5-OXOPROLINEMIA – GLUTATHIONE SYNTHETASE DEFICIENCY
OR
GLUTAMYLCYSTEINE SYNTHETASE DEFICIENCY
OR
5-OXOPROLINASE DEFICIENCY Background 5-Oxoprolinemia is a rare clinical condition caused by a deficiency of any one of three enzymes in the γ-Glutamyl Cycle. The Cycle provides antioxidant for the body in the form of Glutathione. Three enzymes are involved in the sequential processing of 5-Oxoproline to form glutathione. A deficiency of any one of the enzymes causes 5-Oxoprolinemia, and two of the defects lead to low levels of glutathione. Patients with 5-Oxoprolinemia have been described in several ethnic groups around the world.
Clinical
Clinical presentation of these deficiencies is variable, from severe to very mild. Glutathione Synthetase Deficiency is the most common defect, reported in over 40 cases worldwide. It usually presents in the newborn period with marked metabolic acidosis, hemolytic anemia, electrolyte imbalance, and jaundice. Patients who survive the initial onset may later have episodes of metabolic decompensation during intercurrent illnesses. They often develop progressive central nervous system symptoms. 5-Oxoproline can reach very high levels during illness. γ-Glutamylcysteine Synthetase Deficiency is less severe than Glutathione Synthetase Deficiency, lacking the metabolic acidosis and having lower 5-Oxoproline levels in plasma and urine. Patients have mild compensated hemolytic anemia as the most consistent finding. Only a few patients have been reported with 5-Oxoprolinase Deficiency. Their clinical symptoms vary tremendously and may not be due to the metabolic defect. They have normal glutathione levels in erythrocytes and no evidence of hemolytic anemia.
Testing
Newborn Screening of dried blood spots using tandem mass spectrometry identifies 5-Oxoproline. Elevated levels should dictate further diagnostic testing. Glutathione Synthetase and Glutamylcysteine Synthetase activity can be measured in erythrocytes, leukocytes, and fibroblasts. 5-Oxoprolinase is not present in erythrocytes, but is present in leukocytes and fibroblasts. Glutathione Synthetase Deficiency has been diagnosed prenatally by enzyme assay of amniocytes or chorionic villi cells, or by finding elevated 5-Oxoproline in amniotic fluid. The gene is on chromosome 20 and mutations have been found in affected patients, raising the possibility for DNA-based prenatal diagnosis. Glutamylcysteine Synthetase is composed of two different proteins and mutations have been found in one of the genes.
Treatment
Patients with Glutathione Synthetase Deficiency require intravenous sodium bicarbonate for acute episodes and oral alkali for chronic acidosis. Severe anemia is corrected with blood transfusions. Patients with Glutathione Synthetase or Glutamylcysteine Synthetase Deficiencies may benefit from supplementation with Vitamin E and Vitamin C for their antioxidant effects. Because the diagnosis and therapy of 5-Oxoprolinemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.
Inheritance
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.
References Beutler E, Gelbart T, Kondo T, et al. The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood. 94:2890-4, 1999. Konrad, P.N., Richards II, F., Valentine, W.N., et al. ?-Glutamylcysteine Synthetase deficiency. A cause of hereditary hemolytic anemia. New England J Medicine 286:557, 1972. Larson, A. and Anderson, M.E. Glutathione Synthetase Deficiency and Other disorders of the ?-Glutamyl Cycle. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 96, pg. 2205 - 2216. Mayatepek, E., Hoffman, G.F., Carlsson, B., et al. Impaired synthesis of lipoxygenase products in glutathione synthetase deficiency. Pediatric Research 35:307, 1994.
Web Sites SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites. National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.
Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.
(c) 2008 PerkinElmer Genetics, Inc. All Rights Reserved
This information is copyrighted and is only for your personal, non-commercial use, provided that all copyright and other proprietary notices are retained on any copies made of it. The information may not be modified in any way or reproduced or distributed or used for any public or commercial purpose unless expressly permitted. Any use or display of the enclosed information for any purpose is prohibited. |