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Glutathione Synthetase Deficiency Clinical Presentation

  • Author: Darius J Adams, MD; Chief Editor: Luis O Rohena, MD  more...
Updated: Nov 17, 2014


The phenotypic manifestations that have been described in association with glutathione synthetase (GS) deficiency include hemolytic anemia, which occurs in mild glutathione synthetase deficiency, and 5-oxoprolinuria (pyroglutamicaciduria) and variable degrees of secondary neurological involvement (occurring in systemic glutathione synthetase deficiency). As stated in Mortality/Morbidity, authors have suggested glutathione synthetase deficiency be described as mild, moderate, or severe. These categories represent a continuum of disease severity that depends on the degree of enzyme function; therefore, patients can have manifestations anywhere along the continuum of mild to severe glutathione synthetase deficiency.

  • The severe phenotypic manifestation, 5-oxoprolinuria (pyroglutamicaciduria), resulting from systemic glutathione synthetase deficiency, is an autosomal recessive disorder. It is characterized by very large peaks of 5-oxoproline on urine organic acid analysis findings, metabolic acidosis, hemolytic anemia, and eventual CNS damage. Because of deficient enzyme activity, a decreased quantity of glutathione results, which likely causes promoter activation of the GSS gene. The large amounts of gamma-glutamylcysteine synthetase that are produced increase the pool of gamma-glutamylcysteine, which is then converted to 5-oxproline because of the inability of the defective GSS gene to produce glutathione.
  • In moderate glutathione synthetase deficiency, neonatal acidosis and hemolytic anemia are present, but neurological involvement is not. The prognosis for the moderate form is intermediate.
  • In mild glutathione synthetase deficiency, hemolytic anemia is the primary finding with apparently no effects outside of erythrocytes. Individuals with this form do well clinically.


Patients with glutathione synthetase deficiency appear healthy and do not have unusual dysmorphic features.

  • In severe glutathione synthetase deficiency, neurological findings are the most prevalent and may include the following:
    • Spasticity (spastic tetraparesis)
    • Ataxia and other cerebellar findings
    • Intention tremors
    • Dysarthria
    • Mental retardation
    • Psychosis
    • Seizure disorders
    • Eye abnormalities, which tend to be peripheral retinal pigmentation abnormalities
  • Individuals with moderate glutathione synthetase deficiency may have apparent respiratory distress as their bodies try to correct metabolic acidosis; however, other signs are not usually present.
  • In mild glutathione synthetase deficiency, physical findings are not present.


See the list below:

  • Southern blot hybridizations that have been performed with a glutathione synthetase complementary DNA (cDNA) have revealed that only one GSS gene is present in the human genome. It is located at band 20q11.2.
  • Pathogenic mutations in the GSS gene cause glutathione synthetase deficiency, which is inherited in an autosomal recessive pattern. Carriers of one abnormal allele do not have symptoms of the condition.
  • These findings suggest that the different phenotypic types observed in glutathione synthetase deficiency are part of a spectrum of disease that depends on the degree of glutathione synthetase function.
Contributor Information and Disclosures

Darius J Adams, MD Director, Personalized Genomic Medicine, Atlantic Health System; Director, Division of Genetics and Metabolism, Goryeb Children's Hospital

Disclosure: Nothing to disclose.


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

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

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 and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

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Biochemical pathway of glutathione synthetase.
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