Glutathione Synthetase Deficiency 

Updated: May 18, 2017
Author: Reem Saadeh-Haddad, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Glutathione synthetase (GS) deficiency, first described in 1970, is a rare autosomal-recessive inborn error of glutathione metabolism characterized by severe metabolic acidosis, hemolytic anemia, and neurological problems.[1] 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. See the image below.

Biochemical pathway of glutathione synthetase. 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.[2] 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.

Epidemiology

Frequency

United States

The frequency of glutathione synthetase deficiency is unknown.

International

Glutathione synthetase deficiency is very rare. Worldwide, only approximately 40-50 cases in which the patient survived the newborn period have been published. The overall frequency is unknown. It is believed that some cases of glutathione synthetase deficiency may go undiagnosed or misdiagnosed, complicating a determination of its true frequency.

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 of glutathione synthetase deficiency 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 in glutathione synthetase deficiency.

Sex

No sex predilection is known in glutathione synthetase deficiency.

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.

 

Presentation

History

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. Individuals with hemolytic anemia can present with fatigue, pallor, irregular heartbeats, lightheadedness, and shortness of breath.

Hemolytic anemia is found in all forms.

Physical

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
  • Intellectual disabilities
  • Psychomotor 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 other than possible pallor, orthostatic hypotension, and/or irregular heartbeats associated with hemolytic anemia.

Splenomegaly may be present in some individuals with glutathione synthetase deficiency, even the mild form.

Causes

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. Two mutations are required for the condition to exist, one on each copy of the gene. Parents of an affected child are obligate carriers of glutathione synthetase deficiency. The likelihood that they will have another child with the condition is 25%.

The GSS gene is located at 20q11.2.

 

DDx

 

Workup

Laboratory Studies

Electrolyte and blood gas determinations indicate high anion gap metabolic acidosis. The CBC count demonstrates hemolytic anemia. Diagnosis of glutathione synthetase (GS) deficiency is confirmed by the presence of a large peak of 5-oxoproline in the urine. Concentrations of this metabolite are also increased in the cerebrospinal fluid (CSF) and blood. Diagnosis can be confirmed through enzyme analysis of glutathione synthetase (which is found to be deficient) in cultured skin fibroblasts. Upon routine testing, in addition to a hemolytic anemia, episodic neutropenia may occur.

Enzyme assay will show decreased activity of the enzyme glutathione synthetase in erythrocytes or cultured fibroblasts. Moderate and severe forms cannot be differentiated based on enzyme activity, which suggests that other factors are involved in the final phenotypic presentation.

Urine organic acids will show increased 5-oxoproline levels.

Molecular sequencing of the GSS gene can be performed to assist in confirming the diagnosis and for providing accurate recurrence risks to family members.

 

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.[3] 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 is indicated.

 

Medication

Medication Summary

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

Class Summary

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.

Vitamins and antioxidants

Class Summary

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.

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

An antioxidant; one of the fat-soluble vitamins.

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.

Amino acids

Class Summary

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.

 

Follow-up

Further Outpatient Care

Glutathione synthetase (GS) deficiency is a chronic life-threatening disorder. Regular follow-up with a metabolic diseases specialist is indicated. All patients should be encouraged to wear a medical alert bracelet or necklace.

Transfer

Transfer to a center where metabolic diseases specialists are available may be indicated.

Deterrence/Prevention

Because accumulation of 5-oxoproline occurs in all body fluids, especially the urine, of affected individuals, the possibility of prenatal diagnosis with amniotic fluid was realized; most of this fluid is from fetal urine after the first trimester. Measurement of reduced glutathione synthetase activity can also be measured in fetal cells in the amniotic fluid.

In 1994, two pregnancies of two at-risk couples were studied at 16 weeks' gestation.[4] In both cases, the levels of 5-oxoproline were 25-30 times reference range values. Both pregnancies were terminated, and the diagnosis was confirmed in one case by cultured fetal fibroblast enzyme analysis.

Today, prenatal counseling and testing is recommended for any family with a history of glutathione synthetase deficiency. In cases in which the two pathogenic mutations have already been identified in the affected individual, the at-risk pregnancy can then be tested via genetic mutation analysis. Preimplantation genetic diagnosis is also an option for these families. Carrier testing can also be offered to at-risk individuals so that risks to children can be determined.

Prognosis

In the systemic form, chronic metabolic acidosis must be treated, but long-term prognosis is guarded. The lack of glutathione in erythrocytes alone is apparently tolerable, as has been noted with the peripheral form of this condition; however, in severe glutathione synthetase, a progressive loss of function occurs, leading to severe mental retardation, ataxia, and seizure disorders.

The oldest reported survivor of severe glutathione synthetase was aged 24 years and had experienced significant neurological deterioration over the previous few years. Older children with mild and moderate forms who are doing well have been reported.