis. Biofactors 2003; 17: 307-14.
• Janaky R, Shaw, CA, Varga V, Hermann A, Dohovics R, Saransaari P et al. Specific glutathione binding sites in pig cerebral cortical synaptic membranes. Neuroscience 2000; 95: 617-24.
• Oja SS, Jankay R, Varga V, Saransaari P. Modulation of glutamate receptor functions by glutathione. Neurochem Int 2000; 37: 299-306.
• Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother 2003; 57: 145-55.
• Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione Metabolism and Its Implications for Health. J Nutr 2004; 134: 489-92.
• Larsson A, Anderson ME. Glutathione synthetase deficienca and other disorders of the γ-glutamyl cycle. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds.). Metabolic and molecular bases of inherited disease (8th ed.). New York: McGrawHill; 2001, pp 2205-16.
• Richman PG, Meister A. Regulation of γ-glutamyl-cysteine synthetase by nonallosteric feedback inhibition by glutathione. J Biol Chem 1975; 250: 1422-6.
• Polekhina G, Board PG, Gali RR, Rossjohn J, Parker MW. Molecular basis of glutathione synthetase deficiency and a rare gene permutation event. Embo J 1999; 18: 3204-13.
• Ristoff E, Hebert C, Njalsson R, Norgren S, Rooyackers O, Larsson A. Glutathione synthetase deficiency: Is γ-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione? J Inherit Metab Dis 2002; 25: 577-84.
• Jellum E, Kluge T, Borresen HC, Stokke O, Eldjarn L. Pyroglutamic aciduria -a new inborn error of metabolism. Scand J Clin Lab Invest 1970; 26: 327-35.
• Hagenfeldt L, Larsson A, Zetterström R. Pyroglutamic aciduria. Studies in an infant with chronic metabolic acidosis. Acta Paediat Scand 1973; 63: 1-8.
• Wellner VP, Sekura R, Meister A, Larsson A. Glutathione synthetase deficiency, an inborn error of metabolism involving the γ-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Proc Nat Acad Sci 1974; 71: 2505-9.
• Marstein S, Jellum E, Halpern B, Eldjarn L, Perry TL. Biochemical studies of erythrocytes in a patient with pyroglutamic acidemia (5-oxoprolinuria). New Eng J Med 1976; 295; 40612.
• Skullerud K, Marstein S, Schrader H, Brundelet PJ, Jellum E. The cerebral lesions in a patient with generalized glutathione deficiency and pyroglutamic aciduria (5-oxoprolinuria). Acta Neuropathol 1980; 52: 235-8.
• Boxer LA, Oliver JM, Spielberg SP, Alen JM, Schulman JD. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. New Eng J Med 1979; 301: 901-5.
• Spielberg SP, Boxer LA, Oliver JM, Allen JM, Schulman JD. Oxidative damage to neutrophils in glutathione synthetase deficiency. Brit J Haemat 1979; 42: 215-23. 25. Porath U, Schreier K. A family with pyroglutamic aciduria. Deutsch Med Wochenschr 1978; 103:939.
• Larsson A, Wachtmeister L, von Wendt L, Andersson R, Hagenfeldt L, Herrin KM. Ophthalmologieal, psychometrie and therapeutic investigation in two sisters with hereditary glutathione synthetase deficieney (5-oxoprolinuria). Neuropediatrics 1985; 16: 131-6.
• Ristoff E, Burstedt M, Larsson A, Wachtmeister L. Progressive retinal dystrophy in two sisters with glutathione synthetase (GS) deficiency. J Inherit Metab Dis 2007; 30: 102.
• Brüggemann LW, Groenendaal F, Ristoff E, Larsson A, Duran M, van Lier JAC et al. Glutathione synthetase de¢ciency associated with antenatal cerebral bleeding. J Inherit Metab Dis 2004; 27: 175-6.
• Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 2001; 139: 79-84.
• McKenna R, Ahmad Tm Ts´ao CH, Fischer H. Glutathione reductase deficiency and platelet dysfunction induced by 1,3-bis(2-chloroethyl)-1-nitrosourea. J Lab Clin Med 1983; 102: 102-15.
• Pace-Asciak CR, Klein J, Spielberg SP. Human genetic defect in leukotriene C4 synthesis. Biochem Biophys Res Commun 1986; 140: 857-60.
• Naseem KM, Bruckdorfer KR. Hydrogen peroxide at low concentrations strongly enhances the inhibitory effect of nitric oxide on platelets. Biochem J 1995; 310: 149-53.
• Njalsson R, Norgren S. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Acta Paediatr 2005; 94: 132-7.
• Ristoff E, Augustson C, Larsson A. Generalized glutathione synthetase deficiency and pregnancy. J Inher Metab Dis 1999;22:758-9
• Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L. Quantitative Analysis for Organic Acids in BiologicalSamples: Batch Isolation Followed by Gas ChromatographicMassSpectrometric Analysis. Clin Chem 1989; 35: 587-95.
• Mayatepek E. 5-Oxoprolinuria in patients with and without defects in the c-glutamyl cycle. Eur J Pediatr 1999; 158: 221-5.
• Stokke O, Marstein S, Jellum E, Lie SO. Accumulation of pyroglutamic acid (5-oxoproline) in homocystinuria. Scand J Clin Lab Invest. 1982; 42: 361-9.
• Rizzo C, Ribes A, Pastore A, Dionisi-Vici C, Greco M, Rizzoni G et al. Pyroglutamic aciduria and nephropathic cystinosis. J Inherit Metab Dis. 1999; 22: 224-6.
• Jackson AA, Persaud C, Hall M, Smith S, Evans N, Rutter N. Urinary excretion of 5-L-oxoproline (pyroglutamic acid) during early life in term and preterm infants. Arch Dis Child Fetal Neonatal Ed. 1997; 76: F152-7.
• Goto A, Ishida A, Goto R, Hayasaka K, Nanao K, Yamashita A et al. Transient 5-oxoprolinuria in a very low-birthweight infant. J Inherit Metab Dis1992; 15: 284-5.
• Jackson AA, Badaloo AV, Forrester T, Hibbert JM, Persaud C. Urinary excretion of 5-oxoproline (pyroglutamic aciduria) as an index of glycine insufficiency in normal man. Br J Nutr 1987; 58: 207-14.
• Tham R, Nystrom L, Holmstedt B. Identification by mass spectrometry of pyroglutamic acid as a peak in the gas chromatography of human urine. Biochem Pharmacol 1968; 17: 1735-8.
• Bonham JR, Rattenbury JM, Meeks A, Pollitt RJ. Pyroglutamicaciduria from vigabatrin. Lancet 1989; 1: 1452-3.
• Ghauri FY, McLean AE, Beales D, Wilson ID, Nicholson JK. Induction of 5-oxoprolinuria in the rat following chronic feeding with N-acetyl 4-aminophenol (paracetamol). Biochem Pharmacol 1993; 46: 953-7.
• Croal BL, Glen AC, Kelly CJ, Logan RW. Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy. Clin Chem 1998; 44: 336-40.
• Oberholzer VG, Wood CB, Palmer T, Harrison BM. Increased pyroglutamic acid levels in patients on artificial diets. Clin Chim Acta 1975; 62: 299-304.
• Ristoff E, Augustson C, Geissler J, de Rijk T, Carlsson K, Luo JK et al. A missense mutation in the heavy subunit of gamma-glutamylcysteine synthetase gene causes hemolytic anemia. Blood 2000; 95: 2193-6.
• Simon E, Vogel M, Fingerhut R, Ristoff E, Mayatepek E, Spiekerkötter U. Diagnosis of glutathione synthetase deficiency in newborn screening. J Inherit Metab Dis. 2009; Sep 2. [Epub ahead of print]
• Erasmus E, Mienie LJ, de Vries WN, de Wet WJ, Carlsson B, Larsson A. Prenatal analysis in two suspected cases of glutathione synthetase deficiency. J Inherit Metab Dis 1993; 16: 837-43.
• Manning NJ, Davies NP, Olpin SE, Carpenter KH, Smith MF, Pollitt RJ et al. Prenatal diagnosis of glutathione synthase deficiency. Prenat Diagn 1994; 14: 475-8.
• Webb GC, Vaska VL, Gali RR, Ford JH, Board PG. The Gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2. Genomics 1995; 30: 617-9.
• Gali RR, Board PG. Sequencing and expression of a cDNA for human glutathione synthetase. Biochem J 1995; 310: 353-8.
• Whitbread L, Gali RR, Board PG. The structure of the human glutathione synthetase gene. Chem Biol Interact 1998; 111-112: 35-40.
• Shi ZZ, Habib GM, Rhead WJ, Gahl WA, He X, Sazer S et al. Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nat Genet 1996; 14: 361-5.
• Dahl N, Pigg M, Ristoff E, Gali R, Carlsson B, Mannervik B 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 1997; 6: 1147-52.
• Al-Jishi E, Meyer BF, Rashed MS, Al-Essa M, Al-Hamed MH, Sakati N et al. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet 1999; 55: 444-9.
• Njalsson R, Carlsson K, Winkler A, Larsson A, Norgren S. Diagnostics in patients with glutathione synthetase deficiency but without mutations in the exons of the GSS gene. Hum Mutat 2003; 22: 497.
• Njalsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S. Physiological and pathological aspects of GSH metabolism. Hum Genet 2005; 116: 384-9.
• Spielberg SP, Garrick MD, Corash LM, Butler JD, Tietze F, Rogers L et al. Biochemical Heterogeneity in Glutathione Synthetase Deficiency. J Clin Invest 1978; 61: 1417-20.
• Sykut-Cegielska J, Jurecka A, Taybert J, Gradowska W, Pajdowska M, Pronicka E. Trial of erythropoietin treatment in a boy with glutathione synthetase deficiency. J Inherit Metab Dis 2005; 28: 1153-4.
• Fonnum F, Lock EA. Cerebellum as a target for toxic substances. Toxicol Lett 2000; 112-3: 9-16.
• Martensson J, Meister A. Glutathione deficiency decreases tissue ascorbate levels in newborn rats: Ascorbate spares glutathione and protects. Proc Natl Acad Sci USA 1991; 88; 4656-60. (Published erratum appears in Proc Natl Acad Sci USA. 1991; 88: 6898.)
• Jain A, Buist NR, Kennaway NG, Powell BR, Auld PA, Martensson J. Effect of ascorbate or Nacetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency J Pediatr. 1994; 124: 229-33.
• Ristoff E, Larsson A. Disorders of the γ-Glutamyl Cycle. In: Blau N, Hoffmann GF, Leonard J, Clarke JTR (eds.). Physician´s Guide to the Treatment and Follow-Up of Metabolic Diseases. Springer, Berlin/Heidelberg: Springer; 2006, pp 99-103.
• 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; 12:120-30.
• Janaky R, Varga V, Hermann A, Saransaari P, Oja SS. Mechanisms of L-Cysteine Neurotoxicity. Neurochem Res 2000; 25: 1397-405.
• Anderson ME, Levy EJ, Meister A. Preparation and use of glutathione monoesters. Methods Enzymol 1994; 234: 492-9.
• Okun JG, Sauer S, Bähr S, Lenhartz H, Mayatepek E. S-Acetylglutathione normalizes intracellular glutathione content in cultured fibroblasts from patients with glutathione synthetase deficiency. J Inherit Metab Dis 2004; 27: 783-6.