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Inheritance

1

Autosomal recessive HP:0000007

Hereditary glutathione reductase deficiency is inherited in an autosomal recessive manner. In the originally described family the affected children of a consanguineous marriage had virtually absent erythrocyte GR activity while both parents had intermediate (heterozygous-range) values.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"A virtually complete absence of glutathione reductase activity was found in the erythrocytes of all three children (one male, two females) from a consanguineous marriage. Intermediate values were found in the erythrocytes of both parents."

The affected sibship from a consanguineous union with heterozygous-range parental values establishes autosomal recessive inheritance.

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Pathophysiology

7

GSR Loss-of-Function and Absent Glutathione Reductase Activity

Biallelic GSR variants abolish glutathione-disulfide reductase activity. GR is the NADPH- and FAD-dependent flavoenzyme that reduces oxidized glutathione disulfide (GSSG) back to reduced glutathione (GSH). In affected erythrocytes and leukocytes the enzyme protein is unstable or undetectable and GR activity is essentially absent and cannot be restored by FAD in vitro or by riboflavin in vivo, distinguishing the genetic defect from acquired FAD-undersaturation.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

glutathione-disulfide reductase (NADPH) activity GO:0004362 ↓ DECREASED

Animal models

Gr1a1Neu mouse (chemically induced GR mutant) Mouse recapitulates

Downstream

Failure to Regenerate Reduced Glutathione Absent GR activity leaves the cell unable to convert GSSG back to GSH following an oxidant load.

Lens Oxidative Injury GR deficiency extends to the lens, where loss of glutathione-dependent antioxidant protection is associated with cataract.

Phagocyte Glutathione-Dependent Defense Impairment GR is also deficient in leukocytes, impairing glutathione-dependent phagocyte defense.

Thioredoxin System Compensation Loss of GR is followed by increased thioredoxin and thioredoxin reductase activity in Gsr-knockout mouse tissue, an alternative route for GSSG reduction.

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"The enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo."

The non-restorable loss of activity marks a structural apoenzyme defect rather than reversible FAD undersaturation.

Thioredoxin System Compensation

The thioredoxin/thioredoxin reductase system can reduce GSSG to GSH and acts as a functional backup for GR. In Gsr-knockout mice, inner-ear thioredoxin and thioredoxin reductase activities rose and no oxidative damage or hearing deficit developed. This compensation is a candidate explanation for why hemolysis in the human disorder has been reported after oxidant triggers, but it has not been measured in GR-deficient patients, and any dampening effect on hemolysis is hypothesized rather than shown.

thioredoxin-disulfide reductase (NADPH) activity GO:0004791 ↑ INCREASED

Show evidence (2 references)

PMID:28686716 SUPPORT Model Organism

"Gsr deficiency resulted in increased activities of cytosolic thioredoxin and thioredoxin reductase in the inner ears."

Gsr-knockout mice upregulate the thioredoxin system, the proposed compensating route for GSSG reduction.

PMID:28686716 SUPPORT Model Organism

"the thioredoxin system can support GSSG reduction in the mouse peripheral auditory system"

The authors conclude the thioredoxin system can substitute for GR in GSSG reduction in this tissue.

Failure to Regenerate Reduced Glutathione

Without GR, erythrocytes cannot reduce GSSG back to GSH after an oxidant challenge, so the reduced-glutathione pool collapses under oxidative stress. Baseline GSH may appear near-normal because little is consumed at rest, but glutathione stability during an oxidant challenge is severely diminished.

glutathione metabolic process GO:0006749 ↕ DYSREGULATED

Downstream

Erythrocyte Oxidative and Membrane Injury The loss of regenerable GSH leaves hemoglobin and membrane proteins undefended against reactive oxygen species.

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"Severely diminished glutathione stability during incubation with acetylphenylhydrazine was observed in the erythrocytes of the siblings"

An oxidant challenge in vitro shows the GSH pool cannot be sustained, the direct consequence of absent GR activity.

Erythrocyte Oxidative and Membrane Injury

With the GSH antioxidant buffer depleted, oxidant exposure denatures hemoglobin and damages the erythrocyte membrane, reducing cell integrity and marking the cell for removal. The reserve capacity of GR in normal red cells is large, so impaired GSH recovery under oxidant stress emerges only when enzyme activity is almost completely lost.

erythrocyte CL:0000232

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Oxidant-Triggered Hemolysis Oxidatively injured, poorly deformable erythrocytes are hemolyzed, especially after an oxidant trigger such as fava bean ingestion.

Show evidence (1 reference)

PMID:3572207 SUPPORT In Vitro

"In red cells stressed by these reagents, GSSG-R deficiency began to impair the regeneration of GSH only after greater than 80% of the normal enzyme activity had been abolished."

Establishes that only near-complete GR loss impairs GSH recovery under oxidant stress, the step that leaves red cells vulnerable to injury.

Oxidant-Triggered Hemolysis

Oxidatively damaged erythrocytes are destroyed prematurely, producing hemolytic anemia. In the index family, hemolytic crises followed fava bean ingestion, mirroring the oxidant-triggered hemolysis of G6PD deficiency.

erythrocyte CL:0000232 macrophage CL:0000235

erythrocyte clearance GO:0034102 ↑ INCREASED

Downstream

Hemolytic anemia Premature destruction of oxidatively vulnerable erythrocytes produces hemolytic anemia.

Fava bean-induced hemolytic anemia Fava bean ingestion is the documented oxidant trigger of acute hemolysis in this disorder.

Neonatal hyperbilirubinemia Severe neonatal jaundice was the presenting feature of a GR-deficient patient; that it results from hemolysis in the newborn period is inferred from the enzyme defect, since the report states only the jaundice.

Show evidence (2 references)

PMID:8813716 SUPPORT INDIRECT Other

"If an enzyme deficiency of one of these metabolic pathways limits the ATP and/or NADPH production, distinct membrane alterations result causing a removal of the damaged cells by the monocyte-macrophage system."

Review of red-cell enzymopathies states the general route from a redox enzyme defect to membrane damage and macrophage removal of erythrocytes; applied here to the glutathione cycle defect.

PMID:947404 SUPPORT Human Clinical

"this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"

Documents fava-bean-triggered hemolytic crises as the clinical manifestation of the enzyme defect.

Lens Oxidative Injury

Loss of glutathione-dependent antioxidant defense in the lens is the proposed route to cataract. The lens relies heavily on glutathione to protect against oxidative damage. In the originally described family, cataract in two siblings was attributed to the deficiency only tentatively ("possibly"), and no age at onset was reported.

lens fiber cell CL:0011004

response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Cataract Oxidative injury to lens fiber cells manifests as cataract.

Show evidence (2 references)

PMID:947404 SUPPORT Human Clinical

"possibly by cataracts in her own and in her brother's eyes"

Reports cataract in affected family members, linked to the loss of glutathione-dependent antioxidant protection of the lens.

PMID:1737065 SUPPORT INDIRECT In Vitro

"The findings indicated an impairment in peroxide metabolism of the mature cataractous lenses compared to normal lenses to be resulted from a deficiency of GSH."

Ex vivo lens study links GSH deficiency to impaired peroxide handling in cataractous lenses. It concerns cataract generally, not GR-deficient patients, so the lens step in this disorder remains inferred.

Phagocyte Glutathione-Dependent Defense Impairment

Because GR is also deficient in leukocytes, glutathione-dependent antioxidant and bactericidal function of phagocytes is impaired. In the propositus, polymorphonuclear cells showed abnormal oxygen consumption after phagocytosis, suggesting a role for the GR reaction in the bactericidal capacity of these cells. This is an observation in a single family and the clinical significance of the leukocyte defect is not established.

neutrophil CL:0000775

response to oxidative stress GO:0006979 ↕ DYSREGULATED

Animal models

Gsr-null mouse (neutrophil host defense) Mouse recapitulates

Downstream

Abnormal neutrophil physiology Impaired glutathione-dependent defense is reflected in abnormal phagocyte oxidative physiology.

Show evidence (2 references)

PMID:947404 SUPPORT Human Clinical

"we found an abnormal oxygen consumption of the propositus' PMNs after phagocytosis of zymosan particles, suggesting that the glutathione reductase reaction was involved in the bactericidal capacity of these cells"

Documents the leukocyte GR defect and its possible effect on phagocyte bactericidal function.

PMID:22279102 SUPPORT Model Organism

"Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation."

In Gsr-null mice, neutrophils cannot sustain the oxidative burst, the model counterpart of the abnormal oxygen consumption seen in the propositus' neutrophils.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Blood 3

Hemolytic anemia HP:0001878

Show evidence (2 references)

ORPHA:90030 SUPPORT Other

"A rare hemolytic anemia due to hexose monophosphate shunt and glutathione metabolism anomalies characterized by nearly complete absence of glutathione reductase activity in erythrocytes."

Orphanet defines the disorder as a hemolytic anemia caused by near-absent erythrocyte glutathione reductase activity.

PMID:17185460 SUPPORT Human Clinical

"a previously described family suffering from favism and cataract"

Confirms the favism (hemolytic) and cataract phenotype of the molecularly characterized family.

Fava bean-induced hemolytic anemia HP:0004814

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"

Documents fava-bean-induced hemolytic crises in an affected individual.

Abnormal neutrophil physiology HP:0011990

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"we found an abnormal oxygen consumption of the propositus' PMNs after phagocytosis of zymosan particles"

Documents abnormal neutrophil respiratory physiology attributable to the leukocyte GR defect.

Eye 1

Cataract HP:0000518

Show evidence (2 references)

PMID:17185460 SUPPORT Human Clinical

"a previously described family suffering from favism and cataract"

Identifies cataract as a feature of the molecularly characterized GR deficiency family.

PMID:947404 SUPPORT Human Clinical

"possibly by cataracts in her own and in her brother's eyes"

Reports cataract in affected siblings of the index family; the authors state the attribution tentatively.

Metabolism 1

Neonatal hyperbilirubinemia HP:0003265

Show evidence (1 reference)

PMID:17185460 SUPPORT Human Clinical

"a novel patient (2) presenting with severe neonatal jaundice"

Documents severe neonatal jaundice in a molecularly confirmed GR-deficient patient.

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Genetic Associations

1

GSR biallelic loss-of-function variants

Gene: GSR hgnc:4623 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:17185460 SUPPORT Human Clinical

"This is the first identification of mutations in the GR gene causing clinical GR deficiency."

Establishes GSR as the causative gene for hereditary glutathione reductase deficiency.

PMID:17185460 SUPPORT Human Clinical

"Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme."

Documents a loss-of-function GSR deletion producing an inactive enzyme.

PMID:17185460 SUPPORT Human Clinical

"Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele."

Documents biallelic (compound heterozygous) GSR variants in a second patient, consistent with recessive loss of function.

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Medical Actions

3

Avoidance of oxidant triggers

Action: Supportive care, avoidance of oxidant triggers Ontology label: Supportive Care NCIT:C15747

Avoidance of fava beans and other oxidant stressors is the mainstay of preventing acute hemolytic crises, by analogy with the management of oxidant hemolysis in G6PD deficiency and consistent with the fava-bean-triggered crises documented in this disorder.

Show evidence (1 reference)

PMID:947404 SUPPORT INDIRECT Human Clinical

"this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"

Documents the fava bean trigger whose avoidance is the rationale for this supportive measure; the source does not itself report avoidance as a treatment.

Phototherapy for neonatal jaundice

Action: Phototherapy NCIT:C15301

Severe neonatal jaundice is managed with standard phototherapy, with exchange transfusion for severe hyperbilirubinemia, as for other hemolytic causes of neonatal jaundice.

Show evidence (1 reference)

PMID:17185460 SUPPORT INDIRECT Human Clinical

"a novel patient (2) presenting with severe neonatal jaundice"

The documented severe neonatal jaundice is the indication for phototherapy; the source does not report the treatment given.

Blood transfusion

Action: Blood transfusion Ontology label: Blood Transfusion NCIT:C15192

Red cell transfusion is used to support severe hemolytic anemia and hemolytic crises, as for other red-cell enzyme deficiency states.

Show evidence (1 reference)

PMID:145206 SUPPORT INDIRECT Other

"Red cell enzyme deficiency disease states are reviewed to outline the requirements for transfusion therapy in the neonatal period, during spontaneous crises, drug or infection-induced crises and chronic anemia."

Review of red-cell enzyme deficiency states establishes transfusion as supportive therapy for hemolytic crises in these enzymopathies, a class that includes GR deficiency; it does not report GR-deficient patients.

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Biochemical Markers

1

Erythrocyte glutathione reductase activity (Decreased)

Show evidence (1 reference)

PMID:17185460 SUPPORT Human Clinical

"Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting."

Documents absent erythrocyte and leukocyte GR activity with undetectable protein in the molecularly characterized family.

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Diagnosis

3

Erythrocyte glutathione reductase enzyme assay

Diagnosis rests on demonstrating markedly reduced or absent erythrocyte GR activity that is not corrected by FAD, distinguishing hereditary deficiency from acquired riboflavin-related FAD undersaturation, with molecular confirmation of biallelic GSR variants.

Show evidence (1 reference)

PMID:947404 SUPPORT Human Clinical

"The enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo."

The FAD/riboflavin non-restoration test distinguishes the hereditary defect from acquired low activity.

GR protein immunoblot

Western blotting of red-cell and leukocyte lysates shows whether GR protein is absent or reduced, which separates a structural GSR defect from an apoenzyme that is present but undersaturated with FAD.

Western blotting for glutathione reductase protein NCIT:C16357

Show evidence (1 reference)

PMID:17185460 SUPPORT Human Clinical

"Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting."

Western blotting showed undetectable GR protein in the enzyme-null family.

GSR molecular genetic testing

Sequencing and deletion analysis of GSR confirms the diagnosis by identifying biallelic loss-of-function variants, such as the homozygous deletion removing the dimerization domain or compound heterozygosity for a nonsense allele and the destabilizing G330A substitution.

GSR genetic testing NCIT:C15709

Show evidence (2 references)

PMID:17185460 SUPPORT Human Clinical

"Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme."

DNA analysis identified the causal GSR deletion in the original family.

PMID:17185460 SUPPORT Human Clinical

"Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele."

DNA analysis identified the biallelic GSR variants in the second patient.

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Prevalence

1

Worldwide

Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000

Orphanet records the worldwide point prevalence of hereditary glutathione reductase deficiency as below 1 per 1,000,000, documented only at the level of individual cases/families. Causal GSR variants have been characterized in two families, and the enzyme defect was found in only 2 of more than 15,000 blood samples tested.

Show evidence (2 references)

ORPHA:90030 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:947404"

Orphanet epidemiology table reports a worldwide point prevalence of less than 1 per 1,000,000 for this disorder.

PMID:17185460 SUPPORT Human Clinical

"Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples."

Documents the extreme rarity of hereditary GR deficiency in a large screened sample.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Glutathione Reductase Deficiency:

Acquired (riboflavin-deficiency) low erythrocyte glutathione reductase activity

Overlapping Features Low red-cell GR activity is far more commonly acquired, resulting from dietary riboflavin (vitamin B2) insufficiency that leaves the GR apoenzyme undersaturated with its FAD cofactor. Unlike the hereditary defect, this activity is restored in vitro by FAD and in vivo by riboflavin supplementation, and it is not a genetic subtype of this disorder.

Distinguishing Features

Restoration of GR activity by FAD in vitro or riboflavin in vivo indicates acquired FAD undersaturation rather than a structural GSR defect; hereditary deficiency is non-restorable.

Show evidence (2 references)

PMID:5794396 SUPPORT Human Clinical

"Stimulation of glutathione reductase activity of red cells of normal subjects occurred when they were given 5 milligrams of riboflavin daily for 8 days."

Demonstrates that acquired low GR activity reflects riboflavin/FAD status and is corrected by riboflavin, distinguishing it from the hereditary defect.

PMID:11924113 SUPPORT Human Clinical

"17.8% of males and 22.4% of females suffered from GR deficiency due to riboflavin deficiency. This could be easily corrected by dietary supplementation with riboflavin. No cases of severe GR deficiency were identified."

In 1,691 Saudi individuals, riboflavin-related low GR activity was common and correctable, while no severe (hereditary-range) deficiency was found.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Overlapping Features G6PD deficiency is the common cause of oxidant-triggered (including favism) nonspherocytic hemolytic anemia and shares the biochemical endpoint of impaired NADPH-dependent glutathione protection. Inhibition of GR produces a phenocopy of G6PD-deficient cells.

Distinguishing Features

G6PD deficiency is X-linked and reflects deficient NADPH generation, whereas GR deficiency is autosomal recessive and reflects failure to regenerate GSH from GSSG downstream of NADPH.

Show evidence (1 reference)

PMID:3572207 SUPPORT In Vitro

"Only erythrocytes that had been rendered almost totally GSSG-R deficient, that is, had lost greater than 90% of baseline activity, became functionally equivalent to GdA- glucose-6-phosphate dehydrogenase-deficient cells."

Establishes that near-complete GR loss produces a functional phenocopy of G6PD deficiency, the key differential.

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Animal Models

2

Gsr-null mouse (neutrophil host defense)

Gsr-deficient mice have impaired neutrophil oxidative burst, phagocytosis and bacterial killing, reduced neutrophil extracellular trap formation, and increased susceptibility to Escherichia coli and Staphylococcus aureus challenge.

Species

Mouse

Genotype

Gsr homozygous null

Genes

Gsr hgnc:4623

Publication

PMID:22279102

Pathograph links

Phagocyte Glutathione-Dependent Defense Impairment recapitulates fidelity: moderate observes: organism

Limitations: The mouse shows a clear host-defense defect after massive bacterial challenge, whereas clinically significant immunodeficiency has not been reported in GR-deficient patients; only abnormal neutrophil oxygen consumption was described in the index family.

Show evidence (1 reference)

PMID:22279102 SUPPORT Model Organism

"Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation."

The knockout neutrophil reproduces a glutathione-reductase-dependent defect in the phagocyte oxidative burst.

Show evidence (1 reference)

PMID:22279102 SUPPORT Model Organism

"Gsr-null mice exhibited enhanced susceptibility to Escherichia coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality."

Establishes the knockout as a model of the phagocyte branch of GR deficiency.

Gr1a1Neu mouse (chemically induced GR mutant)

A chemically induced glutathione reductase mutant at the Gr1 structural locus on mouse chromosome 8. Homozygotes retain about 2% of normal blood GR activity, with the loss present in blood and other tissues. Without an oxidant challenge their erythrocyte indices are normal, as baseline red-cell GSH is normal in GR-deficient patients; triggered hemolysis was not tested.

Species

Mouse

Genotype

Gr1a1Neu homozygous (about 2% residual GR activity)

Genes

Gsr hgnc:4623

Publication

PMID:10218442

Pathograph links

GSR Loss-of-Function and Absent Glutathione Reductase Activity recapitulates fidelity: moderate observes: organism

Limitations: The mouse allele is a chemically induced mutation at the Gr1 locus, not a human GSR variant, and leaves about 2% residual activity where the human enzyme-null patients have essentially none. The study measured erythrocyte indices only without an oxidant challenge, so it says nothing about oxidant-triggered hemolysis.

Show evidence (1 reference)

PMID:10218442 SUPPORT Model Organism

"The loss of GR activity was evident both in blood and in other tissue extracts."

The mutant reproduces the generalized near-absence of GR activity that defines the human enzyme defect.

Show evidence (1 reference)

PMID:10218442 SUPPORT Model Organism

"Homozygous mutants with only 2% residual enzyme activity were recovered in progeny of inter se matings of heterozygotes."

Documents a near-null GR mutant mouse.

{ }

Source YAML

click to show

name: Glutathione Reductase Deficiency
creation_date: "2026-10-15T01:36:48Z"
category: Mendelian
synonyms:
- Hemolytic anemia due to glutathione reductase deficiency
- Hemolytic anemia due to glutathione reductase (GSR) deficiency
- GSR deficiency
- Hereditary glutathione reductase deficiency
- Inherited glutathione reductase deficiency
description: >-
  Glutathione reductase deficiency is a very rare autosomal recessive disorder
  of erythrocyte antioxidant defense caused by biallelic loss-of-function
  variants in GSR, which encodes glutathione-disulfide reductase (GR, EC
  1.8.1.7). GR is the FAD- and NADPH-dependent flavoenzyme that regenerates
  reduced glutathione (GSH) from oxidized glutathione disulfide (GSSG). When GR
  activity is essentially absent, erythrocytes cannot restore GSH after an
  oxidant load, so hemoglobin and membrane proteins are left unprotected against
  reactive oxygen species. The clinical picture of hereditary GR deficiency is
  dominated by oxidant-triggered (including favism) hemolysis and severe
  neonatal jaundice, with cataract tentatively attributed to the deficiency in
  the original family; because
  the enzyme is also deficient in leukocytes, the propositus family showed
  reduced phagocyte glutathione-dependent defense. The disorder is defined
  genetically and is exceptionally rare: GSR variants abolishing red-cell GR
  activity have been characterized in two families, the originally described
  family and an unrelated patient presenting with severe neonatal jaundice. It
  must be distinguished from the common acquired low red-cell GR
  activity caused by dietary riboflavin (vitamin B2) insufficiency, which reduces
  the FAD saturation of the apoenzyme and is reversible with riboflavin; that
  non-genetic state is not a subtype of this Mendelian disorder.
disease_term:
  preferred_term: hemolytic anemia due to glutathione reductase deficiency
  term:
    id: MONDO:0019531
    label: hemolytic anemia due to glutathione reductase deficiency
parents:
- Congenital Nonspherocytic Hemolytic Anemia
- Inherited Glutathione Metabolism Disease
- Inborn Error of Metabolism
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: >-
    Orphanet records the worldwide point prevalence of hereditary glutathione
    reductase deficiency as below 1 per 1,000,000, documented only at the level
    of individual cases/families. Causal GSR variants have been characterized in
    two families, and the enzyme defect was found in only 2 of more than 15,000
    blood samples tested.
  evidence:
  - reference: ORPHA:90030
    reference_title: "Hemolytic anemia due to glutathione reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:947404"
    explanation: >-
      Orphanet epidemiology table reports a worldwide point prevalence of less
      than 1 per 1,000,000 for this disorder.
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary glutathione reductase (GR) deficiency was found in only 2 cases when testing more than 15 000 blood samples."
    explanation: >-
      Documents the extreme rarity of hereditary GR deficiency in a large
      screened sample.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Hereditary glutathione reductase deficiency is inherited in an autosomal
    recessive manner. In the originally described family the affected children
    of a consanguineous marriage had virtually absent erythrocyte GR activity
    while both parents had intermediate (heterozygous-range) values.
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A virtually complete absence of glutathione reductase activity was found in the erythrocytes of all three children (one male, two females) from a consanguineous marriage. Intermediate values were found in the erythrocytes of both parents."
    explanation: >-
      The affected sibship from a consanguineous union with heterozygous-range
      parental values establishes autosomal recessive inheritance.
genetic:
- name: GSR biallelic loss-of-function variants
  gene_term:
    preferred_term: GSR
    term:
      id: hgnc:4623
      label: GSR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    GSR encodes glutathione-disulfide reductase. Complete hereditary GR
    deficiency was shown to result from loss-of-function mutations in the GSR
    apoprotein: a homozygous large deletion removing the dimerization domain in
    the originally described family, and compound heterozygosity for a premature
    stop codon and a destabilizing G330A missense substitution in a second
    patient. These are the first identified GSR mutations causing clinical GR
    deficiency.
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first identification of mutations in the GR gene causing clinical GR deficiency."
    explanation: >-
      Establishes GSR as the causative gene for hereditary glutathione
      reductase deficiency.
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme."
    explanation: >-
      Documents a loss-of-function GSR deletion producing an inactive enzyme.
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele."
    explanation: >-
      Documents biallelic (compound heterozygous) GSR variants in a second
      patient, consistent with recessive loss of function.
pathophysiology:
- name: GSR Loss-of-Function and Absent Glutathione Reductase Activity
  description: >-
    Biallelic GSR variants abolish glutathione-disulfide reductase activity. GR
    is the NADPH- and FAD-dependent flavoenzyme that reduces oxidized
    glutathione disulfide (GSSG) back to reduced glutathione (GSH). In affected
    erythrocytes and leukocytes the enzyme protein is unstable or undetectable
    and GR activity is essentially absent and cannot be restored by FAD in vitro
    or by riboflavin in vivo, distinguishing the genetic defect from acquired
    FAD-undersaturation.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: glutathione-disulfide reductase (NADPH) activity
    term:
      id: GO:0004362
      label: glutathione-disulfide reductase (NADPH) activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: FAD
    term:
      id: CHEBI:16238
      label: FAD
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo."
    explanation: >-
      The non-restorable loss of activity marks a structural apoenzyme defect
      rather than reversible FAD undersaturation.
  downstream:
  - target: Failure to Regenerate Reduced Glutathione
    causal_link_type: DIRECT
    description: >-
      Absent GR activity leaves the cell unable to convert GSSG back to GSH
      following an oxidant load.
  - target: Lens Oxidative Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GR deficiency extends to the lens, where loss of glutathione-dependent
      antioxidant protection is associated with cataract.
  - target: Phagocyte Glutathione-Dependent Defense Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GR is also deficient in leukocytes, impairing glutathione-dependent
      phagocyte defense.
  - target: Thioredoxin System Compensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of GR is followed by increased thioredoxin and thioredoxin reductase
      activity in Gsr-knockout mouse tissue, an alternative route for GSSG
      reduction.
- name: Thioredoxin System Compensation
  description: >-
    The thioredoxin/thioredoxin reductase system can reduce GSSG to GSH and
    acts as a functional backup for GR. In Gsr-knockout mice, inner-ear
    thioredoxin and thioredoxin reductase activities rose and no oxidative
    damage or hearing deficit developed. This compensation is a candidate
    explanation for why hemolysis in the human disorder has been reported after
    oxidant triggers, but it has not been measured in GR-deficient patients,
    and any dampening effect on hemolysis is hypothesized rather than shown.
  biological_scale: MOLECULAR
  role: compensation
  molecular_functions:
  - preferred_term: thioredoxin-disulfide reductase (NADPH) activity
    term:
      id: GO:0004791
      label: thioredoxin-disulfide reductase (NADPH) activity
    modifier: INCREASED
  evidence:
  - reference: PMID:28686716
    reference_title: "GSR is not essential for the maintenance of antioxidant defenses in mouse cochlea: Possible role of the thioredoxin system as a functional backup for GSR."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Gsr deficiency resulted in increased activities of cytosolic thioredoxin and thioredoxin reductase in the inner ears."
    explanation: >-
      Gsr-knockout mice upregulate the thioredoxin system, the proposed
      compensating route for GSSG reduction.
  - reference: PMID:28686716
    reference_title: "GSR is not essential for the maintenance of antioxidant defenses in mouse cochlea: Possible role of the thioredoxin system as a functional backup for GSR."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the thioredoxin system can support GSSG reduction in the mouse peripheral auditory system"
    explanation: >-
      The authors conclude the thioredoxin system can substitute for GR in GSSG
      reduction in this tissue.
- name: Failure to Regenerate Reduced Glutathione
  description: >-
    Without GR, erythrocytes cannot reduce GSSG back to GSH after an oxidant
    challenge, so the reduced-glutathione pool collapses under oxidative stress.
    Baseline GSH may appear near-normal because little is consumed at rest, but
    glutathione stability during an oxidant challenge is severely diminished.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: glutathione metabolic process
    term:
      id: GO:0006749
      label: glutathione metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: glutathione disulfide
    term:
      id: CHEBI:17858
      label: glutathione disulfide
    modifier: INCREASED
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severely diminished glutathione stability during incubation with acetylphenylhydrazine was observed in the erythrocytes of the siblings"
    explanation: >-
      An oxidant challenge in vitro shows the GSH pool cannot be sustained,
      the direct consequence of absent GR activity.
  downstream:
  - target: Erythrocyte Oxidative and Membrane Injury
    causal_link_type: DIRECT
    description: >-
      The loss of regenerable GSH leaves hemoglobin and membrane proteins
      undefended against reactive oxygen species.
- name: Erythrocyte Oxidative and Membrane Injury
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Oxidative and Membrane Injury"
  description: >-
    With the GSH antioxidant buffer depleted, oxidant exposure denatures
    hemoglobin and damages the erythrocyte membrane, reducing cell integrity and
    marking the cell for removal. The reserve capacity of GR in normal red cells
    is large, so impaired GSH recovery under oxidant stress emerges only when
    enzyme activity is almost completely lost.
  biological_scale: CELLULAR
  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
  evidence:
  - reference: PMID:3572207
    reference_title: "Consequences of erythrocytic glutathione reductase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In red cells stressed by these reagents, GSSG-R deficiency began to impair the regeneration of GSH only after greater than 80% of the normal enzyme activity had been abolished."
    explanation: >-
      Establishes that only near-complete GR loss impairs GSH recovery under
      oxidant stress, the step that leaves red cells vulnerable to injury.
  downstream:
  - target: Oxidant-Triggered Hemolysis
    causal_link_type: DIRECT
    description: >-
      Oxidatively injured, poorly deformable erythrocytes are hemolyzed,
      especially after an oxidant trigger such as fava bean ingestion.
- name: Oxidant-Triggered Hemolysis
  conforms_to: "hemolytic_anemia_erythrocyte_destruction#Premature Erythrocyte Destruction"
  description: >-
    Oxidatively damaged erythrocytes are destroyed prematurely, producing
    hemolytic anemia. In the index family, hemolytic crises followed fava bean
    ingestion, mirroring the oxidant-triggered hemolysis of G6PD deficiency.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: erythrocyte clearance
    term:
      id: GO:0034102
      label: erythrocyte clearance
    modifier: INCREASED
  evidence:
  - reference: PMID:8813716
    reference_title: "Hemolytic anemias due to erythrocyte enzyme deficiencies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "If an enzyme deficiency of one of these metabolic pathways limits the ATP and/or NADPH production, distinct membrane alterations result causing a removal of the damaged cells by the monocyte-macrophage system."
    explanation: >-
      Review of red-cell enzymopathies states the general route from a redox
      enzyme defect to membrane damage and macrophage removal of erythrocytes;
      applied here to the glutathione cycle defect.
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"
    explanation: >-
      Documents fava-bean-triggered hemolytic crises as the clinical
      manifestation of the enzyme defect.
  downstream:
  - target: Hemolytic anemia
    causal_link_type: DIRECT
    description: >-
      Premature destruction of oxidatively vulnerable erythrocytes produces
      hemolytic anemia.
  - target: Fava bean-induced hemolytic anemia
    causal_link_type: DIRECT
    description: >-
      Fava bean ingestion is the documented oxidant trigger of acute hemolysis
      in this disorder.
  - target: Neonatal hyperbilirubinemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe neonatal jaundice was the presenting feature of a GR-deficient
      patient; that it results from hemolysis in the newborn period is inferred
      from the enzyme defect, since the report states only the jaundice.
    evidence:
    - reference: PMID:17185460
      reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The red blood cells from patient 2 did not exhibit GR activity either"
      explanation: >-
        The jaundiced neonate had absent red-cell GR activity; attributing the
        jaundice to hemolysis is an inference from that red-cell defect.
- name: Lens Oxidative Injury
  description: >-
    Loss of glutathione-dependent antioxidant defense in the lens is the
    proposed route to cataract. The lens relies heavily on glutathione to
    protect against oxidative damage. In the originally described family,
    cataract in two siblings was attributed to the deficiency only tentatively
    ("possibly"), and no age at onset was reported.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: lens fiber cell
    term:
      id: CL:0011004
      label: lens fiber cell
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "possibly by cataracts in her own and in her brother's eyes"
    explanation: >-
      Reports cataract in affected family members, linked to the loss of
      glutathione-dependent antioxidant protection of the lens.
  - reference: PMID:1737065
    reference_title: "Peroxide-metabolizing systems of the crystalline lens."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "The findings indicated an impairment in peroxide metabolism of the mature cataractous lenses compared to normal lenses to be resulted from a deficiency of GSH."
    explanation: >-
      Ex vivo lens study links GSH deficiency to impaired peroxide handling in
      cataractous lenses. It concerns cataract generally, not GR-deficient
      patients, so the lens step in this disorder remains inferred.
  downstream:
  - target: Cataract
    causal_link_type: DIRECT
    description: >-
      Oxidative injury to lens fiber cells manifests as cataract.
- name: Phagocyte Glutathione-Dependent Defense Impairment
  description: >-
    Because GR is also deficient in leukocytes, glutathione-dependent
    antioxidant and bactericidal function of phagocytes is impaired. In the
    propositus, polymorphonuclear cells showed abnormal oxygen consumption after
    phagocytosis, suggesting a role for the GR reaction in the bactericidal
    capacity of these cells. This is an observation in a single family and the
    clinical significance of the leukocyte defect is not established.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found an abnormal oxygen consumption of the propositus' PMNs after phagocytosis of zymosan particles, suggesting that the glutathione reductase reaction was involved in the bactericidal capacity of these cells"
    explanation: >-
      Documents the leukocyte GR defect and its possible effect on phagocyte
      bactericidal function.
  - reference: PMID:22279102
    reference_title: "Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation."
    explanation: >-
      In Gsr-null mice, neutrophils cannot sustain the oxidative burst, the
      model counterpart of the abnormal oxygen consumption seen in the
      propositus' neutrophils.
  downstream:
  - target: Abnormal neutrophil physiology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired glutathione-dependent defense is reflected in abnormal phagocyte
      oxidative physiology.
phenotypes:
- name: Hemolytic anemia
  category: Hematologic
  description: >-
    Hemolytic anemia from premature destruction of oxidatively injured
    erythrocytes; the reported episodes followed an oxidant trigger (fava
    beans).
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: ORPHA:90030
    reference_title: "Hemolytic anemia due to glutathione reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare hemolytic anemia due to hexose monophosphate shunt and glutathione metabolism anomalies characterized by nearly complete absence of glutathione reductase activity in erythrocytes."
    explanation: >-
      Orphanet defines the disorder as a hemolytic anemia caused by near-absent
      erythrocyte glutathione reductase activity.
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a previously described family suffering from favism and cataract"
    explanation: >-
      Confirms the favism (hemolytic) and cataract phenotype of the molecularly
      characterized family.
- name: Fava bean-induced hemolytic anemia
  category: Hematologic
  description: >-
    Acute hemolytic crises triggered by ingestion of fava beans (favism), as
    documented in the originally described family.
  phenotype_term:
    preferred_term: Fava bean-induced hemolytic anemia
    term:
      id: HP:0004814
      label: Fava bean-induced hemolytic anemia
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"
    explanation: >-
      Documents fava-bean-induced hemolytic crises in an affected individual.
- name: Cataract
  category: Ophthalmologic
  description: >-
    Cataract in two affected siblings of the original family, attributed to
    the deficiency tentatively ("possibly") by the reporting authors; no age at
    onset was given.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a previously described family suffering from favism and cataract"
    explanation: >-
      Identifies cataract as a feature of the molecularly characterized GR
      deficiency family.
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "possibly by cataracts in her own and in her brother's eyes"
    explanation: >-
      Reports cataract in affected siblings of the index family; the authors
      state the attribution tentatively.
- name: Neonatal hyperbilirubinemia
  category: Hematologic
  description: >-
    Severe neonatal jaundice, the presenting feature of a compound
    heterozygous patient with absent red-cell GR activity.
  phenotype_term:
    preferred_term: Neonatal hyperbilirubinemia
    term:
      id: HP:0003265
      label: Neonatal hyperbilirubinemia
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel patient (2) presenting with severe neonatal jaundice"
    explanation: >-
      Documents severe neonatal jaundice in a molecularly confirmed GR-deficient
      patient.
- name: Abnormal neutrophil physiology
  category: Immunologic
  description: >-
    Abnormal phagocyte oxidative physiology reflecting the leukocyte GR defect,
    observed in the propositus of the index family.
  phenotype_term:
    preferred_term: Abnormal neutrophil physiology
    term:
      id: HP:0011990
      label: Abnormal neutrophil physiology
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found an abnormal oxygen consumption of the propositus' PMNs after phagocytosis of zymosan particles"
    explanation: >-
      Documents abnormal neutrophil respiratory physiology attributable to the
      leukocyte GR defect.
biochemical:
- name: Erythrocyte glutathione reductase activity
  presence: Decreased
  biomarker_term:
    preferred_term: Reduced erythrocyte glutathione reductase activity
    term:
      id: HP:6000525
      label: Reduced erythrocyte glutathione reductase activity
  notes: >-
    In hereditary GR deficiency erythrocyte GR activity is essentially absent
    and, unlike acquired riboflavin-related low activity, is not restored by FAD
    in vitro or riboflavin in vivo.
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting."
    explanation: >-
      Documents absent erythrocyte and leukocyte GR activity with undetectable
      protein in the molecularly characterized family.
diagnosis:
- name: Erythrocyte glutathione reductase enzyme assay
  description: >-
    Diagnosis rests on demonstrating markedly reduced or absent erythrocyte GR
    activity that is not corrected by FAD, distinguishing hereditary deficiency
    from acquired riboflavin-related FAD undersaturation, with molecular
    confirmation of biallelic GSR variants.
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo."
    explanation: >-
      The FAD/riboflavin non-restoration test distinguishes the hereditary
      defect from acquired low activity.
- name: GR protein immunoblot
  description: >-
    Western blotting of red-cell and leukocyte lysates shows whether GR
    protein is absent or reduced, which separates a structural GSR defect from
    an apoenzyme that is present but undersaturated with FAD.
  diagnosis_term:
    preferred_term: Western blotting for glutathione reductase protein
    term:
      id: NCIT:C16357
      label: Western Blotting
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Red blood cells and leukocytes of the patients in family 1 did not contain any GR activity, and the GR protein was undetectable by Western blotting."
    explanation: >-
      Western blotting showed undetectable GR protein in the enzyme-null
      family.
- name: GSR molecular genetic testing
  description: >-
    Sequencing and deletion analysis of GSR confirms the diagnosis by
    identifying biallelic loss-of-function variants, such as the homozygous
    deletion removing the dimerization domain or compound heterozygosity for a
    nonsense allele and the destabilizing G330A substitution.
  diagnosis_term:
    preferred_term: GSR genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Owing to a 2246-bp deletion in the patients' DNA, translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme."
    explanation: >-
      DNA analysis identified the causal GSR deletion in the original family.
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 was found to be a compound heterozygote, with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele."
    explanation: >-
      DNA analysis identified the biallelic GSR variants in the second patient.
treatments:
- name: Avoidance of oxidant triggers
  description: >-
    Avoidance of fava beans and other oxidant stressors is the mainstay of
    preventing acute hemolytic crises, by analogy with the management of oxidant
    hemolysis in G6PD deficiency and consistent with the fava-bean-triggered
    crises documented in this disorder.
  treatment_term:
    preferred_term: Supportive care, avoidance of oxidant triggers
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:947404
    reference_title: "Familial deficiency of glutathione reductase in human blood cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient)"
    explanation: >-
      Documents the fava bean trigger whose avoidance is the rationale for this
      supportive measure; the source does not itself report avoidance as a
      treatment.
- name: Phototherapy for neonatal jaundice
  description: >-
    Severe neonatal jaundice is managed with standard phototherapy, with
    exchange transfusion for severe hyperbilirubinemia, as for other hemolytic
    causes of neonatal jaundice.
  treatment_term:
    preferred_term: Phototherapy
    term:
      id: NCIT:C15301
      label: Phototherapy
  evidence:
  - reference: PMID:17185460
    reference_title: "Molecular basis of glutathione reductase deficiency in human blood cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel patient (2) presenting with severe neonatal jaundice"
    explanation: >-
      The documented severe neonatal jaundice is the indication for
      phototherapy; the source does not report the treatment given.
- name: Blood transfusion
  description: >-
    Red cell transfusion is used to support severe hemolytic anemia and
    hemolytic crises, as for other red-cell enzyme deficiency states.
  treatment_term:
    preferred_term: Blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  evidence:
  - reference: PMID:145206
    reference_title: "Transfusion requirements of patients with enzyme deficient red blood cells."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Red cell enzyme deficiency disease states are reviewed to outline the requirements for transfusion therapy in the neonatal period, during spontaneous crises, drug or infection-induced crises and chronic anemia."
    explanation: >-
      Review of red-cell enzyme deficiency states establishes transfusion as
      supportive therapy for hemolytic crises in these enzymopathies, a class
      that includes GR deficiency; it does not report GR-deficient patients.
differential_diagnoses:
- name: Acquired (riboflavin-deficiency) low erythrocyte glutathione reductase activity
  description: >-
    Low red-cell GR activity is far more commonly acquired, resulting from
    dietary riboflavin (vitamin B2) insufficiency that leaves the GR apoenzyme
    undersaturated with its FAD cofactor. Unlike the hereditary defect, this
    activity is restored in vitro by FAD and in vivo by riboflavin
    supplementation, and it is not a genetic subtype of this disorder.
  distinguishing_features:
  - Restoration of GR activity by FAD in vitro or riboflavin in vivo indicates acquired FAD undersaturation rather than a structural GSR defect; hereditary deficiency is non-restorable.
  evidence:
  - reference: PMID:5794396
    reference_title: "Glutathione reductase: stimulation in normal subjects by riboflavin supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stimulation of glutathione reductase activity of red cells of normal subjects occurred when they were given 5 milligrams of riboflavin daily for 8 days."
    explanation: >-
      Demonstrates that acquired low GR activity reflects riboflavin/FAD status
      and is corrected by riboflavin, distinguishing it from the hereditary
      defect.
  - reference: PMID:11924113
    reference_title: "Glutathione reductase deficiency in Saudi Arabia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "17.8% of males and 22.4% of females suffered from GR deficiency due to riboflavin deficiency. This could be easily corrected by dietary supplementation with riboflavin. No cases of severe GR deficiency were identified."
    explanation: >-
      In 1,691 Saudi individuals, riboflavin-related low GR activity was common
      and correctable, while no severe (hereditary-range) deficiency was found.
- name: Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  description: >-
    G6PD deficiency is the common cause of oxidant-triggered (including favism)
    nonspherocytic hemolytic anemia and shares the biochemical endpoint of
    impaired NADPH-dependent glutathione protection. Inhibition of GR produces a
    phenocopy of G6PD-deficient cells.
  distinguishing_features:
  - G6PD deficiency is X-linked and reflects deficient NADPH generation, whereas GR deficiency is autosomal recessive and reflects failure to regenerate GSH from GSSG downstream of NADPH.
  evidence:
  - reference: PMID:3572207
    reference_title: "Consequences of erythrocytic glutathione reductase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Only erythrocytes that had been rendered almost totally GSSG-R deficient, that is, had lost greater than 90% of baseline activity, became functionally equivalent to GdA- glucose-6-phosphate dehydrogenase-deficient cells."
    explanation: >-
      Establishes that near-complete GR loss produces a functional phenocopy of
      G6PD deficiency, the key differential.
animal_models:
- name: Gsr-null mouse (neutrophil host defense)
  species: Mouse
  genotype: Gsr homozygous null
  publication: PMID:22279102
  description: >-
    Gsr-deficient mice have impaired neutrophil oxidative burst, phagocytosis
    and bacterial killing, reduced neutrophil extracellular trap formation, and
    increased susceptibility to Escherichia coli and Staphylococcus aureus
    challenge.
  genes:
  - preferred_term: Gsr
    term:
      id: hgnc:4623
      label: GSR
  evidence:
  - reference: PMID:22279102
    reference_title: "Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Gsr-null mice exhibited enhanced susceptibility to Escherichia coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality."
    explanation: >-
      Establishes the knockout as a model of the phagocyte branch of GR
      deficiency.
  modeled_mechanisms:
  - target: Phagocyte Glutathione-Dependent Defense Impairment
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      The mouse shows a clear host-defense defect after massive bacterial
      challenge, whereas clinically significant immunodeficiency has not been
      reported in GR-deficient patients; only abnormal neutrophil oxygen
      consumption was described in the index family.
    evidence:
    - reference: PMID:22279102
      reference_title: "Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Unlike wild-type neutrophils that exhibited a sustained oxidative burst upon stimulation with phorbol ester and fMLP, Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation."
      explanation: >-
        The knockout neutrophil reproduces a glutathione-reductase-dependent
        defect in the phagocyte oxidative burst.
- name: Gr1a1Neu mouse (chemically induced GR mutant)
  species: Mouse
  genotype: Gr1a1Neu homozygous (about 2% residual GR activity)
  publication: PMID:10218442
  description: >-
    A chemically induced glutathione reductase mutant at the Gr1 structural
    locus on mouse chromosome 8. Homozygotes retain about 2% of normal blood GR
    activity, with the loss present in blood and other tissues. Without an
    oxidant challenge their erythrocyte indices are normal, as baseline red-cell
    GSH is normal in GR-deficient patients; triggered hemolysis was not tested.
  genes:
  - preferred_term: Gsr
    term:
      id: hgnc:4623
      label: GSR
  evidence:
  - reference: PMID:10218442
    reference_title: "Glutathione reductase activity deficiency in homozygous Gr1a1Neu mice does not cause haemolytic anaemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Homozygous mutants with only 2% residual enzyme activity were recovered in progeny of inter se matings of heterozygotes."
    explanation: >-
      Documents a near-null GR mutant mouse.
  modeled_mechanisms:
  - target: GSR Loss-of-Function and Absent Glutathione Reductase Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      The mouse allele is a chemically induced mutation at the Gr1 locus, not a
      human GSR variant, and leaves about 2% residual activity where the human
      enzyme-null patients have essentially none. The study measured erythrocyte
      indices only without an oxidant challenge, so it says nothing about
      oxidant-triggered hemolysis.
    evidence:
    - reference: PMID:10218442
      reference_title: "Glutathione reductase activity deficiency in homozygous Gr1a1Neu mice does not cause haemolytic anaemia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The loss of GR activity was evident both in blood and in other tissue extracts."
      explanation: >-
        The mutant reproduces the generalized near-absence of GR activity that
        defines the human enzyme defect.
notes: >-
  Hereditary glutathione reductase deficiency is defined by near-absent
  erythrocyte GR activity caused by biallelic GSR variants. Kamerbeek et al.
  (2007) characterized the variants in two families: a homozygous 2246-bp
  deletion in the family originally described by Loos et al. (1976), and
  compound heterozygosity for a nonsense allele and G330A in an unrelated
  patient with severe neonatal jaundice. A 2026 case report from India
  (PMID:41984322) has no abstract and is not cited. The much more common finding of low red-cell GR
  activity is acquired, reflecting dietary riboflavin insufficiency and
  undersaturation of the apoenzyme with FAD; it is reversible with riboflavin and
  is recorded here as a differential diagnosis, not a subtype. The leukocyte GR
  defect and its possible effect on phagocyte bactericidal function rest on a
  single family. Two pathophysiology nodes conform to the
  hemolytic_anemia_erythrocyte_destruction module. Cataract was attributed to
  the deficiency only tentatively in the original family, and the lens step is
  inferred from general cataract biology rather than studied in GR-deficient
  lenses. No GeneReviews chapter exists for this disorder.
references:
- reference: PMID:947404
  title: "Familial deficiency of glutathione reductase in human blood cells."
- reference: PMID:17185460
  title: "Molecular basis of glutathione reductase deficiency in human blood cells."

📚

References & Deep Research

References

2

PMID:947404

Familial deficiency of glutathione reductase in human blood cells.

No top-level findings curated for this source.

PMID:17185460

Molecular basis of glutathione reductase deficiency in human blood cells.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Glutathione_Reductase_Deficiency · 2026-10-15T02:11:15Z · View source

De novo curation of hereditary glutathione reductase deficiency (GSR, MONDO:0019531), an autosomal recessive erythrocyte antioxidant-defense disorder. Causal chain: biallelic GSR loss of function, then absent glutathione reductase activity, then failure to regenerate GSH from GSSG, then erythrocyte oxidative and membrane injury, then oxidant-triggered (favism) hemolysis, ending on hemolytic anemia, fava bean-induced hemolytic anemia and neonatal hyperbilirubinemia. Side branches go to lens oxidative injury (cataract; the lens step is inferred, cited INDIRECT to a general cataract study), to the leukocyte GR defect (abnormal neutrophil physiology), and to a thioredoxin-system compensation node supported only by Gsr-knockout mouse data. Two nodes conform to hemolytic_anemia_erythrocyte_destruction (Oxidative and Membrane Injury; Premature Erythrocyte Destruction). Scope: acquired low red-cell GR activity from riboflavin/FAD undersaturation is recorded as a differential diagnosis, not a subtype (Beutler 1969 PMID:5794396; Saudi cohort PMID:11924113). Two animal models: the Gsr-null mouse (phagocyte branch, RECAPITULATES) and the Gr1a1Neu mouse, which has about 2% residual activity and no hemolytic anemia (FAILS_TO_RECAPITULATE, recorded with limitations). Deep research: one OpenScientist report (research/Glutathione_Reductase_Deficiency-deep-research-openscientist.md). Reference validation: 16/16 references resolved, none unresolved; needs_review was set only by one quote in PMID:11924113 whose mismatch is typographic (the report wrote a >= sign where the abstract has "> or ="). Term validation: 26/27 resolved, none unresolved. just preflight-dr against MONDO:0019531 returned PASS (GSR mentioned 43 times, OMIM 618660 matches). Report leads used after fetching and reading each abstract: PMID:22279102, 28686716, 8813716, 1737065, 11924113. Report suggestions not adopted: its NCIT treatment CURIEs (C15360, C15277, C15349) were not used; the entry's NCIT terms were looked up directly. HP:0006579 (Prolonged neonatal jaundice), which the report offered for neonatal jaundice, was not used; HP:0003265 Neonatal hyperbilirubinemia was bound instead. Claims based on gnomAD constraint, yeast and ferroptosis were left out as outside this entry's scope. PMID:41984322 (2026 case report) was fetched but has no abstract, so it is not cited. ORPHA:90030 was generated by just fetch-reference. The local Orphadata files were newer than the manifest pin, so the cache file is stamped with the 2026-06-23 release; data/orphadata/MANIFEST.yaml was not changed. No GeneReviews chapter exists (just check-genereviews --online: NO_CHAPTER). Validation: validate, validate-terms, 36/36 verified snippets, entity-refs, causal-targets, qualifier-terms, duplicate-keys, block-scalar-comments, coarse/snippet-length/title/snippet-grading gates, model-scale-audit; list-disconnected-phenotypes reports 5/5 phenotypes connected.

OpenScientist ▸

Glutathione Reductase Deficiency: A Comprehensive Disease Characteristics Report

openscientist-autonomous 14 citations 2026-10-15T02:29:26.414517

Glutathione Reductase Deficiency: A Comprehensive Disease Characteristics Report

Disease: Glutathione Reductase Deficiency (hereditary) MONDO ID: MONDO:0019531 OMIM: 618660 (Hemolytic anemia due to glutathione reductase deficiency) Gene: GSR (HGNC:4623), chromosome 8p12 Category: Mendelian, autosomal recessive Report date: 2026-10-15

Summary

Glutathione reductase (GR) deficiency exists in two biologically distinct forms that must not be conflated. The first and overwhelmingly more common form is an acquired, riboflavin-responsive partial deficiency: because GR requires FAD (derived from dietary riboflavin/vitamin B2) as a cofactor, dietary riboflavin insufficiency lowers measured GR activity. This form is reversible with riboflavin supplementation, affects a substantial fraction of some populations (~20–25% partial deficiency in a Saudi cohort), and is clinically benign. The second form — the subject of this report and the entity catalogued under MONDO:0019531 — is a rare, hereditary, autosomal recessive enzymopathy caused by biallelic loss-of-function mutations in the GSR gene. This hereditary form is irreversible (not corrected by riboflavin or FAD) and is extraordinarily rare: only 2 cases were found among >15,000 blood samples screened.

Mechanistically, GSR encodes a homodimeric, FAD-dependent, NADPH-disulfide oxidoreductase (EC 1.8.1.7; UniProt P00390) that regenerates reduced glutathione (GSH) from oxidized glutathione disulfide (GSSG). Loss of this recycling capacity cripples the GSH-dependent antioxidant defense of erythrocytes and the ocular lens, producing the clinical triad of oxidant-triggered (favism) hemolytic anemia, cataracts, and neonatal jaundice. Critically, the phenotype is usually mild and episodic rather than chronic, because a parallel, evolutionarily conserved thioredoxin/thioredoxin-reductase (Trx/TrxR) system partially compensates for the loss of GSSG reduction. This buffering is reflected in population genetics: GSR is completely loss-of-function tolerant in gnomAD (pLI ≈ 0), predicting a biallelic frequency near 1 in 4 million — consistent with the near-absence of hereditary cases in population screens.

Management is limited to oxidant-trigger avoidance (fava beans, oxidant drugs, infection-related oxidative stress) and supportive transfusion during hemolytic crises, mirroring the paradigm established for G6PD deficiency. There is no disease-specific pharmacotherapy, and riboflavin does not help the hereditary form. Prognosis is favorable, with described enzyme-null individuals surviving to adulthood with only episodic, trigger-related hemolysis. A striking inversion of the disease biology is that GSR has been identified as the top cellular suppressor of ferroptosis, making the very function lost in this deficiency an exploitable vulnerability in oncology.

Key Findings

Finding 1 — Hereditary GR deficiency is an ultra-rare autosomal recessive disorder caused by biallelic GSR loss-of-function mutations

Hereditary GR deficiency is defined molecularly by biallelic loss-of-function variants in GSR on chromosome 8p12 (also mapped to 8p21.2 in cytogenetic deletion reports). Its rarity is well documented: Kamerbeek and colleagues found hereditary GR deficiency in only 2 cases when testing more than 15,000 blood samples (PMID: 17185460).

The molecular lesions span the classic loss-of-function spectrum. In one family (presenting with favism and cataract), patients carried a homozygous 2,246-bp deletion such that "translated GR is expected to lack almost the complete dimerization domain, which results in unstable and inactive enzyme" (PMID: 17185460). A second, novel patient presenting with severe neonatal jaundice was a compound heterozygote, "with a premature stop codon on one allele and a substitution of glycine 330, a highly conserved residue in the superfamily of NAD(P)H-dependent disulfide reductases, into alanine on the other allele" (PMID: 17185460). The Gly330Ala substitution drastically impairs thermostability.

The autosomal recessive inheritance was established decades earlier in the landmark consanguineous family of Loos et al., where "a virtually complete absence of glutathione reductase activity was found in the erythrocytes of all three children (one male, two females) from a consanguineous marriage" (PMID: 947404), with intermediate parental enzyme values — the classic signature of recessive inheritance.

Finding 2 — Clinical phenotype: favism-triggered hemolysis, cataracts, and neonatal jaundice

The clinical spectrum is narrow and oxidative-stress-related. In the classic family, "clinically, this deficiency was manifested by hemolytic crises after eating fava beans in the eldest daughter (patient), and possibly by cataracts in her own and in her brother's eyes" (PMID: 947404). The novel compound-heterozygous patient presented "with severe neonatal jaundice" (PMID: 17185460).

The diagnostic hallmark is oxidative instability of erythrocyte glutathione: "severely diminished glutathione stability during incubation with acetylphenylhydrazine was observed in the erythrocytes of the siblings" (PMID: 947404), with intermediate values in the obligate-carrier parents. Importantly, leukocytes are also affected (PMN ~8%, lymphocytes ~4%, monocytes ~15% of normal GR activity), reflecting the ubiquitous expression of the enzyme.

Suggested HPO terms: Hemolytic anemia (HP:0001878), Hemolytic anemia with episodic crises, Cataract (HP:0000518), Neonatal hyperbilirubinemia/Neonatal jaundice (HP:0006579), Jaundice (HP:0000952), Reticulocytosis (HP:0001923).

Finding 3 — Two distinct forms: common acquired (riboflavin-responsive) vs. rare irreversible hereditary

This distinction is central to the disease entity and to its diagnosis. In 1,691 Saudi individuals, "the overall frequency of partial GR deficiency was 24.5% and 20.3% in males and females respectively. In addition, 17.8% of males and 22.4% of females suffered from GR deficiency due to riboflavin deficiency. This could be easily corrected by dietary supplementation with riboflavin. No cases of severe GR deficiency were identified" (PMID: 11924113).

By contrast, the hereditary form is refractory: "the enzyme activity could not be restored either by addition of FAD in vitro or by administration of riboflavin in vivo" (PMID: 947404). The dependence of GR on FAD is also the basis of the erythrocyte glutathione reductase activation coefficient (EGRAC), the standard functional biomarker of riboflavin/vitamin B2 status.

Feature	Acquired (riboflavin-responsive)	Hereditary (GSR mutation)
Cause	Dietary riboflavin/FAD deficiency	Biallelic GSR LoF variants
Frequency	Common (~20–25% partial in some populations)	Ultra-rare (2 / >15,000)
FAD/riboflavin response	Corrects deficiency (EGRAC normalizes)	No response
Enzyme protein	Present	Absent or unstable
Clinical impact	Benign	Episodic hemolysis, cataract, jaundice
Inheritance	Nutritional	Autosomal recessive

Finding 4 — GSR supports neutrophil host defense (model organisms)

Beyond erythrocytes, GSR is required for phagocyte function. In Gsr-null mice, "Gsr-deficient neutrophils displayed a very transient oxidative burst that abruptly ceased shortly after stimulation" and "Gsr-null mice exhibited enhanced susceptibility to Escherichia coli challenge, indicated by dramatically increased bacterial burden, cytokine storm, striking histological abnormalities, and substantially elevated mortality" (PMID: 22279102). GSR also promotes fungal clearance (systemic Candida) and neutrophil extracellular trap (NET) formation. The human correlate appears in the Loos family, where patient neutrophils showed abnormal oxygen consumption after zymosan phagocytosis — though clinically significant immunodeficiency is not a prominent feature of the human hereditary disease, again pointing to compensation. Notably, "Gsr deficiency resulted in increased activities of cytosolic thioredoxin and thioredoxin [reductase]" in mouse cochlea (PMID: 28686716), where the thioredoxin system fully compensates.

Finding 5 — GSR is a homodimeric FAD/NADPH-disulfide oxidoreductase with a defined catalytic cycle

Human GR (EC 1.8.1.7; UniProt P00390) transfers electrons NADPH → FAD → active-site redox-active disulfide → GSSG, regenerating 2 GSH. Near-atomic synchrotron cryocrystallography (1.1–0.95 Å) showed that "the bound NADPH and redox-active disulfide are positioned optimally on opposite sides of the flavin for a 1,2-addition across a flavin double bond" and that "compression in the active site causes overlapping van der Waals radii and distortion in the nicotinamide ring of the NADPH substrate, which enhances catalysis via stereoelectronic effects" (PMID: 18638483).

Pathogenic variants act by destabilizing this fold: the 2,246-bp deletion removes most of the dimerization domain, preventing the functional dimer, while Gly330Ala impairs thermostability (PMID: 17185460). GR belongs to the NAD(P)H-dependent disulfide reductase (Pyr_redox / class-I pyridine nucleotide-disulfide oxidoreductase) superfamily.

Suggested GO terms: glutathione-disulfide reductase activity (GO:0004362), flavin adenine dinucleotide binding (GO:0050660), NADP binding (GO:0050661), cell redox homeostasis (GO:0045454), glutathione metabolic process (GO:0006749). CHEBI: glutathione (CHEBI:16856), glutathione disulfide (CHEBI:17858), NADPH (CHEBI:16474), FAD (CHEBI:16238).

Finding 6 — Pathophysiology: loss of NADPH→GSH recycling impairs antioxidant defense, causing oxidant-triggered hemolysis and cataract

In erythrocytes, NADPH from the oxidative pentose phosphate pathway (PPP) is the principal reductant; GR uses it to regenerate GSH, which — via glutathione peroxidase and in parallel with catalase — detoxifies H2O2 and organic/lipid peroxides. When an enzyme deficiency limits NADPH/GSH supply, "distinct membrane alterations result causing a removal of the damaged cells by the monocyte-macrophage system" (PMID: 8813716). GR deficiency sits among the rare inborn RBC antioxidant defects: "NADPH is the main source of reduction equivalents in RBCs... When NADPH becomes limiting, red cells are prone to being damaged" (PMID: 24316370).

The cataract phenotype reflects a parallel mechanism in the lens: "human cataractous lenses showed decreased activities of glutathione reductase, glutathione peroxidase... superoxide dismutase" with GSH depletion and lipid peroxidation (PMID: 1737065).

Finding 7 — Management is supportive; the hereditary form is generally mild with favorable prognosis

No disease-specific pharmacotherapy exists. Because the hereditary form is riboflavin/FAD-unresponsive (PMID: 947404), management parallels other oxidant-triggered RBC enzymopathies such as G6PD deficiency: a "G6PD-deficient patient... lacks the ability to protect red blood cells against oxidative stresses from certain drugs, metabolic conditions, infections, and ingestion of fava beans" (PMID: 19769422) — the same oxidant-avoidance paradigm applies here. Prognosis is favorable because "the amount of reduced glutathione in the erythrocytes was normal in each case" (PMID: 947404) at baseline, explaining the absence of chronic hemolysis between oxidant challenges, consistent with thioredoxin-system compensation (PMID: 28686716).

Finding 8 — GSR is loss-of-function tolerant in gnomAD, predicting ~1 in 4 million biallelic births

gnomAD v4 constraint for GSR (ENSG00000104687, chr8:30,678,066–30,727,846, GRCh38) shows pLI ≈ 1.8×10⁻¹⁴ (completely LoF-tolerant), observed/expected LoF = 48/56.5 (oe_lof = 0.85, 90% CI 0.67–1.08), LoF Z = 0.96 — no depletion of truncating variants. Across 4,174 variants, 203 high-confidence predicted-LoF variants summed to an allele frequency ≈ 4.9×10⁻⁴, giving a heterozygous carrier frequency ≈ 0.10% (~1 in 1,000) and a predicted biallelic frequency (q²) ≈ 2.4×10⁻⁷ (~1 in 4 million). The two most common stop-gained alleles lie at the extreme 3′ end of the gene, likely truncating only terminal residues, so the true pathogenic-carrier rate is even lower — consistent with "only 2 cases when testing more than 15,000 blood samples" (PMID: 17185460).

Finding 9 — Thioredoxin backup for GSSG reduction is evolutionarily conserved, explaining the mild phenotype

The mildness of the phenotype is explained by a conserved alternative GSSG-reducing system. In Saccharomyces cerevisiae, cells lacking GLR1 (the GSSG-reductase ortholog) survive, and "the thioredoxin-thioredoxin reductase system can function as an alternative system" to reduce GSSG in vivo (PMID: 19951944). Overexpressing TRX1/TRX2 lowers GSSG; deleting them in glr1 cells raises it. Glr1 "has been shown to colocalize to the cytoplasm and mitochondria" (PMID: 15701801), relevant to compartment-specific redox roles. This mirrors mammalian data (mouse cochlea, PMID: 28686716). Orthologs: mouse Gsr (NCBI Gene 14782), S. cerevisiae GLR1 (YPL091W).

Finding 10 — Diagnosis rests on the erythrocyte GR assay (± FAD), EGRAC, and GSR sequencing

The diagnostic workup comprises: (1) a red-cell GR activity assay measuring NADPH-dependent GSSG reduction, performed with and without added FAD — hereditary deficiency is low and FAD-unresponsive, whereas acquired riboflavin deficiency normalizes; the EGRAC is "the functional biomarker... considered to be the gold standard index" of riboflavin status (PMID: 27170501); (2) protein detection by Western blot — "the GR protein was undetectable by Western blotting" in the enzyme-null family (PMID: 17185460); (3) molecular confirmation by GSR sequencing/deletion analysis; (4) functional glutathione-stability testing (acetylphenylhydrazine). In riboflavin-deficiency assessment, "samples with AC ≥ 1.3 were considered riboflavin-deficient" (PMID: 11924113). Differential diagnosis: G6PD deficiency and other hereditary non-spherocytic hemolytic anemias (glutathione synthesis defects, pyruvate kinase deficiency), distinguished by their specific enzyme assays.

Finding 11 — GSR is a top suppressor of ferroptosis — the disease biology in reverse

A genome-wide CRISPR-knockout screen identified that "glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis" and "GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance" (PMID: 42681644). This positions the GSH-regenerating function lost in the deficiency as an exploitable cancer vulnerability, and is consistent with the synthetic-lethal dependence of low-GSR cancers on the thioredoxin system.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic GSR loss-of-function mutation (2,246-bp deletion removing the dimerization domain; nonsense allele; Gly330Ala destabilizing missense) leads to absent or unstable GR protein (demonstrated: undetectable by Western blot; PMID: 17185460).
Loss of functional homodimeric GR results in inability to transfer electrons from NADPH via FAD to reduce GSSG → GSH (demonstrated enzymatically; PMID: 947404).
Impaired GSH regeneration leads to a diminished capacity to buffer acute oxidative loads, although baseline GSH remains normal because consumption is low at rest (demonstrated: normal resting GSH; PMID: 947404).
Branch A (erythrocyte): An exogenous oxidant challenge (fava bean divicine/isouramil, oxidant drugs, infection) results in accumulation of H2O2/organic peroxides that GSH-dependent peroxidases cannot clear → oxidation of hemoglobin and membrane proteins → membrane alterations → macrophage removal of damaged cells → acute hemolytic anemia (PMID: 8813716; PMID: 24316370).
Branch B (neonatal): The oxidative lability of neonatal red cells results in hemolysis-driven neonatal jaundice/hyperbilirubinemia (PMID: 17185460).
Branch C (lens): Chronic failure of lens GSH-dependent peroxide detoxification leads to lipid peroxidation and protein oxidation → cataract (inferred by analogy to cataractous-lens enzyme profiles; PMID: 1737065).
Compensation (dampening node): In parallel, the thioredoxin/thioredoxin-reductase system reduces GSSG and limits oxidative damage, resulting in a phenotype that is episodic rather than chronic (demonstrated in yeast and mouse; PMID: 19951944; PMID: 28686716).

   GSR biallelic LoF mutation
    │
    ▼
   Absent / unstable GR protein
    │
    ▼
   No NADPH→FAD→GSSG electron transfer  ──┐
    │                             │  (parallel)
    ▼                             ▼
   GSH not regenerated            Trx/TrxR system reduces GSSG
    │                             │  (partial compensation
   + OXIDANT TRIGGER                      │   → mild, episodic phenotype)
   (fava bean, drug, infection)          │
    │ ───────────────────────────┘
   ┌────────┼─────────────┐
   ▼        ▼             ▼
 RBC      Neonatal      Lens
 hemolysis jaundice     cataract

Upstream vs downstream: The mutation and loss of enzyme activity are upstream; oxidant-triggered peroxide accumulation is the central node; tissue-specific damage (hemolysis, jaundice, cataract) is downstream. The Trx/TrxR system is a lateral, upstream-acting buffer that sets the overall mildness.

Cell types (CL) and anatomy (UBERON): erythrocyte (CL:0000232), neutrophil (CL:0000775), lens fiber cell (CL:0011004); blood (UBERON:0000178), lens of camera-type eye (UBERON:0000965), liver (UBERON:0002107, secondary via bilirubin handling). Subcellular (GO CC): cytosol (GO:0005829), mitochondrion (GO:0005739) — GR has both cytosolic and mitochondrial isoforms from the single gene.

Evidence Base

PMID	Title (abbrev.)	Evidence type	How it supports the findings
17185460	Molecular basis of GR deficiency in human blood cells	Human clinical/molecular	Defines causal LoF variants, rarity (2/>15,000), absent protein — anchors Findings 1, 2, 5, 8, 10
947404	Familial deficiency of GR in human blood cells	Human clinical	Establishes AR inheritance, favism/cataract phenotype, FAD/riboflavin non-responsiveness, normal baseline GSH — Findings 1, 2, 3, 6, 7
11924113	GR deficiency in Saudi Arabia	Human epidemiology	Quantifies acquired riboflavin-responsive form and absence of hereditary cases — Findings 3, 10
18638483	Catalytic cycle of human GR near 1 Å	Structural/in vitro	Defines the FAD/NADPH catalytic mechanism — Finding 5
22279102	GR facilitates host defense / oxidative burst / NETs	Mouse model	Neutrophil host-defense role, transient burst defect — Finding 4
28686716	GSR not essential in mouse cochlea; Trx backup	Mouse model	Thioredoxin compensation for GSR loss — Findings 4, 7, 9
8813716	Hemolytic anemias due to RBC enzyme deficiencies	Review	Mechanistic link from redox-enzyme deficiency to hemolysis — Findings 6, 10
24316370	Inborn defects in antioxidant systems of RBCs	Review	NADPH as main RBC reductant; GR deficiency context — Finding 6
1737065	Peroxide-metabolizing systems of the lens	Human/in vitro	Links reduced GR + oxidative stress to cataract — Finding 6
19769422	Perioperative management of G6PD-deficient patient	Review	Oxidant-avoidance management paradigm — Finding 7
27170501	Riboflavin status, MTHFR, blood pressure	Review	EGRAC as gold-standard functional assay — Finding 10
19951944	Trx-TrxR as alternative GSSG-reducing system in yeast	Model organism	Conserved thioredoxin backup — Finding 9
15701801	Overlapping cytoplasmic/mitochondrial redox systems in yeast	Model organism	Dual localization of GSR ortholog — Finding 9
42681644	GR deficiency potentiates ferroptosis/cuproptosis immunogenicity	In vitro/CRISPR	GSR as top ferroptosis suppressor — Finding 11
35361806	In silico analysis of deleterious GSR SNPs	Computational	Confirms disease definition; flags candidate deleterious nsSNPs
16528753	8 Mb interstitial 8p12-p21.2 deletion	Human clinical	Confirms GSR chromosomal location within a contiguous-gene region

Section-by-section factual summary

1. Disease information. MONDO:0019531; OMIM 618660; gene GSR (HGNC:4623). Synonyms: hereditary glutathione reductase deficiency, GR deficiency, GSR deficiency, hemolytic anemia due to glutathione reductase deficiency. MeSH concept: Glutathione Reductase/deficiency. Information is derived from a handful of aggregated case reports/families plus population screens — not from large EHR cohorts.

2. Etiology. Primary cause is genetic (biallelic GSR LoF). The sole well-established environmental/trigger factor is oxidative stress (fava bean ingestion — divicine/isouramil, oxidant drugs, infection). Consanguinity is a risk factor (Loos family). No protective genetic alleles are established; the thioredoxin system acts as an endogenous compensatory buffer rather than a protective "allele." Gene–environment interaction is the defining feature: the genotype is clinically silent until an oxidant exposure precipitates hemolysis.

3. Phenotypes. Hemolytic anemia (episodic, oxidant-triggered; HP:0001878), cataract (HP:0000518), neonatal jaundice (HP:0006579). Onset ranges from neonatal (jaundice) to childhood/adult (favism, cataract). Severity is mild-to-moderate and episodic rather than progressive. Frequencies cannot be given as robust percentages owing to the tiny number of described patients.

4. Genetic/molecular. Causal gene GSR (8p12). Variant types observed: large deletion (2,246 bp, LoF), nonsense (premature stop), missense (Gly330Ala, destabilizing). Functional consequence: loss of function via protein instability/loss of dimerization. gnomAD: LoF-tolerant (pLI≈0). No established modifier genes in humans, though the Trx system is the principal functional modifier. No intrinsic epigenetic or chromosomal-abnormality mechanism, though GSR can be deleted within contiguous-gene 8p deletions (PMID: 16528753).

5. Environmental. Oxidant triggers (fava beans/divicine, oxidant drugs, infection). No infectious agent causes the disease.

6. Mechanism. See the causal chain and diagram above.

7. Anatomical structures. Primary: blood/erythrocytes (UBERON:0000178, CL:0000232); lens (UBERON:0000965). Secondary: liver (bilirubin handling); neutrophils (CL:0000775, host-defense — subclinical in humans). Subcellular: cytosol and mitochondria.

8. Temporal development. Onset neonatal to adult; course chronic-lifelong at the genetic level but clinically episodic/trigger-dependent; non-progressive between crises.

9. Inheritance and population. Autosomal recessive; predicted biallelic frequency ~1 in 4 million (gnomAD); carrier frequency ~0.1% upper bound. Complete penetrance of the biochemical deficiency; clinical expressivity variable and trigger-dependent. Consanguinity increases risk. No established sex predilection or founder population.

10. Diagnostics. Erythrocyte GR assay ±FAD; EGRAC; Western blot; GSR sequencing/deletion analysis; acetylphenylhydrazine glutathione-stability test. Differential: G6PD deficiency, other RBC enzymopathies.

11. Prognosis. Favorable; survival to adulthood; episodic hemolysis without chronic anemia; normal baseline GSH.

12. Treatment. Supportive only: oxidant-trigger avoidance; transfusion in crises; phototherapy/exchange transfusion for neonatal jaundice as per standard neonatology. Riboflavin ineffective for the hereditary form. NCIT suggestions: Blood Transfusion (NCIT:C15360), Supportive Care (NCIT:C15277), Phototherapy (NCIT:C15349).

13. Prevention. Genetic counseling for consanguineous/carrier families; trigger avoidance (tertiary prevention). No population screening is warranted given rarity.

14. Other species / natural disease. Gsr-null mice (NCBI Gene 14782) are viable with host-defense and lung-development phenotypes; S. cerevisiae glr1Δ (YPL091W) is a standard antioxidant-deficient model. No prominent naturally occurring companion-animal disease is catalogued.

15. Model organisms. Mouse Gsr knockout (host defense, hyperoxic lung responses), yeast glr1Δ (oxidative-stress sensitivity, thioredoxin compensation). These models recapitulate the biochemical defect and the thioredoxin-buffering principle but do not fully reproduce the human favism-hemolysis phenotype, because mouse/yeast oxidative challenges differ from human fava-bean exposure.

Limitations and Knowledge Gaps

Extremely small patient base. The entire human literature on the hereditary disease rests on a handful of families. Frequencies, penetrance, and genotype–phenotype correlations cannot be estimated with statistical confidence.
Cataract causality is inferential. The lens mechanism is supported by analogy to cataractous-lens enzyme profiles (PMID: 1737065) rather than by direct study of GSR-null lenses.
No natural-history or registry data. There are no longitudinal cohorts, QoL instruments, or mortality statistics specific to this disorder.
gnomAD estimate is a model. The ~1-in-4-million figure assumes LoF-variant pathogenicity; several common "LoF" alleles are 3′-terminal and likely benign, so the estimate is an upper bound on biallelic frequency and a lower bound on rarity.
Human immune phenotype unquantified. The neutrophil host-defense role is robust in mice but not demonstrated to cause clinical immunodeficiency in humans.
No pharmacogenomic or targeted-therapy data exist for the deficiency itself.

Proposed Follow-up Experiments / Actions

GeneMatcher / undiagnosed-disease network query to assemble additional biallelic GSR cases and build a minimal natural-history series.
Functional variant characterization: recombinant expression and thermostability/activity assays of GSR missense variants (e.g., Gly330Ala) to establish an ACMG-aligned functional-evidence pipeline (PS3) for VUS classification.
Patient-derived iPSC erythroid and lens-epithelial models to directly test oxidant-challenge hemolysis and cataractogenesis, and to quantify thioredoxin-system compensation (TXN/TXNRD1 knockdown rescue experiments).
ClinVar curation: deposit/annotate the known pathogenic alleles (2,246-bp deletion, nonsense, Gly330Ala) with supporting PMIDs to improve diagnostic interpretation.
Targeted re-analysis of hemolytic-anemia gene panels (including GSR) in unexplained G6PD-normal non-spherocytic hemolytic anemia and favism-like presentations.
Therapeutic hypothesis test: evaluate whether boosting the thioredoxin arm (or avoiding thioredoxin-reductase inhibitors such as auranofin-class drugs) modulates oxidative susceptibility in GSR-deficient models — a direct translation of the compensation finding.

Consensus Answer

Glutathione Reductase Deficiency (MONDO:0019531) is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in GSR (chromosome 8p12), the gene encoding the FAD/NADPH-dependent flavoenzyme that regenerates reduced glutathione (GSH) from GSSG; its loss cripples erythrocyte and lens antioxidant defense and produces oxidant-triggered (favism) hemolytic anemia, neonatal jaundice, and cataracts. The phenotype is usually mild and episodic because the evolutionarily conserved thioredoxin/thioredoxin-reductase system partially compensates — consistent with GSR being genetically loss-of-function-tolerant (gnomAD pLI≈0; predicted biallelic frequency ≈1 in 4 million) and with viable Gsr-knockout mice and glr1Δ yeast. This rare hereditary enzyme-null disease must be distinguished from the common acquired riboflavin-responsive deficiency (discriminated by the EGRAC), and management is limited to oxidant-trigger avoidance and supportive transfusion, since riboflavin corrects only the acquired form.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	18
Quoted claims found in source	17
Quoted claims not found in source	1
References weighed for topical relevance	16
On topic	10
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:11924113 (abstract only): "samples with AC ≥ 1.3 were considered riboflavin-deficient"
closest text in source: "Samples with AC > or = 1.3 were considered riboflavin-deficient"

Term Validation

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Outcome	Count
Terms checked	27
Resolved	26
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1

26 of 27 terms resolved to a current term; the rest could not be looked up either way.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Glutathione Reductase Deficiency: A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — Hereditary GR deficiency is an ultra-rare autosomal recessive disorder caused by biallelic GSR loss-of-function mutations

Finding 2 — Clinical phenotype: favism-triggered hemolysis, cataracts, and neonatal jaundice

Finding 3 — Two distinct forms: common acquired (riboflavin-responsive) vs. rare irreversible hereditary

Finding 4 — GSR supports neutrophil host defense (model organisms)

Finding 5 — GSR is a homodimeric FAD/NADPH-disulfide oxidoreductase with a defined catalytic cycle

Finding 6 — Pathophysiology: loss of NADPH→GSH recycling impairs antioxidant defense, causing oxidant-triggered hemolysis and cataract

Finding 7 — Management is supportive; the hereditary form is generally mild with favorable prognosis

Finding 8 — GSR is loss-of-function tolerant in gnomAD, predicting ~1 in 4 million biallelic births

Finding 9 — Thioredoxin backup for GSSG reduction is evolutionarily conserved, explaining the mild phenotype

Finding 10 — Diagnosis rests on the erythrocyte GR assay (± FAD), EGRAC, and GSR sequencing

Finding 11 — GSR is a top suppressor of ferroptosis — the disease biology in reverse

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Evidence Base

Section-by-section factual summary

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Consensus Answer

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