Glutathione Synthetase Deficiency


Glutathione Synthetase Deficiency (5-Oxoprolinuria; Pyroglutamic Aciduria) is caused by a defect in the GSS gene which codes for glutathione synthetase. Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. A defect in this enzyme results in accumulation of pyroglutamic acid and gamma-glutamylcysteine in urine and blood; decrease level of glutathione in erythrocytes; increase urinary excretion of 5-oxoproline. Glutathione synthetase deficiency can be classified into three types: mild, moderate and severe. Mild glutathione synthetase deficiency usually results in the destruction of red blood cells (hemolytic anemia). Rarely, affected people also excrete large amounts of a compound called 5-oxoproline in their urine (5-oxoprolinuria). This compound builds up when glutathione is not processed correctly in cells. Individuals with moderate glutathione synthetase deficiency may experience symptoms beginning shortly after birth including hemolytic anemia, 5-oxoprolinuria, and elevated acidity in the blood and tissues (metabolic acidosis). In addition to the features present in moderate glutathione synthetase deficiency, individuals affected by the severe form of this disorder may experience neurological symptoms. These problems may include seizures; a generalized slowing down of physical reactions, movements, and speech (psychomotor retardation); mental retardation; and a loss of coordination (ataxia). Some people with severe glutathione synthetase deficiency also develop recurrent bacterial infections.

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References

  1. Uniprot: P48637
  2. OMIM: Entry 266130
  3. Engelke, U., van der Graaf, M., Heerschap, A., Hoenderop, S., Moolenaar, S., Morava, E., Wevers, R. (2007). Handbook of 1H-NMR spectroscopy in inborn errors of metabolism: body fluid NMR spectroscopy and in vivo MR spectroscopy (pp 81) (2nd ed). Heilbronn: SPS Verlagsgesellschaft
  4. Divry P, Roulaud-Parrot F, Dorche C, Zabot MT, Contraire B, Hagenfeldt L, Larsson A: 5-Oxoprolinuria (glutathione synthetase deficiency): a case with neonatal presentation and rapid fatal outcome. J Inherit Metab Dis. 1991;14(3):341-4. Pubmed
  5. Njalsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S: Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet. 2005 Apr;116(5):384-9. Epub 2005 Feb 17. Pubmed
  6. Robertson PL, Buchanan DN, Muenzer J: 5-Oxoprolinuria in an adolescent with chronic metabolic acidosis, mental retardation, and psychosis. J Pediatr. 1991 Jan;118(1):92-5. Pubmed
  7. Shi ZZ, Habib GM, Rhead WJ, Gahl WA, He X, Sazer S, Lieberman MW: Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. Nat Genet. 1996 Nov;14(3):361-5. Pubmed