Information on the following diseases can be found in the Related Disorders section of this report:

• Oxoprolinase Deficiency
• Glutathionuria (Gamma-Glutamyl Transpeptidase Deficiency)

5-Oxoprolinuria is characterized by excretion of massive amounts of 5- oxoproline (pyroglutamic acid) in the urine, and abnormally high levels of this acid in the blood and cerebrospinal fluid. Without treatment, mental retardation, impaired muscle coordination (cerebellar ataxia), and seizures may occur.

This finding can result from generalized glutathionine synthetase deficiency or 5-oxoprolinase deficiency. It has also been reported where there is no enzyme defect in the gamma-glutamyl cycle in patients with severe burns or Stevens-Johnson syndrome.

Glutathionine Synthetase Deficiency
Glutathionine synthetase deficiency is a metabolic disorder characterized by excretion of the chemical 5-oxoproline in the urine, metabolic acidosis and increased rate of red cell hemolysis (premature breakdown of red blood cells). Some affected individuals also have central nervous system problems such as learning disability, seizures, poor balance and weakness of the limbs.

5-Oxoprolinase Deficiency
5-oxoprolinase deficiency also causes excretion of the chemical 5-oxoproline in the urine. There is no accompanying metabolic acidosis or hemolysis. Since there are only a few known cases, the full clinical picture is as yet unknown.

5-Oxoprolinuria is inherited as an autosomal recessive trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.
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The conditions are present at birth. They are extremely rare disorders.
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Symptoms of the following disorders may be similar to those of 5- Oxoprolinuria. Comparisons may be useful for a differential diagnosis:

5-Oxoprolinase Deficiency is another congenital disorder due to enzyme deficiency: in this case, a deficiency of the enzyme 5-oxoprolinase. A moderate amount of 5-oxoproline is excreted in the urine and blood levels of this substance are higher than normal. This disorder is benign and those afflicted usually exhibit no other symptoms.

Glutathionuria (Gamma-Glutamyl Transpeptidase Deficiency) is another, even more rare enzyme-deficiency disorder. Concentrations of glutathione in blood and urine are excessive. Patients with this disorder may be mildly mentally retarded and/or suffer from behavioral problems.

Glutathionine synthetase deficiency is treated with sodium bicarbonate to correct the metabolic acidosis. Vitamins E and C may also be given. Drugs that precipitate hemolysis should be avoided. There are no standard therapies for 5-oxoprolinase deficiency.

Glutathionine synthetase and 5-oxoprolinase deficiencies are inherited as autosomal recessive traits.

Genetic counseling should be offered to families in whom an inborn error of the gamma-glutamyl cycle is found.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 266130; Last Update: 10/4/2001. Entry No: 601002; Last Update: 4/17/2002. Entry No: 231900; Last Update: 10/4/2001. Entry No: 260005; Last Update: 4/172002.

TEXTBOOKS
Larsson A, Anderson ME. Glutathione synthetase deficiency and other diseases of the ?-glutamyl cycle. In: The Metabolic and Molecular Bases of Inherited Disease. eds., Scriver RS, AL Beaudet AL, Sly WS, et al. 8th ed. New York: McGraw-Hill, 2001, pp. 2205-2216.

Shi ZZ, Habib GM, Lieberman MW. Glutathione synthetase deficiency (5-oxoprolinuria). In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. In Press

JOURNAL ARTICLES
Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patient with glutathione synthetase deficiency. J Pediatr 2001;139:79-84.

Corrons JL, Alvarez R, Pujades A, et al. hereditary non-spherocytic anaemia due to red blood cell glutathione synthetase deficiency in four unrelated patients from Spain. Clinical and molecular studies. Br J Haematol. 2001;112:475-82.

Al-Jishi E, Meyer BF, Rashed MS, et al. Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. Clin Genet. 1999;55:444-49.

Mayatepek E. 5-Oxoprolinuria in patients with and without defects in the gamma-glutamyl cycle. Eur J Pediatr. 1999;158:221-25.

Polekhina G, Board PG, Gali RR, et al. Molecular basis of glutathione synthetase deficiency and a rare gene permutation event. EMBO J. 1999;18:3204-13.

Dahl N, et al. Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological misfunction. Hum Mol Genet. 1997;6:1147-52.

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; 13:361-365.

Jain A, et al. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glatathione synthetase deficiency. J Pediatr. 1994;124:229-33.