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9 Disorders of the Γ-Glutamyl Cycle Ellinor Ristoff, Agne Larsson

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9 Disorders of the Γ-Glutamyl Cycle Ellinor Ristoff, Agne Larsson 9 Disorders of the γ-Glutamyl Cycle Ellinor Ristoff, Agne Larsson 9.1 Introduction Glutathione (GSH), a tripeptide present in all mammalian cells, takes part in several fundamental biological functions, including handling of reactive oxygen species (ROS), detoxification of xenobiotics and carcinogens, redox reactions, biosynthesis of DNA and leukotrienes, as well as neurotransmission and neu- romodulation. Glutathione is metabolised via the γ-glutamyl cycle, which is catalysed by six enzymes. In man, hereditary deficiencies have been found in four of the six enzymes: i. e. γ-glutamylcysteine synthetase, GSH synthetase, γ- glutamyl transpeptidase and 5-oxoprolinase (see Larsson and Anderson 2001). Mutants have not yet been found in γ-glutamyl cyclotransferase and dipepti- dase. Most of the mutations are leaky so that many patients have residual en- zyme activity. Patients with defects in the biosynthesis of GSH (i. e. γ-glutamyl cysteine synthetase and GSH synthetase) have haemolytic anaemia and may also show CNS involvement and metabolic acidosis. The aim of the treatment for these disorders is to avoid haemolytic crises and to support the endogenous defence against reactive oxygen species. The clinical findings in patients with defects in the degradation of GSH are heterogeneous, more complex and frequently include damage to the CNS. No treatment has been recommended for these disorders. γ-Glutamylcysteine synthetase deficiency (OMIM 230450) has been described in 8 patients in six families. All have had well-compensated haemolytic anaemia and three have also had neurological symptoms such as spinocerebellar degen- eration, neuropathy, myopathy, psychosis and learning disabilities (Richards et al. 1974; Beutler et al. 1999). The recommended treatment is to avoid drugs and foods known to precipitate haemolytic crises in patients with glucose-6- phosphate dehydrogenase deficiency. Early supplementation with the antioxi- dant vitamins C and E seems to prevent damage to the CNS in patients with GSH synthetase deficiency (Ristoff et al. 2001). In analogy supplementation with vi- tamins C and E might be worth testing also in patients with γ-glutamylcysteine synthetase deficiency. However, no studies of this treatment have yet been made. Glutathione synthetase deficiency (OMIM 266130) has been confirmed in more than 70 patients in about 60 families. Approximately 25% of these pa- tients have died in childhood – usually in the neonatal period – of electrolyte 100 Disorders of the γ-Glutamyl Cycle imbalance and infections. Treatment in the neonatal period involves correction of acidosis and electrolyte imbalance, and early treatment with the antioxidants vitamins E and C to prevent damage to the CNS (Ristoff et al. 2001). GSH syn- thetase deficiency can be classified according to the severity of clinical signs as mild, moderate or severe (Ristoff et al. 2001). The clinical symptoms range from only haemolytic anaemia to metabolic acidosis, 5-oxoprolinuria, progressive neurological symptoms and sometimes also recurrent bacterial infections, due to defective granulocyte function. In some patients with the severe form, the eyes are affected: e.g. retinal pigmentations, crystalline opacities in the lenses, poor adaptation to darkness and pathological electroretinograms (Larsson et al. 1985). Several patients with a deficiency of GSH synthetase have died, but few have been autopsied. The first patient described with GSH synthetase defi- ciency died at 28 years of age. The autopsy of the CNS showed selective atrophy of the granular cell layer of the cerebellum, focal lesions in the frontoparietal cortex, the visual cortex and thalamus (Skullerud et al. 1980). The lesions in the brain resemble those seen after intoxication with the toxic compound mercury, i. e. Minamata disease, and it has therefore been suggested that treatment of GSH synthetase deficiency with antioxidants may be beneficial (Skullerud et al. 1980). The goal of treatment in patients with GSH synthetase deficiency is to correct the acidosis and to compensate for the lack of antioxidant capacity in the cells. A long-term follow-up study of 28 patients showed that early sup- plementation with the antioxidant vitamins C and E is useful for preventing damage to the CNS in patients with GSH synthetase deficiency (Ristoff et al. 2001). Recommended treatment does not normalize the elevated excretion of 5-oxoproline in urine. A pregnancy in one woman with moderate GSH synthetase deficiency has been described and resulted in a healthy infant (Ristoff et al. 1999). Nomenclature 101 9.2 Nomenclature No. Disorder (symbol) Definitions/comment Gene symbol OMIM No. 9.1 γ-Glutamylcysteine Decreased synthesis of GSH and GLCLC 230450 synthetase deficiency γ-glutamylcysteine due to low activity of (catalytic subunit), γ-glutamylcysteine synthetase GLCLR (regulatory subunit) 9.2.1 Mild GSH synthetase Decreased synthesis of GSH due to low GSS 266130 deficiency activity of GSH synthetase May have 5-oxoprolinuria 601002 9.2.2 Moderate GSH 5-Oxoprolinuria, decreased synthesis of GSS 266130 synthetase deficiency GSH due to low activity of GSH synthetase 601002 9.2.3 Severe GSH synthetase 5-Oxoprolinuria, decreased synthesis of GSS 266130 deficiency GSH due to low activity of GSH synthetase 601002 9.3 γ-Glutamyl transpepti- Glutathionuria, increased levels of GSH GGT 231950 dase (GT) deficiency in plasma, low activity of GT (a multigene family on chromosome 22) 9.4 5-Oxoprolinase 5-Oxoprolinuria, low activity 260005 deficiency of 5-oxoprolinase 9.3 Treatment No. Disorder Treatment/diet Dosage (mg/kg per day) 9.1 γ-Glutamylcysteine Avoidthedrugsandfoodsknowntoprecipitatehaemolytic synthetase deficiency crises in patients with glucose-6-phosphate dehydrogenase deficiency Vitamins C (ascorbic acid) can be tried 100 Vitamin E (α-tocopherol) can be tried 10 9.2 Glutathione (GSH) Correction of acidosis (bicarbonate, citrate or THAM) synthetase deficiency Vitamin C (ascorbic acid)a 100 Vitamin E (α-tocopherol)b 10 Avoidthedrugsandfoodsknowntoprecipitatehaemolytic crises in patients with glucose-6-phosphate dehydrogenase deficiency 9.3 γ-Glutamyl transpepti- No treatment has been recommended dase (GT) deficiency 9.4 5-Oxoprolinase No treatment has been recommended deficiency a A trial with short-term treatment of GSH synthetase-deficient patients with vitamin C has been reported to increase the levels of lymphocyte GSH (Jain et al. 1994). Vitamin C and GSH can spare each other in a rodent model (Martensson et al. 1991) b Vitamin E has been claimed to correct the defective granulocyte function (Boxer et al. 1979) 102 References 9.4 Alternative Therapies/Experimental Trials No. Disorder Treatment/diet Dosage (mg/kg per day) 9.1 γ-Glutamylcysteine synthetase No treatment has been recommended deficiency 9.2 Glutathione synthetase N-Acetylcysteinea 15 deficiency Glutathione estersb 9.3 γ-Glutamyl transpeptidase No treatment has been recommended (GT) deficiency 9.4 5-Oxoprolinase deficiency No treatment has been recommended a Since N-acetylcysteine (NAC) protects cells in vitro from oxidative stress, it has been suggested that NAC supplements (15 mg/kg per day) should be given to GSH-deficient patients. However, today we know that patients with GSH synthetase deficiency accumulate cysteine and, in our opinion, NAC therefore should not be recommended (Ristoff et al. 2002) b Glutathione esters have been tried in animal models of GSH deficiency and in two patients with GSH synthetase deficiency (Anderson et al. 1994; W. Rhead, personal communication). The GSH esters, which are more lipid-soluble, are readily transported into cells and converted intracellularly into GSH. The esters increase GSH levels in several tissues, but their use is limited because of associated toxic effects, i. e. when they are hydrolysed to release GSH, alcohols are produced as aby-product 9.5 Follow-up/Monitoring No. Disorder Clinical investigations Laboratory investigations 9.1 γ-Glutamylcysteine synthetase Neurological investigation Hb, reticulocytes deficiency 9.2 Glutathione synthetase Neurological investigation Acid-base balance deficiency Eye examination Hb, reticulocytes (retinal pigmentations, corneal opacities) 9.3 γ-Glutamyl transpeptidase Neurological investigation (GT) deficiency 9.4 5-Oxoprolinase deficiency Neurological investigation Acid-base balance References 1. Anderson ME, Levy EJ, Meister A (1994) Preparation and use of glutathione monoesters. Methods Enzymol 234:492–499 2. Beutler E, Gelbart T, Kondo T, Matsunaga AT (1999) The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood 94(8):2890–2894 3. Boxer LA, Oliver JM, Spielberg SP, Allen JM, Schulman JD (1979) Protection of granulo- cytes by vitamin E in glutathione synthetase deficiency. New Engl J Med 301(17):901–905 4. Jain A, Buist NR, Kennaway NG, Powell BR, Auld PA, Martensson J (1994) Effect of ascor- bate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatr 124(2):229–233 References 103 5. Larsson A, Anderson M (2001) Glutathione synthetase deficiency and other disorders of the gamma-glutamyl cycle. New York, Mc Graw Hill, pp 2205–2216 6.LarssonA,WachtmeisterL,vonWendtL,AnderssonR,HagenfeldtL,HerrinKM (1985) Ophthalmological, psychometric and therapeutic investigation in two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria). Neuropediatrics 16(3):131–136 7. Martensson J, Meister A (1991) Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.
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