Glutathione Synthetase Deficiency

Author: Darius J Adams, MD; Chief Editor: Bruce Buehler, MD more...

Updated: Oct 14, 2009

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Background
Pathophysiology
Epidemiology
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Background

Glutathione synthetase (GS) deficiency, first described in 1970, is a rare inborn error of glutathione metabolism characterized by severe metabolic acidosis, hemolytic anemia, and neurological problems.^[23]Biochemical findings include massive excretion of 5-oxoproline in the urine. In mild glutathione synthetase deficiency, which is characterized by hemolytic anemia, enzyme deficiency primarily occurs in erythrocytes.

Biochemical pathway of glutathione synthetase.

Pathophysiology

Glutathione is involved in several important biologic functions, including membrane transport, detoxification of xenobiotics, and protection of cells from free radicals. Glutathione is produced from the amino acids cysteine, glycine, and glutamine via the consecutive actions of gamma-glutamylcysteine synthetase and glutathione synthetase. It is also widely used by RBCs, which are vulnerable to oxidative damage caused by peroxides. Reduced glutathione is required as an antioxidant in these cases.

Multiple mutations that cause glutathione synthetase deficiency have been described in the glutathione synthetase gene, GSS. The erythrocyte variant has been linked to a homozygous missense mutation that causes enzyme instability; thus, enzyme deficiency is most significant in erythrocytes and manifests as hemolytic anemia. Thirteen different missense mutations in GSS have been identified in individuals with severe glutathione synthetase deficiency.^[1]The mutations were found in 9 unrelated patients from different geographic areas. Two of these mutations were in individuals who were found to have CNS involvement. In all cases, residual enzyme activity was noted, indicating that a complete loss of enzyme function is probably lethal.

Frequency

United States

Frequency is unknown.

International

This condition is very rare. Worldwide, only approximately 40-50 cases in which the patient survived the newborn period have been published. Overall frequency is unknown.

Mortality/Morbidity

Recently, authors have recommended that 3 forms of glutathione synthetase deficiency be identified: mild, moderate, and severe (see History). In the severe systemic form, chronic metabolic acidosis must be managed. Long-term prognosis is guarded. With careful treatment during infancy, many patients survive, and the metabolic acidosis may become more manageable after infancy. The lack of glutathione in erythrocytes alone is apparently tolerable, as has been noted with the mild form of this condition; however, in severe glutathione synthetase deficiency, a progressive loss of function occurs, leading to severe mental retardation, ataxia, and seizure disorders.

According to one review, the oldest reported survivor with the severe form was aged 24 years and had experienced significant neurological deterioration over the previous few years. Psychotic behavior, tremors, and dysarthria have also been reported. Patients with the moderate or mild forms have been reported to have long-term survival and little or no neurological sequelae.

Race

No race predilection is observed.

Sex

No sex predilection is known.

Age

Most individuals with systemic glutathione synthetase deficiency are diagnosed in the newborn period. However, with the isolated erythrocyte form, the diagnosis may not be made until adulthood, although hemolytic anemia is present at birth.

Proceed to Clinical Presentation

Contributor Information and Disclosures

Author

Darius J Adams, MD Assistant Professor, Department of Pediatrics, Section of Genetics and Metabolism, Albany Medical Center

Darius J Adams, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Coauthor(s)

Melissa P Wasserstein, MD Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine

Melissa P Wasserstein, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert D Steiner, MD Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting; Amicus Consulting

Mary L Windle, PharmD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine

Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Leonard G Feld, MD, PhD, MMM, FAAP Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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