Gamma-glutamyl Transpeptidase Deficiency

Mendelian MONDO:0009285 Pathograph 20 Show in embeddings browser Inherited Glutathione Metabolism Disease Inborn Error of Metabolism

Gamma-glutamyl transpeptidase (GGT) deficiency, or glutathionuria, is an ultra-rare autosomal recessive inborn error of the gamma-glutamyl cycle in which the extracellular, membrane-anchored enzyme that begins glutathione breakdown is missing. GGT1 hydrolyses or transfers the gamma-glutamyl moiety of glutathione and its S-conjugates at the outer face of the plasma membrane, most abundantly on the brush border of the renal proximal tubule. Without it, glutathione filtered at the glomerulus and exported by tissues cannot be broken down, so it accumulates in plasma and is excreted in urine in gram quantities, together with gamma-glutamylcysteine and cysteine. The same block prevents conversion of leukotriene C4 to leukotriene D4. Diagnosis is biochemical (glutathionuria with very low serum or leukocyte GGT activity); a causal GGT1 variant has been identified in only one family, a homozygous 16.9 kb intragenic deletion. The clinical picture is uncertain. Most of the handful of reported patients were identified because of intellectual disability, developmental delay or behavioural problems, so the reported neurological involvement is subject to strong ascertainment bias, and expert review states that whether it belongs to the disease remains to be established. Glutathione-deficient mouse models are far more severe than any reported patient, and human cellular glutathione is reported to be normal.

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1
Inheritance
6
Pathophys.
7
Phenotypes
2
Gaps
20
Pathograph
1
Genes
1
Variants
2
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Affected siblings in the molecularly confirmed family are homozygous for the GGT1 deletion, with heterozygous parents and an unaffected sibling; earlier, carrier parents were inferred from low fibroblast enzyme activity.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:29483667 SUPPORT Human Clinical
"genetic characterization of the patients' parents and a healthy sibling has provided direct genetic evidence regarding the autosomal recessive nature of this disease"
Segregation of the deletion in the family establishes autosomal recessive inheritance.
PMID:6118466 SUPPORT Human Clinical
"An autosomal recessive mode of inheritance is suggested."
Early biochemical family study proposing autosomal recessive inheritance.
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Discussions and Knowledge Gaps

2
Is intellectual disability or other neurological involvement part of gamma-glutamyl transpeptidase deficiency, or an artefact of how the few known patients were found?
KNOWLEDGE GAP OPEN ggt_deficiency_neurological_attribution
Attached to
pathophysiology#Neurodevelopmental and behavioural involvement of uncertain attribution
The disorder is detected only by measuring glutathione, which routine metabolic screening does not do, and the reported patients were largely identified during investigation of intellectual disability or behavioural problems. Five of seven reported patients had central nervous system involvement, but the patients ascertained through a neurological problem cannot show whether the deficiency causes it. The genetically confirmed siblings are only mildly affected, the 2007 review states that whether the symptoms are part of the disease remains to be established, and no mechanism linking extracellular glutathione catabolism to brain function in patients has been shown. Genotype-first ascertainment (homozygous GGT1 loss-of-function in population or newborn sequencing cohorts, or urinary glutathione in an unselected population) would answer it.
Proposed experiments
Genotype-first phenotyping of biallelic GGT1 loss-of-function carriers
exp_ggt1_genotype_first
Identify individuals with biallelic GGT1 loss-of-function variants or deletions in large sequencing cohorts without selecting on neurological status, confirm glutathionuria biochemically, and compare their neurodevelopmental outcomes with matched controls.
Would support
pathophysiology#Neurodevelopmental and behavioural involvement of uncertain attribution
Why do GGT1-deficient mice develop tissue glutathione depletion, growth failure, cataracts and infertility, while patients reportedly have normal cellular glutathione and none of those features?
HUMAN MODEL MISMATCH OPEN ggt_deficiency_mouse_human_mismatch
Attached to
pathophysiology#Systemic cysteine and glutathione salvage failure
The mouse models establish that urinary glutathione loss can deplete tissue glutathione and that cysteine prodrugs rescue the result, but the human disorder shows the biochemical signature without that phenotype. The salvage-failure node is therefore supported in mice and contradicted for humans. Whether the difference reflects cysteine supply, compensation by other GGT family members, or incomplete clinical assessment of the few patients is unknown.
Proposed experiments
Tissue and plasma cysteine and glutathione measurement in GGT1-deficient patients
exp_ggt1_human_tissue_glutathione
Measure plasma cysteine, leukocyte and fibroblast glutathione, and whole-body cysteine balance in molecularly confirmed patients, to test whether the mouse salvage-failure mechanism operates in humans.
Would support
pathophysiology#Systemic cysteine and glutathione salvage failure
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Pathophysiology

6
Loss of GGT1 glutathione hydrolase activity
GGT1 is an extracellular, plasma-membrane-anchored enzyme that hydrolyses or transfers the gamma-glutamyl moiety of glutathione and other gamma-glutamyl compounds; it catalyses the first step of glutathione degradation. In the one molecularly characterised family a homozygous 16.9 kb intragenic GGT1 deletion abolishes it. Activity in affected individuals is very low or below detection in serum, but is not completely absent in all patients studied, consistent with contributions from other members of the GGT gene family.
GGT1 hgnc:4250 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GGT1 (hgnc:4250). hgnc:4250 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous 16.9 kb intragenic deletion of GGT1 with a 13 bp insertion at the junction, in the only family with a molecular diagnosis.
glutathione hydrolase activity GO:0036374 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glutathione hydrolase activity, annotated with glutathione gamma-glutamate hydrolase (GO:0036374). GO:0036374 is a molecular function from the Gene Ontology. leukotriene C4 hydrolase activity GO:0002951 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased leukotriene C4 hydrolase activity, annotated with leukotriene-C(4) hydrolase activity (GO:0002951). GO:0002951 is a molecular function from the Gene Ontology.
Animal models
Ggt1 dwg mouse Mouse recapitulates A Ggt1 loss-of-function allele with severely reduced enzyme activity.
Downstream
Reduced serum gamma-glutamyltransferase Serum GGT activity is the circulating readout of the absent enzyme.
Impaired extracellular glutathione catabolism GGT1 catalyses the first and committing step of extracellular glutathione breakdown, so its loss halts glutathione degradation at the cell surface.
Defective conversion of leukotriene C4 to leukotriene D4 Leukotriene C4 is a glutathione S-conjugate whose gamma-glutamyl residue is removed by GGT to form leukotriene D4.
Show evidence (3 references)
PMID:18357469 SUPPORT REVIEW SYNTHESIS Other
"The well-characterized GGT1 is an extracellular enzyme that is anchored to the plasma membrane of cells. There, it hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors."
Defines the location and catalytic activity of GGT1.
PMID:29483667 SUPPORT Human Clinical
"Whole-genome sequencing revealed the presence of a 16.9 kb homozygous deletion in GGT1, one of the genes encoding enzymes with γ-glutamyl transpeptidase activity in the human genome."
Identifies the causal GGT1 lesion in affected siblings.
PMID:6114489 SUPPORT Human Clinical
"gamma-glutamyl transpeptidase activity is not completely absent in a patient found to have a deficiency of this enzyme"
Documents residual activity in a deficient patient, supporting the description of very low rather than uniformly absent activity.
Impaired extracellular glutathione catabolism
Glutathione is exported from cells and filtered at the glomerulus, and is normally degraded at the luminal brush border of the renal proximal tubule, where GGT is concentrated. Without GGT, filtered and circulating glutathione cannot be broken down for recovery of its constituent amino acids. Older work proposed that the gamma-glutamyl cycle mediates amino-acid transport, but GGT-deficient patients have normal plasma amino acids and renal amino-acid reabsorption, and the extracellular hydrolysis of glutathione is now regarded as the enzyme's physiological role.
epithelial cell of proximal tubule CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
glutathione catabolic process GO:0006751 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutathione catabolic process (GO:0006751). GO:0006751 is a biological process from the Gene Ontology.
proximal tubule UBERON:0004134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in proximal tubule (UBERON:0004134). UBERON:0004134 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Glutathione accumulation in plasma and urine Undegraded glutathione accumulates in plasma and is lost in the urine, largely from the kidney.
Systemic cysteine and glutathione salvage failure Glutathione lost intact in the urine is not degraded and its cysteine is not recovered. In mice this chronic loss depletes tissue glutathione.
Neurodevelopmental and behavioural involvement of uncertain attribution Proposed, not established. Intellectual disability, developmental delay or behavioural problems are reported in most known patients, but these patients were largely found by metabolic screening of people who already had neurological problems, and no mechanism connecting extracellular glutathione catabolism to brain function in this disorder has been shown. The edge is kept so the reported phenotypes are attached to the graph, with its uncertainty stated here and in the knowledge-gap discussion.
Show evidence (3 references)
PMID:42531 SUPPORT Model Organism
"Within the kidney, the enzyme is primarily associated with the luminal surface of the brush border membrane of the proximal straight tubule."
Localises renal GGT to the proximal tubule brush border in the rat.
PMID:42531 SUPPORT REVIEW SYNTHESIS Other
"It now appears that the activities attributed to the gamma-glutamyl cycle do not participate in amino acid transport, but instead constitute three separate metabolic pathways; the intracellular synthesis of glutathione, the intracellular degradation of gamma-glutamyl peptides and the..."
Synthesises the evidence that GGT's role is extracellular glutathione hydrolysis rather than amino-acid transport.
PMID:6118466 SUPPORT INDIRECT Human Clinical
"As in the only other case described in detail, plasma levels and renal reabsorption of the amino acids were normal."
Two deficient patients had normal plasma amino acids and renal amino-acid reabsorption despite absent GGT. That is consistent with the enzyme's physiological role being extracellular glutathione hydrolysis rather than amino-acid transport, which is the role this node describes; the support is by inference, hence INDIRECT.
Glutathione accumulation in plasma and urine
The defining and constant biochemical abnormality. Urinary glutathione reaches up to 1 g per day against under 10 mg in controls, plasma glutathione is raised, and urine and plasma also contain excess gamma-glutamylcysteine, cysteine and cysteinylglycine.
Animal models
Ggt1 enu1 glutathionuric mouse Mouse recapitulates Reproduces the glutathionemia and glutathionuria that define the human disorder.
Downstream
Glutathionuria
Glutathionemia
Show evidence (3 references)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"All patients have had glutathionuria (up to 1 g/day"
Glutathionuria is universal among reported patients and quantified.
PMID:15702405 SUPPORT Human Clinical
"The analyses of sulphydryl compounds in the plasma (and serum for certain test items) and urine indicated high concentrations of glutathione, gamma-glutamylcysteine, cysteine and cysteinylglycine."
Documents the full set of accumulating thiol compounds in plasma and urine.
PMID:6106190 SUPPORT Human Clinical
"a patient with severe gamma-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, gamma-glutamylcysteine, and cysteine in their urine"
Urinary excretion of glutathione, gamma-glutamylcysteine and cysteine in a deficient patient.
Systemic cysteine and glutathione salvage failure
In GGT-deficient mice, chronic urinary loss of glutathione deprives tissues of the cysteine normally recovered from extracellular glutathione, and liver and lens glutathione fall; cysteine-prodrug supplementation reverses the mouse phenotype. This node is supported in mice only. In patients, cellular glutathione is reported to be normal, and no human counterpart of the mouse growth failure, cataract or infertility has been reported, so the node is recorded with contradicting human evidence rather than as an established human mechanism.
Animal models
Ggt1 enu1 glutathionuric mouse Mouse perturbs Shows tissue glutathione depletion from chronic urinary loss, and its reversal by a cysteine prodrug.
Ggt1 dwg mouse Mouse perturbs Shows raised plasma and kidney glutathione with depleted eye and liver glutathione, reversible with N-acetylcysteine.
Show evidence (3 references)
PMID:9139708 SUPPORT Model Organism
"Total glutathione concentration was increased in both blood and urine but decreased in liver homogenates from affected mice."
Shows the combination of extracellular glutathione excess and tissue depletion in a GGT-deficient mouse.
PMID:12757858 SUPPORT Model Organism
"Tissue GSH deficiency is the proximate cause of the phenotypic abnormalities associated with murine gamma-GT deficiency."
Identifies tissue glutathione deficiency as the cause of the mouse phenotype.
PMID:17397529 REFUTE REVIEW SYNTHESIS Other
"Cellular levels of glu- tathione are normal."
For human patients the review states cellular glutathione is normal, which contradicts transferring the mouse tissue-depletion mechanism to the human disease. The snippet reproduces the line-break hyphenation of the cached PDF-derived text.
Defective conversion of leukotriene C4 to leukotriene D4
Patients cannot form leukotriene D4 or E4 from leukotriene C4: urinary leukotriene C4 is markedly raised and leukotriene E4 is undetectable, and stimulated monocytes make no leukotriene D4. Whether this has any clinical consequence is unknown; no phenotype has been attributed to it.
leukotriene D4 biosynthetic process GO:1901750 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased leukotriene D4 biosynthetic process (GO:1901750). GO:1901750 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:14754911 SUPPORT Human Clinical
"Our data demonstrate a complete deficiency of LTD(4) biosynthesis in patients with a genetic deficiency of GGT."
Shows complete loss of leukotriene D4 synthesis in three patients.
PMID:18357469 SUPPORT REVIEW SYNTHESIS Other
"These patients do secrete glutathione in urine and fail to metabolize LTC4."
Summarises the dual glutathione and leukotriene C4 defect in patients.
Neurodevelopmental and behavioural involvement of uncertain attribution
Five of the seven patients counted in a 2007 review had central nervous system involvement (intellectual disability, developmental delay, behavioural problems), and the two genetically confirmed siblings have mild psychomotor delay and mild neurological symptoms. This figure is strongly shaped by ascertainment: the disorder is found by measuring glutathione, which is not part of routine screening, and the early patients were found during metabolic investigation of intellectual disability. No genotype-first or otherwise unselected series exists, so there is no way yet to tell how often a deficient individual is neurologically normal. The review authors state that whether the neurological symptoms are part of the disease remains to be established.
Downstream
Intellectual disability
Global developmental delay
Atypical behavior
Show evidence (2 references)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"Whether these symptoms are part of the clinical picture remains to be established."
The review's statement, immediately after counting CNS involvement in five of seven reported patients, that attributing those symptoms to the disorder is unresolved.
PMID:29483667 SUPPORT Human Clinical
"We report two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum."
Neurological findings in the genetically confirmed siblings are mild.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Gamma-glutamyl Transpeptidase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Genitourinary 1
Glutathionuria VERY_FREQUENT HP:0034586 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glutathionuria (HP:0034586). HP:0034586 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"All patients have had glutathionuria (up to 1 g/day"
Universal and quantified glutathionuria.
PMID:29483667 SUPPORT Human Clinical
"presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum"
Glutathionuria in the genetically confirmed siblings.
Metabolism 2
Glutathionemia VERY_FREQUENT Elevated circulating glutathione concentration HP:0034456 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glutathionemia, annotated with Elevated circulating glutathione concentration (HP:0034456). HP:0034456 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15702405 SUPPORT Human Clinical
"Glutathionaemia and glutathionuria were evident in both brothers."
Raised circulating glutathione in both affected brothers.
PMID:9679548 SUPPORT REVIEW SYNTHESIS Other
"gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria"
Review names glutathionemia as a feature of the disorder.
Reduced serum gamma-glutamyltransferase VERY_FREQUENT Reduced gamma-glutamyltransferase level HP:0034445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced gamma-glutamyltransferase level (HP:0034445). HP:0034445 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15702405 SUPPORT Human Clinical
"gamma-Glutamyltranspeptidase activity was below the detection limit of 1 IU/L in both patients."
Undetectable serum GGT in two patients.
Nervous System 3
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:6118466 SUPPORT Human Clinical
"A mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency."
Intellectual disability in a biochemically confirmed patient.
PMID:15702405 SUPPORT Human Clinical
"Both patients both showed a tendency to retarded mental development."
Mild intellectual impairment in two adult brothers.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29483667 SUPPORT Human Clinical
"We report two siblings with mild psychomotor developmental delay and mild neurological symptoms"
Mild developmental delay in the GGT1-deletion siblings.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioural problems, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6118466 SUPPORT Human Clinical
"A mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency."
Behavioural problems in a deficient patient.
Growth 1
Tall slender habitus with long limbs Disproportionate tall stature HP:0001519 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Marfanoid habitus, annotated with Disproportionate tall stature (HP:0001519). HP:0001519 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15702405 SUPPORT Human Clinical
"The brothers were both tall and slender and had long limbs; the younger was diagnosed as having Marfan syndrome."
Habitus reported in one family, with a concurrent Marfan syndrome diagnosis.
🧬

Genetic Associations

1
GGT1
Gene: GGT1 hgnc:4250 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GGT1 (hgnc:4250). hgnc:4250 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:29483667 SUPPORT Human Clinical
"This is the first report of a genetic variant as the cause of glutathionuria."
First and only published genetic cause of the disorder.
PMID:18357469 SUPPORT REVIEW SYNTHESIS Other
"GGT deficiency in man is rare and for the few patients reported to date, mutations in GGT1 have not been described."
Records that the earlier, biochemically diagnosed patients had no molecular diagnosis, which is why gene-level evidence rests on one family.
Variants (1)
Homozygous 16.9 kb intragenic GGT1 deletion
A 16.9 kb homozygous deletion within GGT1 with a 13 bp insertion at the deletion junction, found by whole-genome sequencing in two affected siblings.
Show evidence (1 reference)
PMID:29483667 SUPPORT Human Clinical
"Close analysis revealed the presence of a 13 bp insertion at the deletion junction."
Characterises the deletion junction.
🔬

Biochemical Markers

4
Increased urinary glutathione (INCREASED)
Context: The diagnostic finding. Measured by chromatographic methods; it is not detected by routine amino-acid screening, which is a main reason the disorder is thought to be underdiagnosed.
Pathograph Readouts
Readout Of Glutathione accumulation in plasma and urine Positive Diagnostic
Urinary glutathione directly reports the failure of extracellular glutathione degradation.
Show evidence (1 reference)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"All patients have had glutathionuria (up to 1 g/day"
Quantifies the urinary glutathione excess.
Increased urinary gamma-glutamylcysteine and cysteine (INCREASED)
Context: Gamma-glutamylcysteine and cysteine are excreted in excess together with glutathione, largely as disulfides.
Pathograph Readouts
Readout Of Glutathione accumulation in plasma and urine Positive Diagnostic
Accompanying gamma-glutamyl and thiol excretion reflects the same catabolic block.
Show evidence (1 reference)
PMID:6106190 SUPPORT Human Clinical
"a patient with severe gamma-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, gamma-glutamylcysteine, and cysteine in their urine"
Documents excess urinary gamma-glutamylcysteine and cysteine.
Increased urinary leukotriene C4 with absent leukotriene E4 (INCREASED)
Context: Urinary leukotriene C4 is raised by several orders of magnitude and leukotriene E4 is undetectable, reflecting the block in cysteinyl leukotriene processing.
Pathograph Readouts
Readout Of Defective conversion of leukotriene C4 to leukotriene D4 Positive Diagnostic
Accumulated leukotriene C4 with absent downstream metabolites reports the GGT-dependent step.
Show evidence (1 reference)
PMID:14754911 SUPPORT Human Clinical
"Analysis of LTs in urine revealed increased concentrations of LTC(4) (12.8-17.9 nmol/mol creatinine; controls, <0.005 nmol/mol creatinine), whereas LTE(4) was below the detection limit"
Quantifies urinary leukotriene C4 excess and absent leukotriene E4.
Reduced gamma-glutamyl transpeptidase activity in nucleated cells (DECREASED)
Context: Confirmatory enzyme assay is done in leukocytes or cultured fibroblasts, because erythrocytes contain an incomplete gamma-glutamyl cycle and lack the enzyme normally.
Pathograph Readouts
Readout Of Loss of GGT1 glutathione hydrolase activity Negative Diagnostic
Measured enzyme activity is the direct readout of the GGT1 lesion.
Show evidence (2 references)
PMID:9679548 SUPPORT REVIEW SYNTHESIS Other
"erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts"
Specifies the cell types in which the enzyme must be assayed.
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"Low activity of γ-glutamyl transpeptidase in nucleated cells such as leukocytes or cultured skin fibroblasts."
States the diagnostic enzyme finding and the cell types in which it is measured.
🔬

Diagnosis

1
Biochemical diagnosis of GGT deficiency
Diagnosis rests on two findings: low GGT activity in nucleated cells (leukocytes or cultured skin fibroblasts; erythrocytes cannot be used because they lack the enzyme normally), and high plasma and urinary glutathione. Glutathione is not detected by routine amino-acid screening and must be measured specifically. GGT1 testing can confirm the diagnosis, but only one causal variant has been published.
Show evidence (2 references)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"Low activity of γ-glutamyl transpeptidase in nucleated cells such as leukocytes or cultured skin fibroblasts."
First diagnostic criterion listed by the review.
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"High levels of glutathione in plasma and urine (up to 1 g/day in urine; controls < 10 mg)."
Second diagnostic criterion, with the magnitude of urinary glutathione against controls.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Fewer than ten patients reported. Both counting sources note the disorder is probably underdiagnosed because glutathione is not measured in routine metabolic screening, so the case count is a floor rather than an estimate of occurrence.
Show evidence (2 references)
PMID:17397529 SUPPORT REVIEW SYNTHESIS Other
"Gamma-glutamyl transpeptidase deficiency is a very rare disease, which has been reported in seven patients in five families worldwide"
Review count of reported patients and families.
PMID:29483667 SUPPORT BACKGROUND Human Clinical
"with only six patients reported in the literature, although this condition has probably been underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples"
Gives the prior case count and states that the disorder is probably underdiagnosed, which is why no prevalence figure is asserted.
🐁

Animal Models

2
Ggt1 enu1 glutathionuric mouse
ENU-induced GGT-deficient mouse found by screening for aminoacidurias. Its phenotype (growth failure, lethargy, cataracts, infertility, shortened life span) is far more severe than anything reported in patients.
Species
Mouse
Genotype
Ggt1(enu1/enu1)
Publication
PMID:9139708
Pathograph links
Glutathione accumulation in plasma and urine recapitulates fidelity: high observes: organism Reproduces the glutathionemia and glutathionuria that define the human disorder.
Show evidence (1 reference)
PMID:9139708 SUPPORT Model Organism
"Total glutathione concentration was increased in both blood and urine but decreased in liver homogenates from affected mice."
Blood and urine glutathione excess mirrors the human biochemistry.
Systemic cysteine and glutathione salvage failure perturbs fidelity: low observes: organism Shows tissue glutathione depletion from chronic urinary loss, and its reversal by a cysteine prodrug.
Limitations: Human patients are reported to have normal cellular glutathione and none has the mouse growth failure, cataracts or infertility, so the mouse tissue-depletion mechanism may not operate, or not to the same degree, in humans.
Divergences from the human mechanism
species mismatch qualifying
The mouse loses enough cysteine through glutathionuria to deplete liver and lens glutathione, whereas cellular glutathione is reported normal in patients; differences in dietary cysteine supply or in compensating GGT family members between species are possible explanations that have not been tested.
Readouts
Growth and behaviour after cysteine-prodrug supplementation
Direction: RESTORED
Interpretation: Rescue by a cysteine prodrug supports cysteine/glutathione deprivation as the cause of the mouse phenotype.
Show evidence (1 reference)
PMID:12757858 SUPPORT Model Organism
"The growth, physical appearance, and behavior of gamma-GT-deficient mice were substantially improved following OTZ supplementation."
Reports phenotypic rescue by OTZ.
Show evidence (1 reference)
PMID:12757858 SUPPORT Model Organism
"Total liver glutathione (GSH) content is significantly reduced in gamma-GT-deficient mice due to chronic excessive GSH loss."
Supports the model as informative for the salvage-failure node in mice.
Show evidence (1 reference)
PMID:9139708 SUPPORT Model Organism
"Glutathionuric mice exhibited lethargy, severe growth failure, shortened life spans and infertility."
Mouse phenotype, which exceeds anything reported in humans.
Ggt1 dwg mouse
Spontaneous Ggt1 mutant (13 nt exon 7 deletion) with dwarfism, cataract and coat colour change but normal survival; residual GGT1 activity about 4% of wild type.
Species
Mouse
Genotype
Ggt1(dwg/dwg)
Publication
PMID:23615310
Pathograph links
Loss of GGT1 glutathione hydrolase activity recapitulates fidelity: moderate observes: molecular A Ggt1 loss-of-function allele with severely reduced enzyme activity.
Show evidence (1 reference)
PMID:23615310 SUPPORT Model Organism
"GGT1 activity in the Ggt1(dwg/dwg) mice was reduced to approximately 4.0% of that in the wild-type mice."
Quantifies residual activity in the model.
Systemic cysteine and glutathione salvage failure perturbs fidelity: low observes: organism Shows raised plasma and kidney glutathione with depleted eye and liver glutathione, reversible with N-acetylcysteine.
Limitations: As for the enu1 model, tissue glutathione depletion and its downstream dwarfism and cataract have no reported counterpart in patients.
Readouts
Growth, lens and bone phenotype after N-acetylcysteine
Direction: RESTORED
Interpretation: N-acetylcysteine reversal implicates glutathione-precursor deprivation.
Show evidence (1 reference)
PMID:23615310 SUPPORT Model Organism
"Growth retardation, degeneration of lens fibers, and an increased number of osteoclasts in the Ggt1(dwg/dwg) mice were reversed by administration of N-acetyl-L-cysteine, a precursor of GSH synthesis."
Reports NAC rescue of the mouse phenotype.
Show evidence (1 reference)
PMID:23615310 SUPPORT Model Organism
"Plasma and kidney GSH levels were markedly increased, while eye and liver GSH levels were markedly decreased, in the Ggt1(dwg/dwg) mice."
Shows the extracellular-excess, tissue-deficit pattern in this model.
{ }

Source YAML

click to show 
name: Gamma-glutamyl Transpeptidase Deficiency
category: Mendelian
creation_date: '2026-10-15T00:00:00Z'
synonyms:
- Glutathionuria
- Glutathioninuria
- GGT deficiency
- GGT1 deficiency
- Gamma-glutamyltransferase deficiency
- Inborn error of glutathione hydrolase activity
description: >
  Gamma-glutamyl transpeptidase (GGT) deficiency, or glutathionuria, is an
  ultra-rare autosomal recessive inborn error of the gamma-glutamyl cycle in
  which the extracellular, membrane-anchored enzyme that begins glutathione
  breakdown is missing. GGT1 hydrolyses or transfers the gamma-glutamyl moiety
  of glutathione and its S-conjugates at the outer face of the plasma membrane,
  most abundantly on the brush border of the renal proximal tubule. Without it,
  glutathione filtered at the glomerulus and exported by tissues cannot be
  broken down, so it accumulates in plasma and is excreted in urine in gram
  quantities, together with gamma-glutamylcysteine and cysteine. The same block
  prevents conversion of leukotriene C4 to leukotriene D4. Diagnosis is
  biochemical (glutathionuria with very low serum or leukocyte GGT activity);
  a causal GGT1 variant has been identified in only one family, a homozygous
  16.9 kb intragenic deletion. The clinical picture is uncertain. Most of the
  handful of reported patients were identified because of intellectual
  disability, developmental delay or behavioural problems, so the reported
  neurological involvement is subject to strong ascertainment bias, and expert
  review states that whether it belongs to the disease remains to be
  established. Glutathione-deficient mouse models are far more severe than any
  reported patient, and human cellular glutathione is reported to be normal.
disease_term:
  preferred_term: gamma-glutamyl transpeptidase deficiency
  term:
    id: MONDO:0009285
    label: gamma-glutamyl transpeptidase deficiency
parents:
- Inherited Glutathione Metabolism Disease
- Inborn Error of Metabolism
notes: >
  The patient count is small and partly overlapping across sources: a 2007
  review counts seven patients in five families, and the 2018 report of the
  first molecularly confirmed family counts six previously reported patients
  before adding its two siblings. Most published patients were diagnosed
  biochemically before any gene was linked to the disorder, so it is not known
  whether all of them carry GGT1 variants; the human genome contains several
  related GGT genes. No specific treatment has been recommended.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    Fewer than ten patients reported. Both counting sources note the disorder
    is probably underdiagnosed because glutathione is not measured in routine
    metabolic screening, so the case count is a floor rather than an estimate
    of occurrence.
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Gamma-glutamyl transpeptidase deficiency is a very rare disease, which has been reported in seven patients in five families worldwide"
    explanation: Review count of reported patients and families.
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "with only six patients reported in the literature, although this condition has probably been underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples"
    explanation: >-
      Gives the prior case count and states that the disorder is probably
      underdiagnosed, which is why no prevalence figure is asserted.
pathophysiology:
- name: Loss of GGT1 glutathione hydrolase activity
  biological_scale: MOLECULAR
  description: >
    GGT1 is an extracellular, plasma-membrane-anchored enzyme that hydrolyses
    or transfers the gamma-glutamyl moiety of glutathione and other
    gamma-glutamyl compounds; it catalyses the first step of glutathione
    degradation. In the one molecularly characterised family a homozygous
    16.9 kb intragenic GGT1 deletion abolishes it. Activity in affected
    individuals is very low or below detection in serum, but is not completely
    absent in all patients studied, consistent with contributions from other
    members of the GGT gene family.
  genes:
  - preferred_term: GGT1
    term:
      id: hgnc:4250
      label: GGT1
  molecular_functions:
  - preferred_term: glutathione hydrolase activity
    term:
      id: GO:0036374
      label: glutathione gamma-glutamate hydrolase
    modifier: DECREASED
  - preferred_term: leukotriene C4 hydrolase activity
    term:
      id: GO:0002951
      label: leukotriene-C(4) hydrolase activity
    modifier: DECREASED
  genetic_context:
    description: >
      Homozygous 16.9 kb intragenic deletion of GGT1 with a 13 bp insertion at
      the junction, in the only family with a molecular diagnosis.
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
  evidence:
  - reference: PMID:18357469
    reference_title: "The human gamma-glutamyltransferase gene family."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The well-characterized GGT1 is an extracellular enzyme that is anchored to the plasma membrane of cells. There, it hydrolyzes and transfers gamma-glutamyl moieties from glutathione and other gamma-glutamyl compounds to acceptors."
    explanation: Defines the location and catalytic activity of GGT1.
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-genome sequencing revealed the presence of a 16.9 kb homozygous deletion in GGT1, one of the genes encoding enzymes with γ-glutamyl transpeptidase activity in the human genome."
    explanation: Identifies the causal GGT1 lesion in affected siblings.
  - reference: PMID:6114489
    reference_title: "Formation of gamma-glutamycyst(e)ine in vivo is catalyzed by gamma-glutamyl transpeptidase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gamma-glutamyl transpeptidase activity is not completely absent in a patient found to have a deficiency of this enzyme"
    explanation: Documents residual activity in a deficient patient, supporting the description of very low rather than uniformly absent activity.
  downstream:
  - target: Reduced serum gamma-glutamyltransferase
    causal_link_type: DIRECT
    description: Serum GGT activity is the circulating readout of the absent enzyme.
  - target: Impaired extracellular glutathione catabolism
    causal_link_type: DIRECT
    description: >
      GGT1 catalyses the first and committing step of extracellular glutathione
      breakdown, so its loss halts glutathione degradation at the cell surface.
    evidence:
    - reference: PMID:17397529
      reference_title: "Inborn errors in the metabolism of glutathione."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Gamma-glutamyl transpeptidase catalyses the first step in the degradation of glutathione"
      explanation: Places the enzyme at the first step of glutathione degradation.
  - target: Defective conversion of leukotriene C4 to leukotriene D4
    causal_link_type: DIRECT
    description: >
      Leukotriene C4 is a glutathione S-conjugate whose gamma-glutamyl residue
      is removed by GGT to form leukotriene D4.
    evidence:
    - reference: PMID:14754911
      reference_title: "Synthesis and metabolism of leukotrienes in gamma-glutamyl transpeptidase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "LTC(4), the primary cysteinyl LT, is cleaved by gamma-glutamyl transpeptidase (GGT), resulting in LTD(4)."
      explanation: States the GGT-dependent step in cysteinyl leukotriene metabolism.
- name: Impaired extracellular glutathione catabolism
  biological_scale: CELLULAR
  description: >
    Glutathione is exported from cells and filtered at the glomerulus, and is
    normally degraded at the luminal brush border of the renal proximal tubule,
    where GGT is concentrated. Without GGT, filtered and circulating glutathione
    cannot be broken down for recovery of its constituent amino acids. Older
    work proposed that the gamma-glutamyl cycle mediates amino-acid transport,
    but GGT-deficient patients have normal plasma amino acids and renal
    amino-acid reabsorption, and the extracellular hydrolysis of glutathione is
    now regarded as the enzyme's physiological role.
  cell_types:
  - preferred_term: epithelial cell of proximal tubule
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  locations:
  - preferred_term: proximal tubule
    term:
      id: UBERON:0004134
      label: proximal tubule
  biological_processes:
  - preferred_term: glutathione catabolic process
    term:
      id: GO:0006751
      label: glutathione catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:42531
    reference_title: "Characterization and physiological function of rat renal gamma-glutamyltranspeptidase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Within the kidney, the enzyme is primarily associated with the luminal surface of the brush border membrane of the proximal straight tubule."
    explanation: Localises renal GGT to the proximal tubule brush border in the rat.
  - reference: PMID:42531
    reference_title: "Characterization and physiological function of rat renal gamma-glutamyltranspeptidase."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It now appears that the activities attributed to the gamma-glutamyl cycle do not participate in amino acid transport, but instead constitute three separate metabolic pathways; the intracellular synthesis of glutathione, the intracellular degradation of gamma-glutamyl peptides and the extracellular hydrolysis of glutathione."
    explanation: Synthesises the evidence that GGT's role is extracellular glutathione hydrolysis rather than amino-acid transport.
  - reference: PMID:6118466
    reference_title: "Glutathionuria: gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in the only other case described in detail, plasma levels and renal reabsorption of the amino acids were normal."
    explanation: >-
      Two deficient patients had normal plasma amino acids and renal
      amino-acid reabsorption despite absent GGT. That is consistent with the
      enzyme's physiological role being extracellular glutathione hydrolysis
      rather than amino-acid transport, which is the role this node describes;
      the support is by inference, hence INDIRECT.
  downstream:
  - target: Glutathione accumulation in plasma and urine
    causal_link_type: DIRECT
    description: >
      Undegraded glutathione accumulates in plasma and is lost in the urine,
      largely from the kidney.
    evidence:
    - reference: PMID:42531
      reference_title: "Characterization and physiological function of rat renal gamma-glutamyltranspeptidase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The glutathionemia and glutathionuria observed in a patient who lacks detectable gamma-glutamyltranspeptidase activity and in mice following specific inhibition of transpeptidase, support the hypothesis that the enzyme plays a major role in glutathione catabolism."
      explanation: Links absent GGT activity in a patient to glutathionemia and glutathionuria via loss of glutathione catabolism.
    - reference: PMID:34150
      reference_title: "Translocation of intracellular glutathione to membrane-bound gamma-glutamyl transpeptidase as a discrete step in the gamma-glutamyl cycle: glutathionuria after inhibition of transpeptidase."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The evidence suggests that a substantial fraction of the urinary glutathione arises from the kidney."
      explanation: Pharmacological GGT inhibition in mice shows the urinary glutathione is largely renal in origin.
  - target: Systemic cysteine and glutathione salvage failure
    causal_link_type: DIRECT
    description: >
      Glutathione lost intact in the urine is not degraded and its cysteine is
      not recovered. In mice this chronic loss depletes tissue glutathione.
    evidence:
    - reference: PMID:12757858
      reference_title: "L-2-oxothiazolidine-4-carboxylate supplementation in murine gamma-GT deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Total liver glutathione (GSH) content is significantly reduced in gamma-GT-deficient mice due to chronic excessive GSH loss."
      explanation: Attributes tissue glutathione depletion in GGT-deficient mice to chronic glutathione loss.
  - target: Neurodevelopmental and behavioural involvement of uncertain attribution
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Proposed, not established. Intellectual disability, developmental delay
      or behavioural problems are reported in most known patients, but these
      patients were largely found by metabolic screening of people who already
      had neurological problems, and no mechanism connecting extracellular
      glutathione catabolism to brain function in this disorder has been shown.
      The edge is kept so the reported phenotypes are attached to the graph,
      with its uncertainty stated here and in the knowledge-gap discussion.
    evidence:
    - reference: PMID:29483667
      reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum."
      explanation: >-
        Co-occurrence of mild neurological findings with the biochemical defect
        in the only genetically confirmed family. It supports association, not
        the causal step, hence INDIRECT.
- name: Glutathione accumulation in plasma and urine
  biological_scale: ORGANISM
  description: >
    The defining and constant biochemical abnormality. Urinary glutathione
    reaches up to 1 g per day against under 10 mg in controls, plasma
    glutathione is raised, and urine and plasma also contain excess
    gamma-glutamylcysteine, cysteine and cysteinylglycine.
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: INCREASED
  - preferred_term: L-gamma-glutamyl-L-cysteine
    term:
      id: CHEBI:17515
      label: L-gamma-glutamyl-L-cysteine
    modifier: INCREASED
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients have had glutathionuria (up to 1 g/day"
    explanation: Glutathionuria is universal among reported patients and quantified.
  - reference: PMID:15702405
    reference_title: "Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The analyses of sulphydryl compounds in the plasma (and serum for certain test items) and urine indicated high concentrations of glutathione, gamma-glutamylcysteine, cysteine and cysteinylglycine."
    explanation: Documents the full set of accumulating thiol compounds in plasma and urine.
  - reference: PMID:6106190
    reference_title: "Excretion of cysteine and gamma-glutamylcysteine moieties in human and experimental animal gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a patient with severe gamma-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, gamma-glutamylcysteine, and cysteine in their urine"
    explanation: Urinary excretion of glutathione, gamma-glutamylcysteine and cysteine in a deficient patient.
  downstream:
  - target: Glutathionuria
    causal_link_type: DIRECT
  - target: Glutathionemia
    causal_link_type: DIRECT
- name: Systemic cysteine and glutathione salvage failure
  biological_scale: ORGANISM
  description: >
    In GGT-deficient mice, chronic urinary loss of glutathione deprives tissues
    of the cysteine normally recovered from extracellular glutathione, and
    liver and lens glutathione fall; cysteine-prodrug supplementation reverses
    the mouse phenotype. This node is supported in mice only. In patients,
    cellular glutathione is reported to be normal, and no human counterpart of
    the mouse growth failure, cataract or infertility has been reported, so the
    node is recorded with contradicting human evidence rather than as an
    established human mechanism.
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  evidence:
  - reference: PMID:9139708
    reference_title: "Mice with genetic gamma-glutamyl transpeptidase deficiency exhibit glutathionuria, severe growth failure, reduced life spans, and infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Total glutathione concentration was increased in both blood and urine but decreased in liver homogenates from affected mice."
    explanation: Shows the combination of extracellular glutathione excess and tissue depletion in a GGT-deficient mouse.
  - reference: PMID:12757858
    reference_title: "L-2-oxothiazolidine-4-carboxylate supplementation in murine gamma-GT deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tissue GSH deficiency is the proximate cause of the phenotypic abnormalities associated with murine gamma-GT deficiency."
    explanation: Identifies tissue glutathione deficiency as the cause of the mouse phenotype.
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cellular levels of glu-\ntathione are normal."
    explanation: >-
      For human patients the review states cellular glutathione is normal,
      which contradicts transferring the mouse tissue-depletion mechanism to
      the human disease. The snippet reproduces the line-break hyphenation of
      the cached PDF-derived text.
- name: Defective conversion of leukotriene C4 to leukotriene D4
  biological_scale: MOLECULAR
  description: >
    Patients cannot form leukotriene D4 or E4 from leukotriene C4: urinary
    leukotriene C4 is markedly raised and leukotriene E4 is undetectable, and
    stimulated monocytes make no leukotriene D4. Whether this has any clinical
    consequence is unknown; no phenotype has been attributed to it.
  biological_processes:
  - preferred_term: leukotriene D4 biosynthetic process
    term:
      id: GO:1901750
      label: leukotriene D4 biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: leukotriene C4
    term:
      id: CHEBI:16978
      label: leukotriene C4
    modifier: INCREASED
  - preferred_term: leukotriene D4
    term:
      id: CHEBI:28666
      label: leukotriene D4
    modifier: DECREASED
  evidence:
  - reference: PMID:14754911
    reference_title: "Synthesis and metabolism of leukotrienes in gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data demonstrate a complete deficiency of LTD(4) biosynthesis in patients with a genetic deficiency of GGT."
    explanation: Shows complete loss of leukotriene D4 synthesis in three patients.
  - reference: PMID:18357469
    reference_title: "The human gamma-glutamyltransferase gene family."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "These patients do secrete glutathione in urine and fail to metabolize LTC4."
    explanation: Summarises the dual glutathione and leukotriene C4 defect in patients.
- name: Neurodevelopmental and behavioural involvement of uncertain attribution
  biological_scale: ORGANISM
  description: >
    Five of the seven patients counted in a 2007 review had central nervous
    system involvement (intellectual disability, developmental delay,
    behavioural problems), and the two genetically confirmed siblings have
    mild psychomotor delay and mild neurological symptoms. This figure is
    strongly shaped by ascertainment: the disorder is found by measuring
    glutathione, which is not part of routine screening, and the early
    patients were found during metabolic investigation of intellectual
    disability. No genotype-first or otherwise unselected series exists, so
    there is no way yet to tell how often a deficient individual is
    neurologically normal. The review authors state that whether the neurological symptoms
    are part of the disease remains to be established.
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Whether these symptoms are part of the clinical picture remains to be established."
    explanation: >-
      The review's statement, immediately after counting CNS involvement in
      five of seven reported patients, that attributing those symptoms to the
      disorder is unresolved.
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum."
    explanation: Neurological findings in the genetically confirmed siblings are mild.
  downstream:
  - target: Intellectual disability
    causal_link_type: UNKNOWN
  - target: Global developmental delay
    causal_link_type: UNKNOWN
  - target: Atypical behavior
    causal_link_type: UNKNOWN
phenotypes:
- category: Metabolic
  name: Glutathionuria
  frequency: VERY_FREQUENT
  description: >
    Marked urinary excretion of glutathione, up to 1 g per day, is present in
    every reported patient and is the diagnostic finding.
  phenotype_term:
    preferred_term: Glutathionuria
    term:
      id: HP:0034586
      label: Glutathionuria
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients have had glutathionuria (up to 1 g/day"
    explanation: Universal and quantified glutathionuria.
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum"
    explanation: Glutathionuria in the genetically confirmed siblings.
- category: Metabolic
  name: Glutathionemia
  frequency: VERY_FREQUENT
  description: Plasma glutathione is raised alongside the urinary excess.
  phenotype_term:
    preferred_term: Glutathionemia
    term:
      id: HP:0034456
      label: Elevated circulating glutathione concentration
  evidence:
  - reference: PMID:15702405
    reference_title: "Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glutathionaemia and glutathionuria were evident in both brothers."
    explanation: Raised circulating glutathione in both affected brothers.
  - reference: PMID:9679548
    reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria"
    explanation: Review names glutathionemia as a feature of the disorder.
- category: Metabolic
  name: Reduced serum gamma-glutamyltransferase
  frequency: VERY_FREQUENT
  description: >
    Serum GGT activity is very low or below the detection limit. The
    confirmatory enzyme assay in leukocytes or fibroblasts is recorded under
    biochemical findings and diagnosis.
  phenotype_term:
    preferred_term: Reduced gamma-glutamyltransferase level
    term:
      id: HP:0034445
      label: Reduced gamma-glutamyltransferase level
  evidence:
  - reference: PMID:15702405
    reference_title: "Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gamma-Glutamyltranspeptidase activity was below the detection limit of 1 IU/L in both patients."
    explanation: Undetectable serum GGT in two patients.
- category: Neurologic
  name: Intellectual disability
  description: >
    Reported in several patients, including the index adult cases. Frequency
    is not asserted because patients were largely ascertained through
    investigation of intellectual disability; see the pathophysiology node on
    uncertain attribution.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:6118466
    reference_title: "Glutathionuria: gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency."
    explanation: Intellectual disability in a biochemically confirmed patient.
  - reference: PMID:15702405
    reference_title: "Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients both showed a tendency to retarded mental development."
    explanation: Mild intellectual impairment in two adult brothers.
- category: Neurologic
  name: Global developmental delay
  description: >
    Mild psychomotor developmental delay in both genetically confirmed
    siblings.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two siblings with mild psychomotor developmental delay and mild neurological symptoms"
    explanation: Mild developmental delay in the GGT1-deletion siblings.
- category: Behavioral
  name: Atypical behavior
  description: Severe behaviour problems were reported in one adult patient.
  phenotype_term:
    preferred_term: Behavioural problems
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:6118466
    reference_title: "Glutathionuria: gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency."
    explanation: Behavioural problems in a deficient patient.
- category: Skeletal
  name: Tall slender habitus with long limbs
  description: >
    Reported in one pair of adult brothers, one of whom carried a diagnosis of
    Marfan syndrome. Single-family observation; no mechanism links it to GGT
    deficiency and a coincident connective-tissue diagnosis was not excluded,
    so it is left unconnected in the pathograph.
  phenotype_term:
    preferred_term: Marfanoid habitus
    term:
      id: HP:0001519
      label: Disproportionate tall stature
  evidence:
  - reference: PMID:15702405
    reference_title: "Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The brothers were both tall and slender and had long limbs; the younger was diagnosed as having Marfan syndrome."
    explanation: Habitus reported in one family, with a concurrent Marfan syndrome diagnosis.
biochemical:
- name: Increased urinary glutathione
  presence: INCREASED
  context: >
    The diagnostic finding. Measured by chromatographic methods; it is not
    detected by routine amino-acid screening, which is a main reason the
    disorder is thought to be underdiagnosed.
  biomarker_term:
    preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  readouts:
  - target: Glutathione accumulation in plasma and urine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Urinary glutathione directly reports the failure of extracellular glutathione degradation.
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "All patients have had glutathionuria (up to 1 g/day"
    explanation: Quantifies the urinary glutathione excess.
- name: Increased urinary gamma-glutamylcysteine and cysteine
  presence: INCREASED
  context: >
    Gamma-glutamylcysteine and cysteine are excreted in excess together with
    glutathione, largely as disulfides.
  biomarker_term:
    preferred_term: L-gamma-glutamyl-L-cysteine
    term:
      id: CHEBI:17515
      label: L-gamma-glutamyl-L-cysteine
  readouts:
  - target: Glutathione accumulation in plasma and urine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Accompanying gamma-glutamyl and thiol excretion reflects the same catabolic block.
  evidence:
  - reference: PMID:6106190
    reference_title: "Excretion of cysteine and gamma-glutamylcysteine moieties in human and experimental animal gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a patient with severe gamma-glutamyl transpeptidase deficiency excrete much larger than normal amounts of glutathione, gamma-glutamylcysteine, and cysteine in their urine"
    explanation: Documents excess urinary gamma-glutamylcysteine and cysteine.
- name: Increased urinary leukotriene C4 with absent leukotriene E4
  presence: INCREASED
  context: >
    Urinary leukotriene C4 is raised by several orders of magnitude and
    leukotriene E4 is undetectable, reflecting the block in cysteinyl
    leukotriene processing.
  biomarker_term:
    preferred_term: leukotriene C4
    term:
      id: CHEBI:16978
      label: leukotriene C4
  readouts:
  - target: Defective conversion of leukotriene C4 to leukotriene D4
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Accumulated leukotriene C4 with absent downstream metabolites reports the GGT-dependent step.
  evidence:
  - reference: PMID:14754911
    reference_title: "Synthesis and metabolism of leukotrienes in gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of LTs in urine revealed increased concentrations of LTC(4) (12.8-17.9 nmol/mol creatinine; controls, <0.005 nmol/mol creatinine), whereas LTE(4) was below the detection limit"
    explanation: Quantifies urinary leukotriene C4 excess and absent leukotriene E4.
- name: Reduced gamma-glutamyl transpeptidase activity in nucleated cells
  presence: DECREASED
  context: >
    Confirmatory enzyme assay is done in leukocytes or cultured fibroblasts,
    because erythrocytes contain an incomplete gamma-glutamyl cycle and lack
    the enzyme normally.
  readouts:
  - target: Loss of GGT1 glutathione hydrolase activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Measured enzyme activity is the direct readout of the GGT1 lesion.
  evidence:
  - reference: PMID:9679548
    reference_title: "Patients with genetic defects in the gamma-glutamyl cycle."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts"
    explanation: Specifies the cell types in which the enzyme must be assayed.
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Low activity of γ-glutamyl transpeptidase in nucleated cells such as leukocytes or cultured skin fibroblasts."
    explanation: States the diagnostic enzyme finding and the cell types in which it is measured.
diagnosis:
- name: Biochemical diagnosis of GGT deficiency
  description: >
    Diagnosis rests on two findings: low GGT activity in nucleated cells
    (leukocytes or cultured skin fibroblasts; erythrocytes cannot be used
    because they lack the enzyme normally), and high plasma and urinary
    glutathione. Glutathione is not detected by routine amino-acid screening
    and must be measured specifically. GGT1 testing can confirm the diagnosis,
    but only one causal variant has been published.
  evidence:
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Low activity of γ-glutamyl transpeptidase in nucleated cells such as leukocytes or cultured skin fibroblasts."
    explanation: First diagnostic criterion listed by the review.
  - reference: PMID:17397529
    reference_title: "Inborn errors in the metabolism of glutathione."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "High levels of glutathione in plasma and urine (up to 1 g/day in urine; controls < 10 mg)."
    explanation: Second diagnostic criterion, with the magnitude of urinary glutathione against controls.
inheritance:
- name: Autosomal recessive
  description: >
    Affected siblings in the molecularly confirmed family are homozygous for
    the GGT1 deletion, with heterozygous parents and an unaffected sibling;
    earlier, carrier parents were inferred from low fibroblast enzyme activity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genetic characterization of the patients' parents and a healthy sibling has provided direct genetic evidence regarding the autosomal recessive nature of this disease"
    explanation: Segregation of the deletion in the family establishes autosomal recessive inheritance.
  - reference: PMID:6118466
    reference_title: "Glutathionuria: gamma-glutamyl transpeptidase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An autosomal recessive mode of inheritance is suggested."
    explanation: Early biochemical family study proposing autosomal recessive inheritance.
genetic:
- name: GGT1
  gene_term:
    preferred_term: GGT1
    term:
      id: hgnc:4250
      label: GGT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >
    Only one family with a molecular diagnosis has been published. Before it, a
    2008 review of the GGT gene family noted that no GGT1 mutation had been
    found in any patient; the earlier patients were diagnosed biochemically and
    have not been genotyped in the literature. No external gene-disease
    validity classification has been copied here.
  variants:
  - name: Homozygous 16.9 kb intragenic GGT1 deletion
    description: >
      A 16.9 kb homozygous deletion within GGT1 with a 13 bp insertion at the
      deletion junction, found by whole-genome sequencing in two affected
      siblings.
    evidence:
    - reference: PMID:29483667
      reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Close analysis revealed the presence of a 13 bp insertion at the deletion junction."
      explanation: Characterises the deletion junction.
  evidence:
  - reference: PMID:29483667
    reference_title: "γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report of a genetic variant as the cause of glutathionuria."
    explanation: First and only published genetic cause of the disorder.
  - reference: PMID:18357469
    reference_title: "The human gamma-glutamyltransferase gene family."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "GGT deficiency in man is rare and for the few patients reported to date, mutations in GGT1 have not been described."
    explanation: >-
      Records that the earlier, biochemically diagnosed patients had no
      molecular diagnosis, which is why gene-level evidence rests on one family.
animal_models:
- name: Ggt1 enu1 glutathionuric mouse
  species: Mouse
  genotype: Ggt1(enu1/enu1)
  publication: PMID:9139708
  description: >
    ENU-induced GGT-deficient mouse found by screening for aminoacidurias. Its
    phenotype (growth failure, lethargy, cataracts, infertility, shortened
    life span) is far more severe than anything reported in patients.
  modeled_mechanisms:
  - target: Glutathione accumulation in plasma and urine
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: Reproduces the glutathionemia and glutathionuria that define the human disorder.
    evidence:
    - reference: PMID:9139708
      reference_title: "Mice with genetic gamma-glutamyl transpeptidase deficiency exhibit glutathionuria, severe growth failure, reduced life spans, and infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Total glutathione concentration was increased in both blood and urine but decreased in liver homogenates from affected mice."
      explanation: Blood and urine glutathione excess mirrors the human biochemistry.
  - target: Systemic cysteine and glutathione salvage failure
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: >
      Shows tissue glutathione depletion from chronic urinary loss, and its
      reversal by a cysteine prodrug.
    limitations: >
      Human patients are reported to have normal cellular glutathione and none
      has the mouse growth failure, cataracts or infertility, so the mouse
      tissue-depletion mechanism may not operate, or not to the same degree, in
      humans.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >
        The mouse loses enough cysteine through glutathionuria to deplete liver
        and lens glutathione, whereas cellular glutathione is reported normal in
        patients; differences in dietary cysteine supply or in compensating GGT
        family members between species are possible explanations that have not
        been tested.
    readouts:
    - name: Growth and behaviour after cysteine-prodrug supplementation
      target: Systemic cysteine and glutathione salvage failure
      direction: RESTORED
      interpretation: Rescue by a cysteine prodrug supports cysteine/glutathione deprivation as the cause of the mouse phenotype.
      evidence:
      - reference: PMID:12757858
        reference_title: "L-2-oxothiazolidine-4-carboxylate supplementation in murine gamma-GT deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The growth, physical appearance, and behavior of gamma-GT-deficient mice were substantially improved following OTZ supplementation."
        explanation: Reports phenotypic rescue by OTZ.
    evidence:
    - reference: PMID:12757858
      reference_title: "L-2-oxothiazolidine-4-carboxylate supplementation in murine gamma-GT deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Total liver glutathione (GSH) content is significantly reduced in gamma-GT-deficient mice due to chronic excessive GSH loss."
      explanation: Supports the model as informative for the salvage-failure node in mice.
  evidence:
  - reference: PMID:9139708
    reference_title: "Mice with genetic gamma-glutamyl transpeptidase deficiency exhibit glutathionuria, severe growth failure, reduced life spans, and infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Glutathionuric mice exhibited lethargy, severe growth failure, shortened life spans and infertility."
    explanation: Mouse phenotype, which exceeds anything reported in humans.
- name: Ggt1 dwg mouse
  species: Mouse
  genotype: Ggt1(dwg/dwg)
  publication: PMID:23615310
  description: >
    Spontaneous Ggt1 mutant (13 nt exon 7 deletion) with dwarfism, cataract and
    coat colour change but normal survival; residual GGT1 activity about 4% of
    wild type.
  modeled_mechanisms:
  - target: Loss of GGT1 glutathione hydrolase activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: A Ggt1 loss-of-function allele with severely reduced enzyme activity.
    evidence:
    - reference: PMID:23615310
      reference_title: "Phenotypic characterization of Ggt1(dwg/dwg) mice,a mouse model for hereditary γ-glutamyltransferase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "GGT1 activity in the Ggt1(dwg/dwg) mice was reduced to approximately 4.0% of that in the wild-type mice."
      explanation: Quantifies residual activity in the model.
  - target: Systemic cysteine and glutathione salvage failure
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    description: Shows raised plasma and kidney glutathione with depleted eye and liver glutathione, reversible with N-acetylcysteine.
    limitations: >
      As for the enu1 model, tissue glutathione depletion and its downstream
      dwarfism and cataract have no reported counterpart in patients.
    readouts:
    - name: Growth, lens and bone phenotype after N-acetylcysteine
      target: Systemic cysteine and glutathione salvage failure
      direction: RESTORED
      interpretation: N-acetylcysteine reversal implicates glutathione-precursor deprivation.
      evidence:
      - reference: PMID:23615310
        reference_title: "Phenotypic characterization of Ggt1(dwg/dwg) mice,a mouse model for hereditary γ-glutamyltransferase deficiency."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Growth retardation, degeneration of lens fibers, and an increased number of osteoclasts in the Ggt1(dwg/dwg) mice were reversed by administration of N-acetyl-L-cysteine, a precursor of GSH synthesis."
        explanation: Reports NAC rescue of the mouse phenotype.
    evidence:
    - reference: PMID:23615310
      reference_title: "Phenotypic characterization of Ggt1(dwg/dwg) mice,a mouse model for hereditary γ-glutamyltransferase deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Plasma and kidney GSH levels were markedly increased, while eye and liver GSH levels were markedly decreased, in the Ggt1(dwg/dwg) mice."
      explanation: Shows the extracellular-excess, tissue-deficit pattern in this model.
discussions:
- discussion_id: ggt_deficiency_neurological_attribution
  prompt: >-
    Is intellectual disability or other neurological involvement part of
    gamma-glutamyl transpeptidase deficiency, or an artefact of how the few
    known patients were found?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Neurodevelopmental and behavioural involvement of uncertain attribution
  rationale: >-
    The disorder is detected only by measuring glutathione, which routine
    metabolic screening does not do, and the reported patients were largely
    identified during investigation of intellectual disability or behavioural
    problems. Five of seven reported patients had central nervous system
    involvement, but the patients ascertained through a neurological problem
    cannot show whether the deficiency causes it. The genetically confirmed
    siblings are only mildly affected, the 2007 review states that whether the
    symptoms are part of the disease remains to be established, and no
    mechanism linking extracellular glutathione catabolism to brain function in
    patients has been shown. Genotype-first ascertainment (homozygous GGT1
    loss-of-function in population or newborn sequencing cohorts, or urinary
    glutathione in an unselected population) would answer it.
  proposed_experiments:
  - experiment_id: exp_ggt1_genotype_first
    name: Genotype-first phenotyping of biallelic GGT1 loss-of-function carriers
    description: >-
      Identify individuals with biallelic GGT1 loss-of-function variants or
      deletions in large sequencing cohorts without selecting on neurological
      status, confirm glutathionuria biochemically, and compare their
      neurodevelopmental outcomes with matched controls.
    would_support:
    - pathophysiology#Neurodevelopmental and behavioural involvement of uncertain attribution
- discussion_id: ggt_deficiency_mouse_human_mismatch
  prompt: >-
    Why do GGT1-deficient mice develop tissue glutathione depletion, growth
    failure, cataracts and infertility, while patients reportedly have normal
    cellular glutathione and none of those features?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Systemic cysteine and glutathione salvage failure
  rationale: >-
    The mouse models establish that urinary glutathione loss can deplete tissue
    glutathione and that cysteine prodrugs rescue the result, but the human
    disorder shows the biochemical signature without that phenotype. The
    salvage-failure node is therefore supported in mice and contradicted for
    humans. Whether the difference reflects cysteine supply, compensation by
    other GGT family members, or incomplete clinical assessment of the few
    patients is unknown.
  proposed_experiments:
  - experiment_id: exp_ggt1_human_tissue_glutathione
    name: Tissue and plasma cysteine and glutathione measurement in GGT1-deficient patients
    description: >-
      Measure plasma cysteine, leukocyte and fibroblast glutathione, and
      whole-body cysteine balance in molecularly confirmed patients, to test
      whether the mouse salvage-failure mechanism operates in humans.
    would_support:
    - pathophysiology#Systemic cysteine and glutathione salvage failure
references:
- reference: PMID:17397529
  title: "Inborn errors in the metabolism of glutathione."
📚

References & Deep Research

References

1
PMID:17397529
Inborn errors in the metabolism of glutathione.
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: Gamma-glutamyl_Transpeptidase_Deficiency · 2026-10-15T02:47:20Z · View source

New entry for gamma-glutamyl transpeptidase deficiency (glutathionuria; MONDO:0009285; GGT1, hgnc:4250). Deep research: falcon failed with an Edison authentication error. An asta run returned only papers about other diseases and was not committed. The entry was first curated from direct PubMed searches for GGT deficiency, glutathionuria and GGT1; an openscientist report (research/Gamma-glutamyl_Transpeptidase_Deficiency-deep-research-openscientist.md; 17/17 references resolved, 17/17 quotes valid, one off-topic bacterial GGT structure paper) then completed and was cross-checked against the entry. Its clinical, genetic and mouse-model content matches the entry and its cited case and mouse papers are already used; it adds mouse reproductive and skeletal papers (PMID:11089562, PMID:12810527) that were not needed for the human entry, and its proposal that GGT-family paralogs and dietary cysteine buffer human cysteine supply is a hypothesis, recorded only as an untested explanation in the mouse-human mismatch discussion. Its HTML/PDF artifacts were not committed. Evidence rests on the 2018 GGT1-deletion family (PMID:29483667), the Wright 1980, Iida 2005 and Griffith/Meister case reports, the Mayatepek 2004 leukotriene study, the Ristoff and Larsson 2007 review, and three GGT-deficient mouse papers. Curation choices: the neurological phenotype is modelled as a node of uncertain attribution with UNKNOWN edges to the phenotypes and a KNOWLEDGE_GAP discussion, because patients were ascertained largely through intellectual disability and the review states attribution remains to be established; phenotype frequencies are omitted for the neurological features. The mouse tissue glutathione-depletion mechanism carries a REFUTE item (human cellular glutathione reported normal) and a HUMAN_MODEL_MISMATCH discussion. The older amino-acid-transport hypothesis carries a REFUTE item (normal plasma amino acids and renal reabsorption). A tall slender habitus reported in one family is recorded but left unconnected. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). Two Ristoff 2007 snippets were shortened or reproduce line-break hyphenation because the committed cache is PDF-derived text. Validation: just validate, validate-terms, count-verified-snippets (51/51), check-entity-refs, check-causal-targets, check-duplicate-keys and validate-disorders all pass.

OpenScientist ▸
Gamma-glutamyl Transpeptidase Deficiency (Glutathionuria): Comprehensive Disease Characteristics Report
openscientist-autonomous 13 citations 2026-10-15T03:05:50.702117

Gamma-glutamyl Transpeptidase Deficiency (Glutathionuria): Comprehensive Disease Characteristics Report

Disease: Gamma-glutamyl Transpeptidase Deficiency (Glutathionuria) MONDO ID: MONDO:0009285 · OMIM: 231950 · Category: Mendelian (autosomal recessive inborn error of metabolism) Report date: 2026-10-15

Summary

Gamma-glutamyl transpeptidase (GGT) deficiency, historically termed glutathionuria, is an ultra-rare autosomal recessive inborn error of the γ-glutamyl (glutathione) cycle caused by biallelic loss-of-function variants in GGT1 on chromosome 22q11.23. The disease was described biochemically in the 1970s–1980s but its molecular cause was only proven in 2018, when whole-genome sequencing of two affected siblings revealed a 16.9 kb homozygous intragenic deletion in GGT1, with the parents and a healthy sibling confirmed as carriers/wild-type — providing the first direct genetic evidence of autosomal recessive inheritance PMID: 29483667.

The core biochemical defect is a failure of extracellular glutathione (GSH) catabolism. GGT is a membrane-bound ectoenzyme on the apical (brush-border) surface of transport/secretory epithelia — most importantly the renal proximal tubule — where it initiates breakdown of filtered and plasma glutathione and salvages cysteine. When the enzyme is absent, glutathione cannot be reclaimed and is lost in the urine. This produces the diagnostic hallmark of glutathionuria plus glutathionemia, accompanied by elevated plasma γ-glutamylcysteine, cysteine and cysteinylglycine, with serum/tissue GGT activity that is very low or undetectable. Notably, plasma amino acid levels and renal amino acid reabsorption remain normal, demonstrating that the γ-glutamyl cycle is not essential for amino acid transport.

The human clinical phenotype is remarkably mild relative to the dramatic biochemical abnormality: fewer than ~8 patients have ever been reported, and the dominant features are neurological/cognitive (intellectual disability, developmental delay, behavioral problems), with variable, generally mild, expressivity. By contrast, Ggt1-knockout and ENU-mutant mice display a severe multisystem phenotype — growth failure, cataracts, lethargy, infertility, osteopenia and shortened lifespan — all traced to systemic cysteine/GSH depletion and all reversible with cysteine repletion (N-acetylcysteine or the cysteine prodrug L-2-oxothiazolidine-4-carboxylate, OTZ). The species discrepancy likely reflects paralog redundancy (the human GGT family has 13 homologous genes) and differences in GSH handling. No approved disease-specific therapy exists for humans; management is supportive, and prevention relies on genetic counseling and cascade testing. Mechanistic causality (cysteine depletion as the proximate cause) is proven only in the mouse model and is inferred, but not formally trialed, in humans.

1. Disease Information

Overview. GGT deficiency is a Mendelian inborn error of metabolism in which absence of the ectoenzyme gamma-glutamyl transpeptidase blocks the first step of extracellular glutathione degradation. The clinical and biochemical entity is defined by massive urinary and plasma glutathione accumulation ("glutathionuria" / "glutathionemia") in the setting of absent GGT enzyme activity.

Key identifiers.

Resource Identifier
MONDO MONDO:0009285
OMIM 231950 (Glutathionuria)
Gene GGT1 — HGNC:4250; NCBI Gene 2678; Ensembl ENSG00000100031
Cytogenetic locus 22q11.23 (GRCh38 chr22:24,594,811–24,629,005)
Orphanet Glutathionuria (gamma-glutamyltransferase deficiency) — rare metabolic disease
MeSH Closest concepts: "gamma-Glutamyltransferase"; "Glutathione / metabolism"

Synonyms / alternative names: Glutathionuria; Gamma-glutamyltransferase deficiency; Gamma-glutamyl transferase deficiency; γ-GT deficiency; Glutathionemia (describes the associated plasma finding).

Source of information. The knowledge base is derived almost entirely from aggregated disease-level resources and individual published case reports (not EHR-scale data). The total human experience is fewer than ~8 patients, so the evidence is case-level, supplemented substantially by mouse model data. "A rare disease, with only six patients reported in the literature" PMID: 29483667.

2. Etiology

Primary cause — genetic. The disease is caused by biallelic loss-of-function variants in GGT1, inherited in an autosomal recessive pattern. The first molecular proof was a 16.9 kb homozygous intragenic deletion in GGT1 with a 13 bp insertion at the breakpoint identified by whole-genome sequencing in two affected siblings: "Whole-genome sequencing revealed the presence of a 16.9 kb homozygous deletion in GGT1, one of the genes encoding enzymes with γ-glutamyl transpeptidase activity in the human genome" PMID: 29483667. Earlier case series inferred autosomal recessive inheritance from reduced fibroblast GGT activity in clinically normal, presumably heterozygous, parents PMID: 6118466; PMID: 238530.

Genetic risk factors. The sole established genetic risk factor is inheritance of two pathogenic GGT1 alleles. No susceptibility loci or modifier genes have been formally established in humans (the ultra-rare case count precludes association studies). gnomAD constraint metrics indicate GGT1 is moderately intolerant to heterozygous LOF (see Section 4), yet heterozygous carriers are clinically healthy, consistent with recessive disease.

Environmental risk factors. None established. There is no evidence that toxins, lifestyle, occupational exposure, age or sex trigger or modify the primary Mendelian disease. (Separately, acquired/pharmacologic GGT inhibition can phenocopy the biochemistry: administration of γ-glutamyl amino acids or transpeptidase inhibitors induces glutathionuria in mice — relevant mechanistically but not an etiology of the inherited disease PMID: 2873573; PMID: 34150.)

Protective factors. None characterized in humans. In mice, provision of an alternative cysteine source (N-acetylcysteine, OTZ) is "protective" against the downstream consequences — not a protection against the genetic lesion itself but a bypass of its metabolic consequence.

Gene–environment interactions. Not characterized for this Mendelian disorder. Mechanistically, dietary cysteine/protein intake would be expected to modulate the severity of cysteine deficiency (as shown pharmacologically in mice), but this interaction has not been formally studied in human patients.

3. Phenotypes

The human phenotype is dominated by neurological/cognitive and behavioral features, superimposed on a profound but clinically "silent" biochemical abnormality.

Phenotype Type HPO term (suggested) Onset Severity Frequency (of reported cases)
Glutathionuria (massive urinary GSH) Laboratory abnormality — (metabolite; CHEBI:16856 glutathione) Congenital/neonatal (biochemical) Marked/constant ~100% (defining)
Glutathionemia (elevated plasma GSH) Laboratory abnormality — Congenital (biochemical) Marked/constant ~100% (defining)
Intellectual disability Clinical sign HP:0001249 Childhood Mild–moderate, variable Several reported cases
Developmental delay / psychomotor delay Clinical sign HP:0001263 Infancy/childhood Mild Molecularly confirmed siblings
Behavioral abnormality Behavioral HP:0000708 Childhood Variable (severe in one case) Multiple cases
Mild neurological symptoms (non-specific) Clinical sign HP:0000707 (abnormality of nervous system) Childhood Mild Confirmed cases
Tall, slender (Marfanoid) habitus Physical manifestation HP:0001519 / HP:0001548 Childhood/adolescence — 1 case report

Key supporting quotes: "A mentally retarded young woman with severe behaviour problems was found to excrete large amounts of glutathione due to a generalized gamma-glutamyl transpeptidase deficiency" PMID: 6118466; and the two molecularly confirmed siblings presented as "two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine" PMID: 29483667. Two Japanese brothers showed retarded mental development and a tall slender (Marfan-like) habitus PMID: 15702405.

Phenotype characteristics. Onset is effectively congenital for the biochemical defect; clinical (cognitive/behavioral) features emerge in childhood. Severity is variable and generally mild in the genetically confirmed patients. Progression appears stable/non-progressive rather than degenerative, though natural-history data are essentially absent.

Quality-of-life impact. Not formally measured with any instrument (EQ-5D/SF-36/PROMIS). Impact is inferred to arise chiefly from the degree of intellectual disability and behavioral difficulties; the biochemical abnormality itself appears clinically well-tolerated.

4. Genetic / Molecular Information

Causal gene. GGT1 (HGNC:4250; NCBI Gene 2678; Ensembl ENSG00000100031), chromosome 22q11.23, GRCh38 chr22:24,594,811–24,629,005; canonical transcript ENST00000400382.

Pathogenic variants. - The index molecularly proven lesion is a 16.9 kb homozygous intragenic deletion (structural/copy-number variant) with a 13 bp insertion at the breakpoint — a loss-of-function allele requiring WGS/CNV analysis to detect (standard exome would likely miss it) PMID: 29483667. - Variant classification: pathogenic (biallelic LOF causing a loss-of-function disease). - Variant types expected across the disorder: structural deletions, and (by inference) nonsense/frameshift/splice/missense LOF alleles. - Somatic vs germline: germline. - Functional consequence: loss of function (absent enzyme activity).

gnomAD constraint (v2). Observed/expected LOF = 21/56 (oe_lof 0.375; 90% CI 0.27–0.54), pLI 0.82, missense Z 4.88 — GGT1 is relatively intolerant to heterozygous LOF, yet heterozygous carriers are clinically healthy, consistent with a recessive mechanism.

Protein and family. GGT belongs to the N-terminal nucleophile (Ntn) hydrolase superfamily. It is translated as a single-chain precursor that undergoes autocatalytic cleavage into a large and a small subunit, forming the mature, membrane-bound heterodimeric ectoenzyme; the N-terminal threonine of the small subunit (human hGGT1 Thr-381) is the catalytic nucleophile. "γ-Glutamyl transpeptidases (γ-GTs) are members of N-terminal nucleophile hydrolase superfamily. They are synthetized as single-chain precursors, which are then cleaved to form mature enzymes" PMID: 26536828; "Thr-381 is locked into a single conformation as an acyl bond forms between the substrate and the enzyme" PMID: 33187988.

Paralogs / redundancy. The human GGT family comprises 13 homologous genes (GGT1–7 and GGTLC1–3) on chromosomes 20 and 22: "The human GGT family comprises 13 homologous genes (e.g., GGT1-7 and GGTLC1-3) localized on chromosomes 20 and 22" PMID: 41316810 — a likely explanation for residual activity and the comparatively mild human phenotype.

Modifier genes / epigenetics / chromosomal abnormalities. No disease-specific modifier genes, epigenetic marks, or recurrent chromosomal abnormalities have been established for GGT deficiency. The causal lesion (structural deletion within 22q11.23) is itself a focal copy-number change but not a large cytogenetic abnormality.

Suggested ontology terms: HGNC:4250 (GGT1); GO:0036374 (glutathione hydrolase activity); GO:0006751 (glutathione catabolic process); CHEBI:16856 (glutathione).

5. Environmental Information

  • Environmental factors: None established as causal or contributory to the inherited disease.
  • Lifestyle factors: None established. Dietary cysteine/protein intake is a mechanistically plausible modifier of downstream cysteine deficiency (by analogy to cysteine supplementation rescuing mice), but this is not demonstrated in patients.
  • Infectious agents: Not applicable — this is a Mendelian metabolic disorder with no infectious etiology or trigger.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variants in GGT1 (e.g., 16.9 kb homozygous deletion) → loss of functional GGT protein on epithelial brush-border membranes (demonstrated in humans; PMID: 29483667).
  2. Absent membrane-bound GGT → failure to hydrolyze extracellular/filtered glutathione at the renal proximal tubule brush border and other epithelia (demonstrated; PMID: 42531).
  3. Failure of GSH breakdown → glutathione is not reclaimed and is lost in urine → glutathionuria + glutathionemia, with accumulation of γ-glutamylcysteine, cysteine and cysteinylglycine in plasma (demonstrated in humans; PMID: 15702405).
  4. Loss of extracellular GSH → impaired cysteine salvage (GGT normally liberates cysteine for de novo intracellular GSH/protein synthesis) → intracellular cysteine deficiency (proven in mouse; inferred in human; PMID: 11089562).
  5. Branch A (mouse, severe): Tissue cysteine/GSH depletion → growth failure, cataracts, lethargy, shortened lifespan; reproductive failure via suppressed IGF-1 and FSH; skeletal osteopenia/dwarfism via chondrocyte proliferation defect and osteoblast/osteoclast imbalance → all reversible with N-acetylcysteine / OTZ (proven in mouse; PMID: 12757858; PMID: 11089562; PMID: 12810527).
  6. Branch B (human, mild): Residual cysteine supply (likely from paralogous GGT enzymes and dietary intake) limits systemic depletion → mild, mainly neurological/cognitive phenotype (intellectual disability, developmental delay, behavioral problems) rather than the severe mouse syndrome (inferred; PMID: 29483667; PMID: 41316810).
GGT1 biallelic LOF
      │
      ▼
Absent brush-border GGT ectoenzyme (kidney proximal tubule, etc.)
      │
      ▼
Extracellular/filtered glutathione NOT hydrolyzed
      │
      ├────────────► Urinary GSH loss ─► GLUTATHIONURIA + GLUTATHIONEMIA
      │                                   (↑ γ-glutamylcysteine, cysteine, cysteinylglycine)
      ▼
Impaired cysteine salvage ─► intracellular cysteine deficiency
      │
      ├── MOUSE (severe): growth failure, cataracts, infertility (↓IGF-1/↓FSH),
      │                   osteopenia  ── reversible by NAC / OTZ
      │
      └── HUMAN (mild): neurocognitive/behavioral phenotype
                        (buffered by GGT paralogs + diet)

Supporting detail by category

  • Molecular pathways / biochemistry: The γ-glutamyl cycle / glutathione catabolism. GGT initiates extracellular GSH degradation, "hydrolyzing extracellular GSH and providing the cell with the recovery of cysteine, which is necessary for de novo intracellular GSH and protein biosynthesis" PMID: 37739139. KEGG: glutathione metabolism (map00480).
  • Cellular processes: Redox homeostasis maintenance via cysteine supply; in mouse, chondrocyte proliferation and osteoblast/osteoclast balance are affected PMID: 12810527.
  • Protein dysfunction: Complete loss of function of the Ntn-hydrolase ectoenzyme (no functional heterodimer formed).
  • Metabolic changes: Disrupted glutathione and sulfur-amino-acid (cysteine) metabolism; "Tissue GSH deficiency is the proximate cause of the phenotypic abnormalities associated with murine gamma-GT deficiency" PMID: 12757858.
  • Immune involvement: Not a feature of the inherited deficiency.
  • Tissue damage mechanisms: Secondary to cysteine/GSH depletion (impaired antioxidant capacity) in mouse tissues.
  • Biochemical abnormality: Enzyme deficiency — absent γ-glutamyl transpeptidase activity (<1 IU/L serum).
  • Molecular profiling: No disease-specific transcriptomic/proteomic/metabolomic datasets exist for human patients beyond targeted metabolite measurements (elevated GSH and thiols).

Suggested ontology terms: GO:0006751 (glutathione catabolic process); GO:0036374 (glutathione hydrolase activity); GO:0006534 (cysteine metabolic process); GO:0006749 (glutathione metabolic process); CL:1000838 (kidney proximal convoluted tubule epithelial cell); CHEBI:16856 (glutathione); CHEBI:17561 (L-cysteine).

7. Anatomical Structures Affected

Organ level. - Primary site of metabolic lesion / GSH wasting: the kidney, specifically the proximal tubule brush border. "the enzyme is primarily associated with the luminal surface of the brush border membrane of the proximal straight tubule" PMID: 42531. - Clinically affected system (human): central nervous system / brain (cognitive and behavioral phenotype). - GGT is also expressed in other transport/secretory epithelia: "found in certain epithelial cells in anatomical sites that are involved in transport and secretory activities (e.g., renal tubule, jejunal villi, choroid plexus, ciliary body)" PMID: 45011 — hence biliary tract, jejunum, choroid plexus and ciliary body are enzyme-expressing sites. - Body systems involved: urinary (biochemical), nervous (clinical), and (in mouse) reproductive, skeletal, ocular.

Tissue and cell level. Epithelial tissue — chiefly renal proximal tubule epithelial cells (apical brush border). Suggested CL terms: CL:1000838 (kidney proximal convoluted tubule epithelial cell), CL:0000066 (epithelial cell).

Subcellular level. GGT is a plasma-membrane ectoenzyme anchored on the external/apical surface. Suggested GO cellular component: GO:0005886 (plasma membrane); GO:0016324 (apical plasma membrane); GO:0031526 (brush border membrane).

Localization. Suggested UBERON terms: UBERON:0001231 (nephron tubule) / UBERON:0004134 (proximal convoluted tubule); UBERON:0001088 (urine); UBERON:0000955 (brain). Lateralization is bilateral/systemic (the enzyme defect is generalized, not focal).

8. Temporal Development

  • Onset: The biochemical defect is congenital; clinical (neurocognitive) features present in infancy/childhood. Onset pattern is insidious/chronic rather than acute.
  • Progression: Appears stable/non-progressive based on the few reported cases; no staging system exists. Natural-history and longitudinal data are essentially absent.
  • Disease course: Chronic, lifelong metabolic abnormality.
  • Remission: No spontaneous remission of the biochemical defect; metabolic consequences are (in mouse) treatment-reversible with cysteine repletion.
  • Critical periods: Not defined in humans; by analogy to mouse growth/reproductive phenotypes, childhood/developmental windows would be the plausible period for any metabolic intervention.

9. Inheritance and Population

Epidemiology. Ultra-rare. Fewer than ~8 patients have ever been reported worldwide; precise prevalence/incidence are unknown and almost certainly underestimated. "this condition has probably been underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples" PMID: 29483667.

Genetic parameters. - Inheritance pattern: Autosomal recessive, now directly proven by segregation in a confirmed family: "genetic characterization of the patients' parents and a healthy sibling has provided direct genetic evidence regarding the autosomal recessive nature of this disease" PMID: 29483667. - Penetrance/expressivity: The biochemical phenotype appears fully penetrant; the neurological phenotype shows variable expressivity and uncertain penetrance given tiny numbers. More broadly for γ-glutamyl cycle disorders: "All disorders are very rare and inherited in an autosomal recessive manner. Most of the mutations are leaky so that many patients have residual enzyme activity" PMID: 17397529. - Genetic anticipation: Not applicable (not a repeat-expansion disorder). - Germline mosaicism / founder effects: None documented. - Consanguinity: Homozygosity for a structural deletion in the index family is consistent with a role for shared ancestry/consanguinity, as is typical of rare AR disease, though not explicitly characterized. - Carrier frequency: Unknown; cannot be reliably estimated from gnomAD for a disease defined largely by structural variants.

Population demographics. No ethnic predilection established (reported cases include European and Japanese patients PMID: 15702405). No defined geographic clustering, sex ratio, or age distribution given the few cases.

10. Diagnostics

Diagnostic approach. Diagnosis rests on the biochemical demonstration of glutathionuria + glutathionemia together with very low/absent serum and tissue GGT activity (<1 IU/L), confirmed by GGT1 sequencing PMID: 15702405; PMID: 6118466.

Clinical/laboratory tests. - Quantitative urine and plasma glutathione (markedly elevated), plus γ-glutamylcysteine, cysteine, cysteinylglycine. "Glutathionaemia and glutathionuria were evident in both brothers. The analyses of sulphydryl compounds in the plasma ... and urine indicated high concentrations of glutathione, gamma-glutamylcysteine, cysteine and cysteinylglycine" PMID: 15702405. - Serum GGT enzyme activity (very low/undetectable). LOINC: serum GGT activity (e.g., LOINC 2324-2). - Diagnostic pitfall: on routine amino-acid chromatography, thiol compounds produce "a large peak in the citrulline position," which can mislead — "Urine amino acid analysis on an automatic analyser showed a slightly increased excretion of cystine and a large peak in the citrulline position due, at least in part, to thio-compounds" PMID: 15702405.

Genetic testing. GGT1 sequencing is confirmatory. Because the index lesion was a 16.9 kb structural deletion, WGS or CNV/deletion-duplication analysis may be required — standard whole-exome sequencing can miss such events PMID: 29483667. Single-gene testing or a metabolic gene panel including GGT1 is appropriate; chromosomal microarray may detect larger deletions.

Omics-based diagnostics. Targeted metabolomics (thiol/glutathione quantification by HPLC/LC-MS) is effectively the functional diagnostic test; no transcriptomic/proteomic diagnostic is established.

Clinical criteria / differential diagnosis. No formal consensus diagnostic criteria exist. Differential diagnosis includes other γ-glutamyl cycle / glutathione-metabolism disorders (e.g., glutathione synthetase deficiency / 5-oxoprolinuria, γ-glutamylcysteine synthetase deficiency) — distinguished by their specific metabolite patterns and enzyme assays PMID: 17397529. The citrulline-position peak also raises a spurious concern for a urea-cycle abnormality that must be excluded.

Screening. Not included in standard newborn screening because glutathione is not measured in routine metabolic panels PMID: 29483667. Cascade/carrier testing is feasible once a family's GGT1 variant is known.

11. Outcome / Prognosis

  • Survival/mortality: No evidence of reduced survival in reported human patients; the biochemical abnormality appears compatible with normal life span. (Mouse knockouts, by contrast, have shortened life spans.)
  • Morbidity/function: Driven by the neurocognitive phenotype — intellectual disability and behavioral difficulties account for functional impact. No validated QoL data.
  • Disease course/complications: Chronic and apparently non-progressive; no characteristic organ-failure complications documented in humans.
  • Recovery potential: The genetic/biochemical defect is permanent. Downstream metabolic consequences are, in principle, modifiable (mouse data), but human cognitive outcomes are not known to be reversible.
  • Prognostic factors/biomarkers: None validated. Degree of intellectual disability is the main determinant of outcome in reported cases; true genotype–phenotype correlations cannot be drawn from <8 patients.

12. Treatment

There is no approved disease-specific pharmacotherapy; human management is supportive. No targeted, gene, cell, RNA, immunologic or surgical therapy exists.

Rational (mechanism-based, mouse-validated) strategy — cysteine repletion. In Ggt-deficient mice, supplying an alternative cysteine source corrects the downstream phenotype: - N-acetylcysteine (NAC) restores gonad size, hormone levels and fertility, and ameliorates skeletal abnormalities: "N-acetylcysteine treatment of GGT-/- mice ameliorates their skeletal abnormalities by normalizing chondrocytes proliferation and osteoblastic function" PMID: 12810527; reproductive rescue PMID: 11089562. Suggested NCIT: Acetylcysteine (NCIT:C28159). - L-2-oxothiazolidine-4-carboxylate (OTZ / procysteine), a cysteine prodrug, partially restores liver GSH and improves growth/behavior in mice PMID: 12757858.

These approaches are not formally trialed in human patients — they represent a biologically rational but unproven therapeutic avenue for humans.

Supportive/rehabilitative care. Developmental, educational and behavioral support for intellectual disability and behavioral problems, as for other causes of neurodevelopmental impairment.

Pharmacogenomics / personalized medicine: Not applicable beyond genotype-confirmed diagnosis guiding counseling.

13. Prevention

  • Primary prevention: Not possible for a Mendelian disorder; relies on genetic counseling and reproductive options for at-risk couples.
  • Secondary prevention / early detection: Not currently part of newborn screening (glutathione is not routinely measured) PMID: 29483667. Targeted glutathione measurement should be considered in unexplained intellectual disability with abnormal amino-acid chromatography (the citrulline-position pitfall).
  • Tertiary prevention: Mechanistically, cysteine repletion (NAC/OTZ) could in theory prevent downstream metabolic complications, extrapolating from mouse data; unproven in humans.
  • Genetic screening/counseling: Once a family's GGT1 variant(s) are known, carrier testing, cascade screening, prenatal and preimplantation genetic testing are feasible. Genetic counseling (25% recurrence risk per pregnancy for carrier couples) is the mainstay of prevention.
  • Immunization / public-health / environmental interventions: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy: Best-characterized outside humans in the house mouse (Mus musculus; NCBI Taxon 10090).
  • Orthologous gene: mouse Ggt1 (NCBI Gene 14598; MGI).
  • Natural disease: No well-documented naturally occurring GGT1-deficiency disease in companion animals or wildlife is recorded in the knowledge base; the mouse disease is experimentally induced (ENU mutagenesis or targeted knockout), not naturally arising.
  • Comparative biology: The mouse recapitulates the core metabolic lesion (glutathionuria, glutathionemia, reduced liver GSH) well, but is far more severe than human disease — a key cross-species difference likely reflecting human GGT paralog redundancy (13 family genes; PMID: 41316810) and species differences in GSH handling.
  • Evolutionary conservation: The Ntn-hydrolase GGT mechanism is deeply conserved from bacteria to mammals PMID: 26536828.
  • Transmission / zoonosis: Not applicable (non-infectious genetic disease).

15. Model Organisms

Principal models — mouse. Two mouse models are the main disease models: 1. ENU-induced GGTenu1 mutant, discovered via aminoaciduria screening: "A mouse mutant with glutathionuria was discovered by screening for amino acidurias in the progeny of ethylnitrosourea-mutagenized mice" PMID: 9139708. 2. Targeted Ggt1 knockout (Lieberman lab) PMID: 11089562; PMID: 12810527.

Model characteristics / phenotype recapitulation. Both reproduce the biochemistry faithfully: autosomal-recessive glutathionuria/glutathionemia, reduced liver GSH. Additional (more severe than human) features: growth failure, cataracts, coat-color defects, lethargy, infertility, osteopenia/dwarfism, and shortened life span PMID: 9139708; PMID: 12757858. Reproductive failure is attributed to intracellular cysteine deficiency: mice are "growth retarded as a result of cysteine deficiency secondary to excessive glutathione excretion in urine" PMID: 11089562.

Model limitations. The mouse is more severe than human disease and does not model the predominantly mild neurocognitive human phenotype — a discrepancy attributed to paralog redundancy and species GSH-handling differences.

Applications. The models established the proximate mechanism (tissue GSH/cysteine deficiency) and therapeutic reversibility (NAC/OTZ), underpinning the rational treatment hypothesis for humans.

Resources: MGI (mouse Ggt1, Gene 14598). No established zebrafish/Drosophila/C. elegans/organoid disease models are recorded for this condition in the knowledge base.

Mechanistic Model / Interpretation

The disease is best understood as a failure of the salvage arm of the glutathione (γ-glutamyl) cycle. Glutathione synthesized intracellularly (predominantly in liver) is exported to plasma and filtered at the glomerulus; the renal proximal-tubule brush-border GGT normally hydrolyzes this extracellular GSH, releasing amino acids (notably cysteine) for reuptake and reuse. When GGT1 is lost, this salvage step fails: glutathione cannot be reclaimed and spills into urine (glutathionuria) while accumulating in plasma (glutathionemia), and the cell is deprived of recovered cysteine.

Whether that cysteine deprivation becomes clinically significant depends on how much redundant/alternative cysteine supply remains. In mice — with the sharpest metabolic dependence and (apparently) less effective buffering — systemic cysteine/GSH depletion produces a severe, multisystem, life-shortening phenotype that is fully bypassable by feeding cysteine (NAC) or a cysteine prodrug (OTZ). In humans, the presence of 13 GGT-family paralogs plus dietary cysteine appears to buffer systemic cysteine supply, so the phenotype is limited to a mild, chiefly neurocognitive presentation. This two-branch model (identical upstream lesion; divergent downstream severity set by cysteine-supply redundancy) reconciles the dramatic human biochemistry with the surprisingly benign human clinical course, and it directly motivates cysteine-repletion therapy as the rational — though still unproven in humans — intervention.

Feature Human disease Mouse model
Glutathionuria / glutathionemia Yes (marked) Yes (marked)
Serum GGT activity Absent/very low Absent/very low
Growth failure Not prominent Severe
Cataracts / infertility / osteopenia Not reported Present
Neurocognitive phenotype Prominent (mild-moderate ID, behavior) Not the focus
Life span Apparently normal Shortened
Rescue by NAC / OTZ Untested Demonstrated

Evidence Base

PMID Title (abbrev.) Role
29483667 GGT deficiency from large homozygous GGT1 deletion Molecular proof of causal gene & AR inheritance; rarity/underdiagnosis; mild human phenotype
15702405 Two Japanese brothers with hereditary GGT deficiency Biochemical signature; diagnostic pitfall (citrulline peak); Marfanoid habitus
6118466 Glutathionuria: GGT deficiency Human CNS/behavioral phenotype; normal amino-acid transport
238530 Glutathionuria: inborn error from tissue GGT deficiency Early definition; tissue enzyme deficiency
42531 Rat renal GGT characterization Localizes GGT to proximal-tubule brush border; GSH reclamation; normal amino-acid reabsorption
45011 New aspects of glutathione metabolism/translocation Epithelial anatomical distribution of GGT
34150 Translocation of GSH to GGT; glutathionuria after inhibition Mechanism: GSH translocation; inhibition phenocopies disease
2873573 Induction of glutathionuria by γ-glutamyl amino acids Pharmacologic phenocopy; substrate competition
9139708 Mice with genetic GGT deficiency ENU GGTenu1 model origin & phenotype
11089562 Reproductive defects in GGT-deficient mice Cysteine-deficiency mechanism; NAC rescue of fertility
12757858 OTZ supplementation in murine GGT deficiency Tissue GSH deficiency as proximate cause; OTZ rescue
12810527 Reversible skeletal abnormalities in GGT-deficient mice Bone phenotype; NAC reversibility
26536828 Maturation mechanism of γ-GTs Ntn-hydrolase family; autocatalytic maturation
33187988 Crystal structures of human GGT1 Catalytic Thr-381 mechanism
37739139 Targeting GGT (review) Physiologic role: cysteine recovery, redox homeostasis
41316810 GGT molecular family 13-gene paralog family (redundancy rationale)
17397529 Inborn errors of glutathione metabolism AR inheritance; leaky mutations/variable expressivity

Consistency. The findings are internally consistent: physiologic localization studies (brush border; PMID: 42531) explain the urinary-loss phenotype; pharmacologic inhibition experiments (PMID: 34150; PMID: 2873573) phenocopy the inherited defect; mouse genetics (PMID: 11089562; PMID: 12757858; PMID: 12810527) establish causality and reversibility; and human genetics (PMID: 29483667) confirm the gene and inheritance. The main tension in the evidence base is the severity mismatch between mouse and human, addressed by the paralog-redundancy hypothesis.

Limitations and Knowledge Gaps

  1. Tiny human sample (<8 patients): prevalence, penetrance, expressivity, sex ratio, and genotype–phenotype correlations cannot be reliably estimated.
  2. Mechanism in humans is inferred: cysteine depletion as the proximate cause and NAC/OTZ reversibility are proven only in mice; never formally demonstrated or trialed in human patients.
  3. No validated biomarkers of prognosis and no natural-history studies.
  4. Causal spectrum incomplete: only a structural deletion is molecularly proven; the full allelic spectrum (point mutations) and carrier frequency remain undefined; structural variants may be missed by standard exome sequencing.
  5. Species discrepancy unresolved at the molecular level: the paralog-redundancy explanation is plausible but not directly tested.
  6. No disease-specific therapy is approved or trialed in humans.
  7. Under-ascertainment: glutathione is not in standard screens, so the true disease burden is unknown.

Proposed Follow-up Experiments / Actions

  1. International case finding / registry: Prospectively measure urine and plasma glutathione in unexplained intellectual disability with the "citrulline-position" chromatographic peak; aggregate cases to estimate prevalence and phenotype spectrum.
  2. Define the GGT1 allelic spectrum: Apply WGS/CNV-aware pipelines (not exome alone) in suspected cases to catalog point and structural variants; estimate carrier frequency from large population datasets with structural-variant calling.
  3. Test the cysteine-depletion mechanism in humans: Measure intracellular/erythrocyte cysteine and GSH in confirmed patients; correlate with clinical severity.
  4. Pilot cysteine-repletion therapy: Given mouse reversibility and NAC's established safety, consider an n-of-1 or small compassionate-use trial of NAC/OTZ with biochemical (plasma/urine GSH, cysteine) and developmental endpoints.
  5. Interrogate paralog redundancy: Quantify residual GGT activity from paralogs (GGT5, etc.) in patient tissues/iPSC-derived cells; model double-paralog loss to test the severity-buffering hypothesis.
  6. Improve the human-relevant model: Engineer humanized or paralog-sensitized mouse/organoid models that reproduce the mild human neurocognitive phenotype for mechanism and therapy testing.
  7. Ontology/knowledge-base annotation: Finalize mappings (MONDO:0009285; GGT1/HGNC:4250; HP:0001249, HP:0001263, HP:0000708; GO:0006751/GO:0036374; UBERON proximal tubule; CHEBI:16856 glutathione; NCIT:C28159 acetylcysteine) for the disease entry.

Evidence source legend: Human clinical = case reports/series (PMID: 29483667, 15702405, 6118466, 238530); Model organism = mouse (PMID: 9139708, 11089562, 12757858, 12810527); In vitro/structural (PMID: 33187988, 26536828); Reviews (PMID: 37739139, 17397529, 41316810).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 17
Quoted claims found in source 17
Quoted claims not found in source 0
References weighed for topical relevance 17
On topic 11
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:26536828 (7 mentions) - The maturation mechanism of γ-glutamyl transpeptidases: Insights from the crystal structure of a precursor mimic of the enzyme from Bacillus licheniformis and from site-directed mutagenesis studies.
  • shared terms: enzyme, genetic

Weighed against this report's own most characteristic terms: human, disease, cysteine, glutathione, phenotype, ggt, mouse, deficiency, ggt1, gsh, glutathionuria, biochemical, patient, metabolic, enzyme, gene, genetic, otz, activity, clinical.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 24
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 20
Terms named correctly 12
Terms named as a different term 3
Terms whose name is worth a second look 5

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0009285 (3 mentions) - the report calls it "MONDO"; MONDO calls it gamma-glutamyl transpeptidase deficiency
  • HP:0001249 (2 mentions) - the report calls it "Clinical sign"; HP calls it Intellectual disability
  • HP:0001263 (2 mentions) - the report calls it "Clinical sign"; HP calls it Global developmental delay

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0006534 (obsolete cysteine metabolic process) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000708 (2 mentions) - the report calls it "Behavioral"; HP calls it Atypical behavior, and lists "Behavioral changes" among its other names
  • HP:0000707 (1 mention) - the report calls it "abnormality of nervous system"; HP calls it Abnormality of the nervous system
  • GO:0036374 (3 mentions) - the report calls it "glutathione hydrolase activity"; GO calls it glutathione gamma-glutamate hydrolase, and lists "glutathione hydrolase activity" among its other names
  • GO:0006534 (1 mention) - the report calls it "cysteine metabolic process"; GO calls it obsolete cysteine metabolic process
  • UBERON:0004134 (1 mention) - the report calls it "proximal convoluted tubule"; UBERON calls it proximal tubule, and lists "proximal kidney tubule" among its other names