Primary Hyperoxaluria Type 1

Metabolic Disorder MONDO:0009823 Pathograph 5 Show in embeddings browser Inborn Error of Metabolism Primary Hyperoxaluria Genetic Kidney Disease

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of hepatic peroxisomal glyoxylate metabolism caused by biallelic AGXT pathogenic variants. Deficient alanine-glyoxylate aminotransferase activity prevents glyoxylate conversion to glycine, diverts glyoxylate to oxalate, and drives excessive endogenous oxalate production. Oxalate must be cleared by the kidney; high urinary oxalate causes calcium oxalate supersaturation, nephrolithiasis, nephrocalcinosis, progressive chronic kidney disease, and systemic oxalosis after advanced kidney failure.

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1
Inheritance
5
Pathophys.
4
Phenotypes
5
Pathograph
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"PH1 is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance for PH1.
⚙

Pathophysiology

5
AGXT Alanine-Glyoxylate Aminotransferase Deficiency
Biallelic AGXT pathogenic variants reduce or abolish hepatic peroxisomal alanine-glyoxylate aminotransferase activity, the reaction that converts glyoxylate to glycine.
hepatocyte CL:0000182
AGXT hgnc:341
glyoxylate metabolic process GO:0046487 ↕ DYSREGULATED
L-alanine:glyoxylate transaminase activity GO:0008453 ↓ DECREASED
peroxisome GO:0005777
Downstream
Glyoxylate Diversion to Oxalate Reduced AGT activity leaves glyoxylate available for conversion to oxalate.
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine."
Supports the AGXT/AGT enzyme deficiency and peroxisomal hepatic glyoxylate reaction.
Glyoxylate Diversion to Oxalate
Failure to transaminate glyoxylate to glycine diverts glyoxylate into oxalate production. Oxalate is not further metabolized in humans, so the endogenous overproduction raises urinary and, with kidney failure, plasma oxalate burden.
glyoxylate metabolic process GO:0046487 ↕ DYSREGULATED
Downstream
Urinary Calcium Oxalate Supersaturation Excess oxalate excretion raises urinary calcium oxalate supersaturation.
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys."
Supports oxalate overproduction as the biochemical consequence of AGT deficiency.
Urinary Calcium Oxalate Supersaturation
High urinary oxalate concentration promotes formation of insoluble calcium oxalate crystals, specializing the nephrolithiasis supersaturation module to PH1.
Renal Excretion of Oxalate GO:0007588 ↑ INCREASED
Downstream
Calcium Oxalate Nephrolithiasis and Nephrocalcinosis Calcium oxalate crystals aggregate into stones and deposit in renal parenchyma.
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"Insoluble calcium oxalate crystals form due to high urinary oxalate concentration."
Directly supports urinary oxalate-driven calcium oxalate crystallization.
Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
Calcium oxalate crystal aggregation causes recurrent stones in the renal pelvis and urinary tract, while deposition in renal parenchyma produces nephrocalcinosis.
kidney UBERON:0002113
Downstream
Progressive Kidney Failure and Systemic Oxalosis Recurrent obstruction, infection, and nephrocalcinosis drive CKD; after advanced CKD, oxalate deposits systemically.
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones)"
Supports calcium oxalate nephrolithiasis as a downstream consequence of urinary crystallization.
Progressive Kidney Failure and Systemic Oxalosis
Untreated PH1 can cause progressive kidney-function loss. When renal oxalate clearance fails, plasma oxalate rises and calcium oxalate deposits in extra-renal tissues such as bone, heart, and retina.
Show evidence (2 references)
PMID:20301460 SUPPORT Other
"The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis"
Supports progressive kidney dysfunction after stones and nephrocalcinosis.
PMID:20301460 SUPPORT Other
"high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis")"
Supports systemic oxalosis after advanced CKD.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Primary Hyperoxaluria Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Genitourinary 1
Stage 5 chronic kidney disease Stage 5 chronic kidney disease HP:0003774
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement."
Supports kidney failure as a severe outcome of untreated PH1.
Other 3
Hyperoxaluria Hyperoxaluria HP:0003159
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"supportive laboratory findings (excess excretion of oxalate in the urine and/or markedly increased plasma oxalate concentration)"
GeneReviews identifies excess urine oxalate as a supportive laboratory finding.
Calcium oxalate nephrolithiasis Calcium oxalate nephrolithiasis HP:0008672
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones)"
Supports calcium oxalate kidney stones in PH1.
Nephrocalcinosis Nephrocalcinosis HP:0000121
Show evidence (1 reference)
PMID:20301460 SUPPORT Other
"often the crystals deposit in kidney parenchyma (nephrocalcinosis)."
Supports nephrocalcinosis in PH1.
{ }

Source YAML

click to show 
name: Primary Hyperoxaluria Type 1
creation_date: "2026-07-06T06:09:44Z"
description: >-
  Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of
  hepatic peroxisomal glyoxylate metabolism caused by biallelic AGXT pathogenic
  variants. Deficient alanine-glyoxylate aminotransferase activity prevents
  glyoxylate conversion to glycine, diverts glyoxylate to oxalate, and drives
  excessive endogenous oxalate production. Oxalate must be cleared by the
  kidney; high urinary oxalate causes calcium oxalate supersaturation,
  nephrolithiasis, nephrocalcinosis, progressive chronic kidney disease, and
  systemic oxalosis after advanced kidney failure.
category: Metabolic Disorder
parents:
- Inborn Error of Metabolism
- Primary Hyperoxaluria
- Genetic Kidney Disease
synonyms:
- PH1
- AGXT deficiency
- Alanine-glyoxylate aminotransferase deficiency
classifications:
  icimd_category:
  - classification_value: glyoxylate_and_oxalate
    notes: >-
      ICIMD category 13.1, disorders of glyoxylate and oxalate metabolism.
      PH1 is the AGXT/alanine-glyoxylate aminotransferase defect in this group.
disease_term:
  preferred_term: primary hyperoxaluria type 1
  term:
    id: MONDO:0009823
    label: primary hyperoxaluria type 1
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PH1 is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the mode of inheritance for PH1.
pathophysiology:
- name: AGXT Alanine-Glyoxylate Aminotransferase Deficiency
  description: >-
    Biallelic AGXT pathogenic variants reduce or abolish hepatic peroxisomal
    alanine-glyoxylate aminotransferase activity, the reaction that converts
    glyoxylate to glycine.
  role: trigger
  genes:
  - preferred_term: AGXT
    term:
      id: hgnc:341
      label: AGXT
  molecular_functions:
  - preferred_term: L-alanine:glyoxylate transaminase activity
    term:
      id: GO:0008453
      label: L-alanine:glyoxylate transaminase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  biological_processes:
  - preferred_term: glyoxylate metabolic process
    term:
      id: GO:0046487
      label: glyoxylate metabolic process
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine."
    explanation: Supports the AGXT/AGT enzyme deficiency and peroxisomal hepatic glyoxylate reaction.
  downstream:
  - target: Glyoxylate Diversion to Oxalate
    causal_link_type: DIRECT
    description: Reduced AGT activity leaves glyoxylate available for conversion to oxalate.
    evidence:
    - reference: PMID:20301460
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys."
      explanation: Directly links AGT loss to oxalate generation and renal excretion.
- name: Glyoxylate Diversion to Oxalate
  description: >-
    Failure to transaminate glyoxylate to glycine diverts glyoxylate into
    oxalate production. Oxalate is not further metabolized in humans, so the
    endogenous overproduction raises urinary and, with kidney failure, plasma
    oxalate burden.
  role: amplifier
  biological_processes:
  - preferred_term: glyoxylate metabolic process
    term:
      id: GO:0046487
      label: glyoxylate metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: glyoxylate
    term:
      id: CHEBI:36655
      label: glyoxylate
    modifier: ABNORMAL
  - preferred_term: oxalate
    term:
      id: CHEBI:132952
      label: oxalate
    modifier: INCREASED
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys."
    explanation: Supports oxalate overproduction as the biochemical consequence of AGT deficiency.
  downstream:
  - target: Urinary Calcium Oxalate Supersaturation
    causal_link_type: DIRECT
    description: Excess oxalate excretion raises urinary calcium oxalate supersaturation.
- name: Urinary Calcium Oxalate Supersaturation
  conforms_to: "nephrolithiasis_crystal_nucleation#Urinary Supersaturation"
  description: >-
    High urinary oxalate concentration promotes formation of insoluble calcium
    oxalate crystals, specializing the nephrolithiasis supersaturation module to
    PH1.
  role: central_effector
  biological_processes:
  - preferred_term: Renal Excretion of Oxalate
    term:
      id: GO:0007588
      label: excretion
    modifier: INCREASED
  chemical_entities:
  - preferred_term: oxalate
    term:
      id: CHEBI:132952
      label: oxalate
    modifier: INCREASED
  - preferred_term: calcium oxalate
    term:
      id: CHEBI:60579
      label: calcium oxalate
    modifier: INCREASED
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Insoluble calcium oxalate crystals form due to high urinary oxalate concentration."
    explanation: Directly supports urinary oxalate-driven calcium oxalate crystallization.
  downstream:
  - target: Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
    causal_link_type: DIRECT
    description: Calcium oxalate crystals aggregate into stones and deposit in renal parenchyma.
- name: Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
  conforms_to: "nephrolithiasis_crystal_nucleation#Symptomatic Kidney Stones"
  description: >-
    Calcium oxalate crystal aggregation causes recurrent stones in the renal
    pelvis and urinary tract, while deposition in renal parenchyma produces
    nephrocalcinosis.
  role: consequence
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones)"
    explanation: Supports calcium oxalate nephrolithiasis as a downstream consequence of urinary crystallization.
  downstream:
  - target: Progressive Kidney Failure and Systemic Oxalosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Recurrent obstruction, infection, and nephrocalcinosis drive CKD; after advanced CKD, oxalate deposits systemically.
- name: Progressive Kidney Failure and Systemic Oxalosis
  description: >-
    Untreated PH1 can cause progressive kidney-function loss. When renal oxalate
    clearance fails, plasma oxalate rises and calcium oxalate deposits in
    extra-renal tissues such as bone, heart, and retina.
  role: consequence
  chemical_entities:
  - preferred_term: oxalate
    term:
      id: CHEBI:132952
      label: oxalate
    modifier: INCREASED
  - preferred_term: calcium oxalate
    term:
      id: CHEBI:60579
      label: calcium oxalate
    modifier: INCREASED
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis"
    explanation: Supports progressive kidney dysfunction after stones and nephrocalcinosis.
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., \"oxalosis\")"
    explanation: Supports systemic oxalosis after advanced CKD.
phenotypes:
- category: Biochemical
  name: Hyperoxaluria
  description: Excess urinary oxalate excretion is the diagnostic biochemical marker of PH1.
  phenotype_term:
    preferred_term: Hyperoxaluria
    term:
      id: HP:0003159
      label: Hyperoxaluria
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "supportive laboratory findings (excess excretion of oxalate in the urine and/or markedly increased plasma oxalate concentration)"
    explanation: GeneReviews identifies excess urine oxalate as a supportive laboratory finding.
- category: Clinical
  name: Calcium oxalate nephrolithiasis
  description: High urinary oxalate drives calcium oxalate kidney stones.
  phenotype_term:
    preferred_term: Calcium oxalate nephrolithiasis
    term:
      id: HP:0008672
      label: Calcium oxalate nephrolithiasis
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones)"
    explanation: Supports calcium oxalate kidney stones in PH1.
- category: Clinical
  name: Nephrocalcinosis
  description: Calcium oxalate crystals frequently deposit in renal parenchyma.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "often the crystals deposit in kidney parenchyma (nephrocalcinosis)."
    explanation: Supports nephrocalcinosis in PH1.
- category: Clinical
  name: Stage 5 chronic kidney disease
  description: Advanced PH1 can progress to kidney failure.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:20301460
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement."
    explanation: Supports kidney failure as a severe outcome of untreated PH1.
notes: >-
  Package seed 13.1.04.01; OMIM:259900. MONDO provides an exact disease term
  for PH1, so this is curated as a separate Disease entry rather than as a
  subtype of a broader primary hyperoxaluria entry.