Glutathione Synthetase Deficiency

Mendelian MONDO:0017909 Pathograph 15 Show in embeddings browser Inherited Glutathione Metabolism Disease Inborn Error of Metabolism

Glutathione synthetase deficiency is an autosomal recessive inborn error of the gamma-glutamyl cycle caused by biallelic variants in GSS, which encodes glutathione synthetase (glutathione synthase). The enzyme catalyzes the second, ATP-dependent step of glutathione (GSH) biosynthesis, condensing gamma-glutamylcysteine with glycine. Deficient activity produces a generalized glutathione deficiency that reduces cellular antioxidant defense and shortens erythrocyte survival, causing hemolytic anemia across the clinical spectrum. In the moderate and severe (systemic) forms, the fall in GSH releases gamma-glutamylcysteine synthetase from feedback inhibition; the resulting overproduced gamma-glutamylcysteine is cyclized to 5-oxoproline faster than 5-oxoprolinase can clear it, generating 5-oxoprolinuria and high-anion-gap metabolic acidosis. The most severely affected patients additionally develop progressive central-nervous-system dysfunction (seizures, psychomotor retardation) and recurrent bacterial infections. It is the most frequently recognized of the hereditary gamma-glutamyl-cycle disorders and is conventionally classified into three clinical phenotypes: mild (erythrocyte glutathione synthetase deficiency limited to hemolytic anemia, without 5-oxoprolinuria), moderate, and severe.

Ask OpenScientist

Ask a research question about Glutathione Synthetase Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
4
Pathophys.
6
Phenotypes
15
Pathograph
1
Genes
1
Variants
1
Medical Actions
2
Subtypes
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:9215686 SUPPORT Human Clinical
"The disorder is inherited in an autosomal recessive mode"
Establishes autosomal recessive inheritance for glutathione synthetase deficiency.
◆

Subtypes

2
Glutathione synthetase deficiency with 5-oxoprolinuria (moderate to severe / systemic) MONDO:0009947
The systemic (moderate and severe) form, corresponding to MONDO:0009947 / OMIM:266130. Generalized glutathione synthetase deficiency produces hemolytic anemia together with 5-oxoprolinuria and high-anion-gap metabolic acidosis; the severe end of the spectrum adds progressive neurological dysfunction (seizures, psychomotor retardation) and recurrent bacterial infections.
Glutathione synthetase deficiency without 5-oxoprolinuria (mild) MONDO:0009284
The mild form, corresponding to MONDO:0009284 / OMIM:231900, in which the enzyme deficiency is essentially limited to erythrocytes. Patients present with compensated or mild hemolytic anemia; because glutathione synthetase activity is preserved in other tissues, gamma-glutamylcysteine is not overproduced systemically, so 5-oxoprolinuria and metabolic acidosis are absent.
⚙

Pathophysiology

4
Glutathione synthetase molecular function deficiency
Biallelic GSS variants reduce glutathione synthetase (glutathione synthase) activity, the ATP-dependent enzyme that condenses gamma-glutamylcysteine with glycine in the second and final step of glutathione biosynthesis. Most disease alleles are missense with residual activity; complete loss of both alleles is thought to be lethal.
GSS hgnc:4624 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GSS (hgnc:4624). hgnc:4624 is a gene from the HUGO Gene Nomenclature Committee.
glutathione biosynthetic process GO:0006750 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutathione biosynthetic process (GO:0006750). GO:0006750 is a biological process from the Gene Ontology. ↓ DECREASED
glutathione synthase activity GO:0004363 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glutathione synthase activity (GO:0004363). GO:0004363 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Generalized glutathione deficiency Reduced glutathione synthetase activity lowers cellular glutathione.
Show evidence (2 references)
PMID:9215686 SUPPORT Human Clinical
"enzymatic block of the gamma-glutamyl cycle leads to a generalized glutathione deficiency."
Establishes that the GSS enzymatic block within the gamma-glutamyl cycle causes generalized glutathione deficiency.
PMID:9215686 SUPPORT In Vitro
"Our results suggest that complete loss of function of both GS alleles is probably lethal."
Supports that pathogenic alleles are typically hypomorphic (residual activity) because complete loss is lethal.
Generalized glutathione deficiency
Glutathione is a tripeptide of glutamate, cysteine and glycine that is central to free-radical scavenging and cellular redox homeostasis. Depletion impairs antioxidant defense, which reduces erythrocyte survival and, in the severe form, contributes to central-nervous-system injury and susceptibility to bacterial infection.
canonical
glutathione metabolic process GO:0006749 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated glutathione metabolic process (GO:0006749). GO:0006749 is a biological process from the Gene Ontology. ↕ DYSREGULATED cell redox homeostasis GO:0045454 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell redox homeostasis (GO:0045454). GO:0045454 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Oxidative erythrocyte injury Glutathione depletion reduces erythrocyte antioxidant defense, increasing oxidative stress and hemolysis.
Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation Low glutathione releases gamma-glutamylcysteine synthetase from feedback inhibition; excess gamma-glutamylcysteine is cyclized to 5-oxoproline, overwhelming 5-oxoprolinase in the systemic forms. canonical
Progressive central nervous system dysfunction In the severe form, impaired antioxidant defense contributes to progressive neurological injury.
Recurrent bacterial infections Reduced glutathione-dependent host defense predisposes severely affected patients to recurrent bacterial infections.
Show evidence (1 reference)
PMID:17397529 SUPPORT Other
"Glutathione is a tripeptide composed of glutamate, cysteine and glycine."
Defines glutathione's composition and its role in the affected gamma-glutamyl cycle.
Oxidative erythrocyte injury
Glutathione depletion impairs erythrocyte antioxidant defense. Oxidative stress increases erythrocyte injury and premature destruction, producing the hemolytic anemia seen across the clinical spectrum.
erythrocyte CL:0000232 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythrocyte (CL:0000232). CL:0000232 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED erythrocyte clearance GO:0034102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased erythrocyte clearance (GO:0034102). GO:0034102 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hemolytic anemia Premature destruction of oxidatively vulnerable erythrocytes produces hemolytic anemia.
Show evidence (2 references)
PMID:9215686 SUPPORT Human Clinical
"generalized glutathione deficiency. Clinically affected patients present with severe metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis"
Establishes the sequence from generalized glutathione deficiency to increased hemolysis in affected patients.
PMID:11445798 SUPPORT Human Clinical
"decrease in erythrocyte or fibroblast glutathione"
Supports reduced erythrocyte glutathione as the cellular biochemical context for erythrocyte vulnerability.
Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation
In the systemic (moderate and severe) forms, disinhibited gamma-glutamylcysteine synthesis floods the gamma-glutamyl cycle; gamma-glutamylcysteine is converted to 5-oxoproline (pyroglutamate), producing the diagnostic 5-oxoprolinuria and a high-anion-gap metabolic acidosis.
glutathione metabolic process GO:0006749 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated glutathione metabolic process (GO:0006749). GO:0006749 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Increased urinary L-pyroglutamic acid Accumulated 5-oxoproline is excreted, producing 5-oxoprolinuria (increased urinary L-pyroglutamic acid).
Metabolic acidosis 5-oxoproline accumulation generates a high-anion-gap metabolic acidosis in the systemic forms.
Show evidence (1 reference)
PMID:15717202 SUPPORT Human Clinical
"severe clinical phenotypes including haemolytic anaemia, 5-oxoprolinuria, and (in several forms) neurodevelopmental signs."
Ties 5-oxoprolinuria to the moderate and severe phenotypes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Progressive central nervous system dysfunction' (from 'Generalized glutathione deficiency') not found in named elements
Pathograph: causal mechanism network for Glutathione Synthetase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Blood 1
Hemolytic anemia VERY_FREQUENT HP:0001878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemolytic anemia (HP:0001878). HP:0001878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17397529 SUPPORT Other
"severe form, it is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria"
Review lists hemolytic anemia as a core feature of glutathione synthetase deficiency.
Metabolism 1
Metabolic acidosis FREQUENT HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37050856 SUPPORT Human Clinical
"metabolic acidosis with 5-oxoprolinuria, progressive neurological symptoms, and recurrent bacterial infections"
Case report lists metabolic acidosis with 5-oxoprolinuria in the severe form.
Nervous System 2
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"severely affected with neurologic symptoms such as seizures and psychomotor retardation"
Outcome series reports seizures among severely affected patients.
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"severely affected with neurologic symptoms such as seizures and psychomotor retardation"
Outcome series reports psychomotor retardation in severely affected patients.
Other 2
Increased urinary L-pyroglutamic acid VERY_FREQUENT Increased level of L-pyroglutamic acid in urine HP:0410132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased level of L-pyroglutamic acid in urine (HP:0410132). HP:0410132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9215686 SUPPORT Human Clinical
"severe metabolic acidosis, 5-oxoprolinuria"
5-oxoprolinuria is documented in the systemic form.
Recurrent bacterial infections OCCASIONAL HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"Five patients had recurrent bacterial infections."
Outcome series reports recurrent bacterial infections in five patients.
🧬

Genetic Associations

1
GSS variants
Gene: GSS hgnc:4624 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GSS (hgnc:4624). hgnc:4624 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (2 references)
PMID:15717202 SUPPORT Human Clinical
"nearly 30 different mutations in the GSS gene have been identified."
Summarizes the mutational spectrum of GSS.
PMID:15717202 SUPPORT Human Clinical
"The type of mutation involved can, to some extent, predict a mild versus a more severe phenotype."
Supports a partial genotype-phenotype correlation.
Variants (1)
Biallelic GSS variants (predominantly missense)
Affected individuals are homozygous or compound heterozygous for GSS variants. Missense variants that leave residual activity predominate, whereas frameshift, nonsense and splice variants are associated with the moderate and severe phenotypes.
Show evidence (2 references)
PMID:15717202 SUPPORT Human Clinical
"premature stop codons or aberrant splicing were associated with moderate or severe clinical phenotypes"
Genotype-phenotype study links loss-of-function variant classes to more severe disease.
PMID:9215686 SUPPORT In Vitro
"Reduced enzymatic activities were demonstrated in recombinant protein expressed from cDNAs in four cases with different missense mutations."
Functional expression confirms reduced activity for disease missense variants.
💊

Medical Actions

1
Correction of acidosis and antioxidant vitamin supplementation
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Agent: L-ascorbic acid CHEBI:29073 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-ascorbic acid (CHEBI:29073). CHEBI:29073 is a therapeutic agent from Chemical Entities of Biological Interest. vitamin E CHEBI:33234 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vitamin E (CHEBI:33234). CHEBI:33234 is a therapeutic agent from Chemical Entities of Biological Interest.
Management aims to avoid hemolytic crises and to increase defense against reactive oxygen species. Treatment usually includes correction of the metabolic acidosis and supplementation with vitamins C and E; early supplementation with both vitamins from the neonatal period may improve long-term outcome. Blood transfusion is used for acute hemolytic anemia.
Target Phenotypes: Hemolytic anemia HP:0001878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hemolytic anemia (HP:0001878). HP:0001878 is a phenotype from the Human Phenotype Ontology. Metabolic acidosis HP:0001942 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11445798 SUPPORT Human Clinical
"correction of acidosis and supplementation with vitamins C and/or E."
Describes the standard management of correcting acidosis and antioxidant vitamin supplementation.
PMID:11445798 SUPPORT Human Clinical
"early supplementation with vitamins C and E may improve the long-term clinical outcome."
Supports early antioxidant vitamin supplementation as outcome-improving.
🔬

Biochemical Markers

3
Reduced erythrocyte glutathione (DECREASED)
Context: Erythrocyte (and fibroblast) glutathione is reduced, reflecting the block in glutathione biosynthesis; it is a supportive diagnostic finding.
Pathograph Readouts
Readout Of Generalized glutathione deficiency Negative Diagnostic
Reduced erythrocyte glutathione directly reports the generalized glutathione deficiency.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"decrease in erythrocyte or fibroblast glutathione"
Diagnostic workup demonstrates decreased erythrocyte or fibroblast glutathione.
Reduced glutathione synthetase activity (DECREASED)
Context: A marked decrease in glutathione synthetase activity in erythrocytes or cultured fibroblasts is the primary enzymatic diagnostic criterion.
Pathograph Readouts
Readout Of Glutathione synthetase molecular function deficiency Negative Diagnostic
Reduced measured enzyme activity is the direct functional readout of the GSS molecular defect.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"a marked decrease in GS activity in erythrocytes or cultured fibroblasts in all patients"
Enzyme-activity assay is the primary diagnostic demonstration of deficiency.
Increased urinary 5-oxoproline (INCREASED)
Context: Urinary 5-oxoproline (L-pyroglutamic acid) is markedly increased in the systemic forms and, with the enzyme assay, establishes the diagnosis.
Pathograph Readouts
Readout Of Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation Positive Diagnostic
Urinary 5-oxoproline reports the systemic overproduction and accumulation of 5-oxoproline.
Show evidence (1 reference)
PMID:11445798 SUPPORT Human Clinical
"presence of 5-oxoprolinuria"
5-oxoprolinuria is a supportive diagnostic biochemical finding.
📈

Progression

1
Three clinical severity forms (mild, moderate, severe)
On the basis of clinical symptoms, glutathione synthetase deficiency is classified into three phenotypes. The mild form is limited to hemolytic anemia; the moderate form adds 5-oxoprolinuria and metabolic acidosis; and the severe form additionally shows progressive neurological involvement and recurrent bacterial infections. Neonatal onset is typical for the systemic forms.
Show evidence (2 references)
PMID:11445798 SUPPORT Human Clinical
"patients with GS deficiency can be classified into 3 phenotypes: mild, moderate, and severe."
Long-term outcome series defines the three-phenotype clinical classification.
PMID:9215686 SUPPORT Human Clinical
"rare genetic disorder with neonatal onset."
Supports neonatal onset of the severe systemic form.
📊

Prevalence

1
Worldwide
Point Prevalence 0.1 per 100,000 <1 in 1,000,000
Reported as an ultra-rare disorder occurring in approximately 1 in 1,000,000 individuals; only case reports and small series are available rather than population-based incidence data.
Show evidence (1 reference)
PMID:37050856 SUPPORT Human Clinical
"occur in 1 in 1 million individuals"
Case report states an approximate occurrence of 1 in 1,000,000 individuals.
{ }

Source YAML

click to show 
name: Glutathione Synthetase Deficiency
category: Mendelian
creation_date: '2026-07-07T00:00:00Z'
synonyms:
- GSS deficiency
- Glutathione synthase deficiency
- 5-oxoprolinuria due to glutathione synthetase deficiency
- Pyroglutamic aciduria due to glutathione synthetase deficiency
description: >
  Glutathione synthetase deficiency is an autosomal recessive inborn error of
  the gamma-glutamyl cycle caused by biallelic variants in GSS, which encodes
  glutathione synthetase (glutathione synthase). The enzyme catalyzes the second,
  ATP-dependent step of glutathione (GSH) biosynthesis, condensing
  gamma-glutamylcysteine with glycine. Deficient activity produces a generalized
  glutathione deficiency that reduces cellular antioxidant defense and shortens
  erythrocyte survival, causing hemolytic anemia across the clinical spectrum. In
  the moderate and severe (systemic) forms, the fall in GSH releases
  gamma-glutamylcysteine synthetase from feedback inhibition; the resulting
  overproduced gamma-glutamylcysteine is cyclized to 5-oxoproline faster than
  5-oxoprolinase can clear it, generating 5-oxoprolinuria and high-anion-gap
  metabolic acidosis. The most severely affected patients additionally develop
  progressive central-nervous-system dysfunction (seizures, psychomotor
  retardation) and recurrent bacterial infections. It is the most frequently
  recognized of the hereditary gamma-glutamyl-cycle disorders and is
  conventionally classified into three clinical phenotypes: mild (erythrocyte
  glutathione synthetase deficiency limited to hemolytic anemia, without
  5-oxoprolinuria), moderate, and severe.
disease_term:
  preferred_term: inherited glutathione synthetase deficiency
  term:
    id: MONDO:0017909
    label: inherited glutathione synthetase deficiency
parents:
- Inherited Glutathione Metabolism Disease
- Inborn Error of Metabolism
has_subtypes:
- name: With 5-Oxoprolinuria
  display_name: Glutathione synthetase deficiency with 5-oxoprolinuria (moderate to severe / systemic)
  subtype_term:
    preferred_term: glutathione synthetase deficiency with 5-oxoprolinuria
    term:
      id: MONDO:0009947
      label: glutathione synthetase deficiency with 5-oxoprolinuria
  description: >
    The systemic (moderate and severe) form, corresponding to
    MONDO:0009947 / OMIM:266130. Generalized glutathione synthetase deficiency
    produces hemolytic anemia together with 5-oxoprolinuria and high-anion-gap
    metabolic acidosis; the severe end of the spectrum adds progressive
    neurological dysfunction (seizures, psychomotor retardation) and recurrent
    bacterial infections.
- name: Without 5-Oxoprolinuria
  display_name: Glutathione synthetase deficiency without 5-oxoprolinuria (mild)
  subtype_term:
    preferred_term: glutathione synthetase deficiency without 5-oxoprolinuria
    term:
      id: MONDO:0009284
      label: glutathione synthetase deficiency without 5-oxoprolinuria
  description: >
    The mild form, corresponding to MONDO:0009284 / OMIM:231900, in which the
    enzyme deficiency is essentially limited to erythrocytes. Patients present
    with compensated or mild hemolytic anemia; because glutathione synthetase
    activity is preserved in other tissues, gamma-glutamylcysteine is not
    overproduced systemically, so 5-oxoprolinuria and metabolic acidosis are
    absent.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.1
  notes: >
    Reported as an ultra-rare disorder occurring in approximately 1 in 1,000,000
    individuals; only case reports and small series are available rather than
    population-based incidence data.
  evidence:
  - reference: PMID:37050856
    reference_title: "Severe Hemolytic Anemia and Metabolic Acidosis at Birth with Glutathione Synthetase Deficiency and Progressive Neurological Symptoms on Follow-Up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occur in 1 in \n1 million individuals"
    explanation: Case report states an approximate occurrence of 1 in 1,000,000 individuals.
progression:
- phase: Three clinical severity forms (mild, moderate, severe)
  notes: >
    On the basis of clinical symptoms, glutathione synthetase deficiency is
    classified into three phenotypes. The mild form is limited to hemolytic
    anemia; the moderate form adds 5-oxoprolinuria and metabolic acidosis; and
    the severe form additionally shows progressive neurological involvement and
    recurrent bacterial infections. Neonatal onset is typical for the systemic
    forms.
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with GS deficiency can \nbe classified into 3 phenotypes: mild, moderate, and severe."
    explanation: Long-term outcome series defines the three-phenotype clinical classification.
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rare genetic disorder with \nneonatal onset."
    explanation: Supports neonatal onset of the severe systemic form.
pathophysiology:
- name: Glutathione synthetase molecular function deficiency
  description: >
    Biallelic GSS variants reduce glutathione synthetase (glutathione synthase)
    activity, the ATP-dependent enzyme that condenses gamma-glutamylcysteine with
    glycine in the second and final step of glutathione biosynthesis. Most
    disease alleles are missense with residual activity; complete loss of both
    alleles is thought to be lethal.
  genes:
  - preferred_term: GSS
    term:
      id: hgnc:4624
      label: GSS
  molecular_functions:
  - preferred_term: glutathione synthase activity
    term:
      id: GO:0004363
      label: glutathione synthase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: glutathione biosynthetic process
    term:
      id: GO:0006750
      label: glutathione biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-gamma-glutamyl-L-cysteine
    term:
      id: CHEBI:17515
      label: L-gamma-glutamyl-L-cysteine
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  evidence:
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enzymatic block of the gamma-glutamyl cycle leads to a \ngeneralized glutathione deficiency."
    explanation: Establishes that the GSS enzymatic block within the gamma-glutamyl cycle causes generalized glutathione deficiency.
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results suggest that complete loss of \nfunction of both GS alleles is probably lethal."
    explanation: Supports that pathogenic alleles are typically hypomorphic (residual activity) because complete loss is lethal.
  downstream:
  - target: Generalized glutathione deficiency
    causal_link_type: DIRECT
    description: Reduced glutathione synthetase activity lowers cellular glutathione.
    evidence:
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "enzymatic block of the gamma-glutamyl cycle leads to a \ngeneralized glutathione deficiency."
      explanation: Directly links the enzyme block to generalized glutathione deficiency.
- name: Generalized glutathione deficiency
  description: >
    Glutathione is a tripeptide of glutamate, cysteine and glycine that is
    central to free-radical scavenging and cellular redox homeostasis. Depletion
    impairs antioxidant defense, which reduces erythrocyte survival and, in the
    severe form, contributes to central-nervous-system injury and susceptibility
    to bacterial infection.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  - preferred_term: cell redox homeostasis
    term:
      id: GO:0045454
      label: cell redox homeostasis
    modifier: DECREASED
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Glutathione is a tripeptide composed of glutamate, cysteine and glycine."
    explanation: Defines glutathione's composition and its role in the affected gamma-glutamyl cycle.
  downstream:
  - target: Oxidative erythrocyte injury
    causal_link_type: DIRECT
    description: Glutathione depletion reduces erythrocyte antioxidant defense, increasing oxidative stress and hemolysis.
    evidence:
    - reference: PMID:17397529
      reference_title: "Inborn errors in the metabolism of glutathione."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "free\nradical scavenging, detoxification of xenobiotics and carcinogens, redox\nreactions"
      explanation: Review identifies glutathione as central to free-radical scavenging and redox reactions.
  - target: Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation
    causal_link_type: DIRECT
    description: >
      Low glutathione releases gamma-glutamylcysteine synthetase from feedback
      inhibition; excess gamma-glutamylcysteine is cyclized to 5-oxoproline,
      overwhelming 5-oxoprolinase in the systemic forms.
    hypothesis_groups:
    - canonical
    evidence:
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Clinically affected patients present with \nsevere metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis and \ndefective function of the central nervous system."
      explanation: Documents 5-oxoprolinuria and metabolic acidosis as consequences of the systemic enzyme block.
  - target: Progressive central nervous system dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: In the severe form, impaired antioxidant defense contributes to progressive neurological injury.
    evidence:
    - reference: PMID:17397529
      reference_title: "Inborn errors in the metabolism of glutathione."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "central nervous system (CNS) damage and recurrent bacterial infections."
      explanation: Review associates the severe form with CNS damage; specific molecular intermediates are unresolved.
  - target: Recurrent bacterial infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced glutathione-dependent host defense predisposes severely affected patients to recurrent bacterial infections.
    evidence:
    - reference: PMID:11445798
      reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Five patients had recurrent bacterial infections."
      explanation: Outcome series reports recurrent bacterial infections in a subset of patients.
- name: Oxidative erythrocyte injury
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >
    Glutathione depletion impairs erythrocyte antioxidant defense. Oxidative
    stress increases erythrocyte injury and premature destruction, producing the
    hemolytic anemia seen across the clinical spectrum.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  evidence:
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "generalized glutathione deficiency. Clinically affected patients present with \nsevere metabolic acidosis, 5-oxoprolinuria, increased rate of hemolysis"
    explanation: Establishes the sequence from generalized glutathione deficiency to increased hemolysis in affected patients.
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "decrease in erythrocyte or fibroblast glutathione"
    explanation: Supports reduced erythrocyte glutathione as the cellular biochemical context for erythrocyte vulnerability.
  downstream:
  - target: Hemolytic anemia
    causal_link_type: DIRECT
    description: Premature destruction of oxidatively vulnerable erythrocytes produces hemolytic anemia.
    evidence:
    - reference: PMID:17397529
      reference_title: "Inborn errors in the metabolism of glutathione."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "severe form,\nit is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria"
      explanation: Review lists hemolytic anemia as a core manifestation of glutathione synthetase deficiency.
- name: Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation
  description: >
    In the systemic (moderate and severe) forms, disinhibited gamma-glutamylcysteine
    synthesis floods the gamma-glutamyl cycle; gamma-glutamylcysteine is converted
    to 5-oxoproline (pyroglutamate), producing the diagnostic 5-oxoprolinuria and a
    high-anion-gap metabolic acidosis.
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: L-gamma-glutamyl-L-cysteine
    term:
      id: CHEBI:17515
      label: L-gamma-glutamyl-L-cysteine
    modifier: INCREASED
  - preferred_term: 5-oxo-L-proline
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
    modifier: INCREASED
  evidence:
  - reference: PMID:15717202
    reference_title: "Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe clinical phenotypes including haemolytic anaemia, 5-oxoprolinuria, and \n(in several forms) neurodevelopmental signs."
    explanation: Ties 5-oxoprolinuria to the moderate and severe phenotypes.
  downstream:
  - target: Increased urinary L-pyroglutamic acid
    causal_link_type: DIRECT
    description: Accumulated 5-oxoproline is excreted, producing 5-oxoprolinuria (increased urinary L-pyroglutamic acid).
    evidence:
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "severe metabolic acidosis, 5-oxoprolinuria"
      explanation: Documents 5-oxoprolinuria as a direct biochemical consequence.
  - target: Metabolic acidosis
    causal_link_type: DIRECT
    description: 5-oxoproline accumulation generates a high-anion-gap metabolic acidosis in the systemic forms.
    evidence:
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "severe metabolic acidosis, 5-oxoprolinuria"
      explanation: Documents metabolic acidosis co-occurring with 5-oxoprolinuria.
phenotypes:
- name: Hemolytic anemia
  frequency: VERY_FREQUENT
  description: >
    Hemolytic anemia occurs across the clinical spectrum and is the sole
    manifestation in the mild form; it results from reduced glutathione-dependent
    erythrocyte antioxidant defense.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "severe form,\nit is associated with hemolytic anemia, metabolic acidosis, 5-oxoprolinuria"
    explanation: Review lists hemolytic anemia as a core feature of glutathione synthetase deficiency.
- name: Increased urinary L-pyroglutamic acid
  subtype: With 5-Oxoprolinuria
  frequency: VERY_FREQUENT
  description: 5-oxoprolinuria (increased urinary L-pyroglutamic acid) is the diagnostic organic-acid finding of the systemic forms.
  phenotype_term:
    preferred_term: Increased level of L-pyroglutamic acid in urine
    term:
      id: HP:0410132
      label: Increased level of L-pyroglutamic acid in urine
  evidence:
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe metabolic acidosis, 5-oxoprolinuria"
    explanation: 5-oxoprolinuria is documented in the systemic form.
- name: Metabolic acidosis
  subtype: With 5-Oxoprolinuria
  frequency: FREQUENT
  description: High-anion-gap metabolic acidosis accompanies 5-oxoprolinuria in the moderate and severe forms.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:37050856
    reference_title: "Severe Hemolytic Anemia and Metabolic Acidosis at Birth with Glutathione Synthetase Deficiency and Progressive Neurological Symptoms on Follow-Up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "metabolic acidosis with 5-oxoprolinuria, progressive neurological \nsymptoms, and recurrent bacterial infections"
    explanation: Case report lists metabolic acidosis with 5-oxoprolinuria in the severe form.
- name: Seizure
  subtype: With 5-Oxoprolinuria
  frequency: FREQUENT
  description: Seizures are part of the progressive neurological involvement of severely affected patients.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severely affected with neurologic symptoms such \nas seizures and psychomotor retardation"
    explanation: Outcome series reports seizures among severely affected patients.
- name: Global developmental delay
  subtype: With 5-Oxoprolinuria
  frequency: FREQUENT
  description: Psychomotor retardation and neurodevelopmental delay characterize the severe form.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severely affected with neurologic symptoms such \nas seizures and psychomotor retardation"
    explanation: Outcome series reports psychomotor retardation in severely affected patients.
- name: Recurrent bacterial infections
  subtype: With 5-Oxoprolinuria
  frequency: OCCASIONAL
  description: A subset of severely affected patients experience recurrent bacterial infections attributed to impaired glutathione-dependent host defense.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five patients had recurrent bacterial infections."
    explanation: Outcome series reports recurrent bacterial infections in five patients.
biochemical:
- name: Reduced erythrocyte glutathione
  presence: DECREASED
  context: >
    Erythrocyte (and fibroblast) glutathione is reduced, reflecting the block in
    glutathione biosynthesis; it is a supportive diagnostic finding.
  biomarker_term:
    preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  readouts:
  - target: Generalized glutathione deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced erythrocyte glutathione directly reports the generalized glutathione deficiency.
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "decrease in erythrocyte or fibroblast glutathione"
    explanation: Diagnostic workup demonstrates decreased erythrocyte or fibroblast glutathione.
- name: Reduced glutathione synthetase activity
  presence: DECREASED
  context: >
    A marked decrease in glutathione synthetase activity in erythrocytes or
    cultured fibroblasts is the primary enzymatic diagnostic criterion.
  readouts:
  - target: Glutathione synthetase molecular function deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced measured enzyme activity is the direct functional readout of the GSS molecular defect.
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a marked decrease in GS \nactivity in erythrocytes or cultured fibroblasts in all patients"
    explanation: Enzyme-activity assay is the primary diagnostic demonstration of deficiency.
- name: Increased urinary 5-oxoproline
  presence: INCREASED
  context: >
    Urinary 5-oxoproline (L-pyroglutamic acid) is markedly increased in the
    systemic forms and, with the enzyme assay, establishes the diagnosis.
  biomarker_term:
    preferred_term: 5-oxo-L-proline
    term:
      id: CHEBI:18183
      label: 5-oxo-L-proline
  readouts:
  - target: Gamma-glutamylcysteine overproduction and 5-oxoproline accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Urinary 5-oxoproline reports the systemic overproduction and accumulation of 5-oxoproline.
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presence of 5-oxoprolinuria"
    explanation: 5-oxoprolinuria is a supportive diagnostic biochemical finding.
treatments:
- name: Correction of acidosis and antioxidant vitamin supplementation
  description: >
    Management aims to avoid hemolytic crises and to increase defense against
    reactive oxygen species. Treatment usually includes correction of the
    metabolic acidosis and supplementation with vitamins C and E; early
    supplementation with both vitamins from the neonatal period may improve
    long-term outcome. Blood transfusion is used for acute hemolytic anemia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: L-ascorbic acid
      term:
        id: CHEBI:29073
        label: L-ascorbic acid
    - preferred_term: vitamin E
      term:
        id: CHEBI:33234
        label: vitamin E
  target_phenotypes:
  - preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  - preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "correction of acidosis and supplementation with vitamins C and/or E."
    explanation: Describes the standard management of correcting acidosis and antioxidant vitamin supplementation.
  - reference: PMID:11445798
    reference_title: "Long-term clinical outcome in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early supplementation with vitamins C and E may improve the \nlong-term clinical outcome."
    explanation: Supports early antioxidant vitamin supplementation as outcome-improving.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9215686
    reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder is inherited in \nan autosomal recessive mode"
    explanation: Establishes autosomal recessive inheritance for glutathione synthetase deficiency.
genetic:
- name: GSS variants
  gene_term:
    preferred_term: GSS
    term:
      id: hgnc:4624
      label: GSS
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disorder is inherited in \nan autosomal recessive mode"
      explanation: Establishes autosomal recessive inheritance.
  variants:
  - name: Biallelic GSS variants (predominantly missense)
    description: >
      Affected individuals are homozygous or compound heterozygous for GSS
      variants. Missense variants that leave residual activity predominate,
      whereas frameshift, nonsense and splice variants are associated with the
      moderate and severe phenotypes.
    evidence:
    - reference: PMID:15717202
      reference_title: "Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "premature stop codons or aberrant splicing were associated with moderate or \nsevere clinical phenotypes"
      explanation: Genotype-phenotype study links loss-of-function variant classes to more severe disease.
    - reference: PMID:9215686
      reference_title: "Missense mutations in the human glutathione synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and neurological dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Reduced enzymatic activities were demonstrated in recombinant \nprotein expressed from cDNAs in four cases with different missense mutations."
      explanation: Functional expression confirms reduced activity for disease missense variants.
  features: >
    Nearly 30 different GSS mutations have been reported. The type of variant
    partly predicts phenotype, with hypomorphic missense alleles trending milder
    and loss-of-function classes trending toward the moderate and severe forms.
  evidence:
  - reference: PMID:15717202
    reference_title: "Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nearly 30 different mutations in the \nGSS gene have been identified."
    explanation: Summarizes the mutational spectrum of GSS.
  - reference: PMID:15717202
    reference_title: "Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The type of mutation involved can, to some \nextent, predict a mild versus a more severe phenotype."
    explanation: Supports a partial genotype-phenotype correlation.
notes: >-
  Glutathione synthetase deficiency is the most frequently recognized hereditary
  gamma-glutamyl-cycle disorder. The 5-oxoprolinuria of the systemic forms is
  shared with 5-oxoprolinase (OPLAH) deficiency; the two are distinguished by the
  deficient enzyme and by the accompanying hemolytic anemia and generalized
  glutathione deficiency in glutathione synthetase deficiency. The modeled
  oxidative erythrocyte injury node conforms to the
  hemolytic_anemia_erythrocyte_destruction mechanism module. MONDO splits the disorder into
  glutathione synthetase deficiency with 5-oxoprolinuria (MONDO:0009947 /
  OMIM:266130) and without 5-oxoprolinuria (MONDO:0009284 / OMIM:231900); the
  top-level entry anchors the umbrella term MONDO:0017909.