eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glutathione Synthetase Deficiency: Treatment & Medication

Author: Darius J Adams, MD, Assistant Professor, Department of Pediatrics, Section of Genetics and Metabolism, Albany Medical Center
Coauthor(s): Melissa P Wasserstein, MD, Associate Professor, Departments of Genetics and Genomic Sciences and Pediatrics, Mount Sinai School of Medicine
Contributor Information and Disclosures

Updated: Oct 14, 2009

Treatment

Medical Care

Treatment of individuals who have been diagnosed with glutathione synthetase (GS) deficiency involves providing supplements to correct the metabolic acidosis and supplying antioxidants such as vitamin E and vitamin C. A combination of sodium citrate and citric acid (Bicitra) may be used as an oral medication and can maintain plasma bicarbonate levels within the reference range. Alternatively, bicarbonate may be used; however, very large doses may be needed.

  • The prognosis for glutathione synthetase deficiency widely varies. In some cases, early use of sodium citrate and citric acid (Bicitra) or other buffers, vitamin C, and vitamin E may allow normal development to occur.
  • Experiments using lipoic acid as an intracerebral antioxidant have been performed in animal models. Lipoic acid penetrates the blood-brain barrier well and may prevent the onset of learning disabilities in children with glutathione synthetase deficiency. However, individuals may have an absolute requirement of glutathione for the production of certain leukotrienes and possibly even neurotransmitters. If this is the case, lipoic acid may not effectively correct the problem.
  • N -acetylcysteine (NAC) has been used in patients with glutathione synthetase deficiency because it is thought to increase the low intracellular glutathione concentrations and cysteine availability in the leukocytes of these patients. Whether these findings in leukocytes may result in similar changes in neurons is not yet known.

Consultations

  • Consultations with a clinical biochemical geneticist, metabolic diseases specialist, or hematologist may be indicated.

Medication

Treatment of individuals who have been diagnosed with glutathione synthetase (GS) deficiency involves providing supplements to correct the metabolic acidosis and supplying antioxidants such as vitamin E and vitamin C. NAC has been used in patients with glutathione synthetase deficiency because it is thought to increase the low intracellular glutathione concentrations and cysteine availability in the leukocytes of patients with this disorder. Use of sodium citrate and citric acid (Bicitra), vitamin C and vitamin E, thioctic acid (ie, lipoic acid), and NAC are included here.

Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs. Citric acid mixtures may also be used. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.


Sodium citrate and citric acid (Bicitra)

PO medication useful in outpatient treatment of individuals with persistent acidosis. Each mL contains 1 mEq sodium ion and is equivalent to 1 mEq of bicarbonate. Also contains butylparaben, flavoring, and sodium saccharin. In certain situations, potassium citrate (as contained in Polycitra-K) may be preferable.
Palatability enhanced if chilled before swallowing.

Adult

2-6 tsp (10-30 mL) diluted in 1-3 oz water, followed by additional water if desired, PO pc and qhs or as directed

Pediatric

<2 years: Based on consultation with physician
>2 years: 1-3 tsp (5-15 mL) diluted in 1-3 oz water, followed by additional water if desired, PO pc and qhs or as directed

Urine alkalinization may decrease serum levels of lithium, chlorpropamide, methenamine, methotrexate, salicylates, or tetracyclines; urine alkalinization may increase serum levels of flecainide, quinidine, or sympathomimetics; coadministration with aluminum-containing antacids may increase serum aluminum levels

Renal insufficiency and patients in sodium-restricted diet

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with low urinary output unless under the supervision of a physician; adequately dilute with water and ingest each dose pc; caution in patients with cardiac failure, hypertension, impaired renal function, peripheral and pulmonary edema, and toxemia of pregnancy; periodic examinations and determinations of serum electrolytes, particularly serum bicarbonate level, should be done in those patients with renal disease
Conversion to bicarbonate may be impaired in hepatic failure, shock, and in severely ill patients

Vitamins and antioxidants

These are organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are used clinically for the prevention and treatment of specific vitamin deficiency states.


Ascorbic acid (Vita-C, Cecon)

An antioxidant; one of the water-soluble vitamins.

Adult

200-4000 mg/d or 100 mg/kg/d PO

Pediatric

100 mg/kg/d PO

Decreases effects of warfarin and fluphenazine; increases aspirin levels

Documented hypersensitivity; patients with renal failure have difficulty clearing vitamin C, which can result in acidosis

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Prolonged high doses may cause renal calculi, especially in patients with diabetes


Vitamin E (Vita-Plus E Softgels, Aquasol E)

An antioxidant; one of the fat-soluble vitamins.

Adult

10 mg/kg/d PO; up to 3000 mg/d has been used and is probably safe

Pediatric

Administer as in adults

Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Pregnancy category C with doses exceeding the RDA; may induce vitamin K deficiency; necrotizing enterocolitis may occur with large doses


Thioctic acid (Thiocid)

Also called alpha-lipoic acid. An antioxidant considered to be more effective than vitamin E or C in crossing the blood-brain barrier.

Adult

100 mg/d PO; administer on empty stomach

Pediatric

Administer as in adults

Ethanol may antagonize actions; additive effect with insulin or PO hypoglycemic agents; antagonizes cisplatin effects

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May decrease blood glucose; temporary worsening of neuropathy following initiation of treatment has been observed

Amino acids

NAC is the N -acetyl derivative of the amino acid cysteine. NAC enhances the levels of glutathione in the liver, plasma, and bronchioalveolar lavage fluid. It is used to treat various diseases with the underlying etiology of decreased glutathione.


N-acetylcysteine (Mucomyst)

Has been used with GS deficiency because it is thought to increase low intracellular glutathione concentrations and cysteine availability in leukocytes.

Adult

Nebulization into a face mask, mouth piece, or tracheostomy: 1-10 mL of the 20% solution or 2-20 mL of the 10% solution may be given q2-6h; recommended dose for most patients is 3-5 mL of the 20% solution or 6-10 mL of the 10% solution tid/qid

Pediatric

Administer as in adults

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Possible transient disagreeable odor upon initiation of treatment but soon not noticeable; with face mask, stickiness on face may occur after nebulization, which is easily removed with water
Under certain conditions, color change may take place in the solution of acetylcysteine in opened bottle; light purple color is result of chemical reaction that does not significantly impair the safety or mucolytic effectiveness of acetylcysteine
Continued nebulization of acetylcysteine solution with a dry gas results in increased concentration of drug in nebulizer because of evaporation of solvent; extreme concentration may impede nebulization and efficient delivery of drug; dilution of nebulizing solutions with sterile water for injection, USP as concentration occurs, obviates this problem

More on Glutathione Synthetase Deficiency

Overview: Glutathione Synthetase Deficiency
Differential Diagnoses & Workup: Glutathione Synthetase Deficiency
Treatment & Medication: Glutathione Synthetase Deficiency
Follow-up: Glutathione Synthetase Deficiency
Multimedia: Glutathione Synthetase Deficiency
References
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References

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  2. Manning NJ, Davies NP, Olpin SE, et al. Prenatal diagnosis of glutathione synthase deficiency. Prenat Diagn. Jun 1994;14(6):475-8. [Medline].

  3. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. Aug 2007;7(4):355-9. [Medline].

  4. Boxer LA, Oliver JM, Spielberg SP, et al. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. N Engl J Med. Oct 25 1979;301(17):901-5. [Medline].

  5. Bruggemann LW, Groenendaal F, Ristoff E, et al. Glutathione synthetase deficiency associated with antenatal cerebral bleeding. J Inherit Metab Dis. 2004;27(2):275-6. [Medline].

  6. Divry P, Roulaud-Parrot F, Dorche C, et al. 5-Oxoprolinuria (glutathione synthetase deficiency): a case with neonatal presentation and rapid fatal outcome. J Inherit Metab Dis. 1991;14(3):341-4. [Medline].

  7. Erasmus E, Mienie LJ, de Vries WN, et al. Prenatal analysis in two suspected cases of glutathione synthetase deficiency. J Inherit Metab Dis. 1993;16(5):837-43. [Medline].

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  19. Spielberg SP, Boxer LA, Oliver JM, et al. Oxidative damage to neutrophils in glutathione synthetase deficiency. Br J Haematol. Jun 1979;42(2):215-23. [Medline].

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Further Reading

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Keywords

glutathione synthetase deficiency, GS deficiency, 5-oxoprolinemia, 5-oxoprolinuria, pyroglutamicaciduria, pyroglutamic aciduria, pyroglutamic acidemia, high anion gap metabolic acidosis, severe metabolic acidosis, chronic metabolic acidosis, hemolytic anemia, enzyme deficiency, glutathione, neutropenia, GSS, GSHS, inborn error of glutathione metabolism, ataxia, dysarthria, tremors, psychotic behavior

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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.

Medical Editor

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

Pharmacy Editor

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

Managing Editor

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.

CME Editor

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.

 
 
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