Primary Hyperoxaluria Type 2

Metabolic Disorder MONDO:0009824 Pathograph 5 Show in embeddings browser Inborn Error of Metabolism Primary Hyperoxaluria Genetic Kidney Disease

Primary hyperoxaluria type 2 (PH2) is an autosomal recessive disorder of hepatic glyoxylate metabolism caused by biallelic GRHPR pathogenic variants. Deficient glyoxylate reductase/hydroxypyruvate reductase activity reduces glyoxylate-to-glycolate and hydroxypyruvate-to-D-glycerate flux, causing increased urinary oxalate and L-glycerate. Increased oxalate excretion drives calcium oxalate nephrolithiasis, nephrocalcinosis, and in some individuals kidney failure with systemic oxalate deposition.

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1
Inheritance
5
Pathophys.
4
Phenotypes
5
Pathograph
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
glyoxylate and oxalate
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301742 SUPPORT Other
"PH2 is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance for PH2.
⚙

Pathophysiology

5
GRHPR Glyoxylate Reductase Deficiency
Biallelic GRHPR pathogenic variants reduce glyoxylate reductase/hydroxypyruvate reductase activity, disrupting reduction of glyoxylate to glycolate and hydroxypyruvate to D-glycerate.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
GRHPR hgnc:4570 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GRHPR (hgnc:4570). hgnc:4570 is a gene from the HUGO Gene Nomenclature Committee.
glyoxylate metabolic process GO:0046487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated glyoxylate metabolic process (GO:0046487). GO:0046487 is a biological process from the Gene Ontology. ↕ DYSREGULATED
glyoxylate reductase activity GO:0106345 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glyoxylate reductase activity (GO:0106345). GO:0106345 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Oxalate and L-Glycerate Overexcretion Loss of GRHPR activity raises urinary oxalate and L-glycerate.
Show evidence (2 references)
PMID:14635115 SUPPORT Human Clinical
"Primary hyperoxaluria type 2, an inherited autosomal recessive disorder of endogenous oxalate overproduction, is caused by mutations in the GRHPR gene encoding the glyoxylate/hydroxypyruvate reductase enzyme."
Supports GRHPR mutations and enzyme deficiency as the proximal PH2 lesion.
PMID:14635115 SUPPORT In Vitro
"our study shows that GRHPR protein distribution is predominantly hepatic and concludes that PH2, like the related type 1 disease, is primarily a disorder affecting hepatic glyoxylate metabolism."
Supports the hepatocyte cell-type annotation and the framing of PH2 as a primarily hepatic glyoxylate-metabolism defect.
Oxalate and L-Glycerate Overexcretion
GRHPR deficiency increases urinary oxalate and L-glycerate, indicating both glyoxylate and hydroxypyruvate pathway disruption.
glyoxylate metabolic process GO:0046487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated glyoxylate metabolic process (GO:0046487). GO:0046487 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Urinary Calcium Oxalate Supersaturation Increased urinary oxalate raises calcium oxalate supersaturation.
Show evidence (1 reference)
PMID:10484776 SUPPORT Human Clinical
"The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate."
Supports the defining biochemical profile.
Urinary Calcium Oxalate Supersaturation
Increased urinary oxalate raises the calcium oxalate crystallization burden in PH2, specializing the nephrolithiasis supersaturation module to GRHPR deficiency.
Renal Excretion of Oxalate GO:0007588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Renal Excretion of Oxalate, annotated with excretion (GO:0007588). GO:0007588 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Calcium Oxalate Nephrolithiasis and Nephrocalcinosis Calcium oxalate supersaturation leads to stones and parenchymal calcification.
Show evidence (1 reference)
PMID:10484776 SUPPORT Human Clinical
"The increased oxalate excretion can cause nephrolithiasis"
Supports oxalate excretion as the upstream cause of stone formation.
Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
PH2 commonly presents with recurrent calcium oxalate nephrolithiasis and nephrocalcinosis; severe disease can progress to end-stage kidney disease and systemic oxalate deposition.
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Systemic Oxalate Deposition After advanced kidney failure, calcium oxalate can deposit systemically.
Show evidence (2 references)
PMID:20301742 SUPPORT Other
"PH2, caused by deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), is characterized by recurrent nephrolithiasis"
Supports recurrent nephrolithiasis in PH2.
PMID:20301742 SUPPORT Other
"nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), and end-stage kidney disease (ESKD)."
Supports nephrocalcinosis and severe kidney outcome in PH2.
Systemic Oxalate Deposition
With end-stage kidney disease, PH2 can progress to oxalosis, with widespread tissue calcium oxalate deposition.
Show evidence (1 reference)
PMID:20301742 SUPPORT Other
"After ESKD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops."
Supports systemic oxalate deposition after kidney failure.
⬡

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 2 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 HP:0003774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stage 5 chronic kidney disease (HP:0003774). HP:0003774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301742 SUPPORT Other
"and end-stage kidney disease (ESKD)."
Supports ESKD as a severe PH2 outcome.
Other 3
Hyperoxaluria HP:0003159 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperoxaluria (HP:0003159). HP:0003159 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10484776 SUPPORT Human Clinical
"The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate."
Supports hyperoxaluria as a biochemical feature.
Calcium oxalate nephrolithiasis HP:0008672 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Calcium oxalate nephrolithiasis (HP:0008672). HP:0008672 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301742 SUPPORT Other
"recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis"
Supports recurrent calcium oxalate nephrolithiasis.
Nephrocalcinosis HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301742 SUPPORT Other
"nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma)"
Supports nephrocalcinosis in PH2.
{ }

Source YAML

click to show 
name: Primary Hyperoxaluria Type 2
creation_date: "2026-07-06T06:09:44Z"
description: >-
  Primary hyperoxaluria type 2 (PH2) is an autosomal recessive disorder of
  hepatic glyoxylate metabolism caused by biallelic GRHPR pathogenic variants.
  Deficient glyoxylate reductase/hydroxypyruvate reductase activity reduces
  glyoxylate-to-glycolate and hydroxypyruvate-to-D-glycerate flux, causing
  increased urinary oxalate and L-glycerate. Increased oxalate excretion drives
  calcium oxalate nephrolithiasis, nephrocalcinosis, and in some individuals
  kidney failure with systemic oxalate deposition.
category: Metabolic Disorder
parents:
- Inborn Error of Metabolism
- Primary Hyperoxaluria
- Genetic Kidney Disease
synonyms:
- PH2
- GRHPR deficiency
- Glyoxylate reductase/hydroxypyruvate reductase deficiency
classifications:
  icimd_category:
  - classification_value: glyoxylate_and_oxalate
    notes: >-
      ICIMD category 13.1, disorders of glyoxylate and oxalate metabolism.
      PH2 is the GRHPR/glyoxylate reductase-hydroxypyruvate reductase defect.
disease_term:
  preferred_term: primary hyperoxaluria type 2
  term:
    id: MONDO:0009824
    label: primary hyperoxaluria type 2
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PH2 is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the mode of inheritance for PH2.
pathophysiology:
- name: GRHPR Glyoxylate Reductase Deficiency
  description: >-
    Biallelic GRHPR pathogenic variants reduce glyoxylate
    reductase/hydroxypyruvate reductase activity, disrupting reduction of
    glyoxylate to glycolate and hydroxypyruvate to D-glycerate.
  role: trigger
  genes:
  - preferred_term: GRHPR
    term:
      id: hgnc:4570
      label: GRHPR
  molecular_functions:
  - preferred_term: glyoxylate reductase activity
    term:
      id: GO:0106345
      label: glyoxylate reductase activity
    modifier: DECREASED
  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:14635115
    reference_title: "Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary hyperoxaluria type 2, an inherited autosomal recessive disorder of endogenous oxalate overproduction, is caused by mutations in the GRHPR gene encoding the glyoxylate/hydroxypyruvate reductase enzyme."
    explanation: Supports GRHPR mutations and enzyme deficiency as the proximal PH2 lesion.
  - reference: PMID:14635115
    reference_title: "Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our study shows that GRHPR protein distribution is predominantly hepatic and concludes that PH2, like the related type 1 disease, is primarily a disorder affecting hepatic glyoxylate metabolism."
    explanation: Supports the hepatocyte cell-type annotation and the framing of PH2 as a primarily hepatic glyoxylate-metabolism defect.
  downstream:
  - target: Oxalate and L-Glycerate Overexcretion
    causal_link_type: DIRECT
    description: Loss of GRHPR activity raises urinary oxalate and L-glycerate.
    evidence:
    - reference: PMID:10484776
      reference_title: "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate."
      explanation: Directly links PH2 to urinary oxalate and L-glycerate overexcretion.
- name: Oxalate and L-Glycerate Overexcretion
  description: >-
    GRHPR deficiency increases urinary oxalate and L-glycerate, indicating both
    glyoxylate and hydroxypyruvate pathway disruption.
  role: amplifier
  biological_processes:
  - preferred_term: glyoxylate metabolic process
    term:
      id: GO:0046487
      label: glyoxylate metabolic process
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: oxalate
    term:
      id: CHEBI:132952
      label: oxalate
    modifier: INCREASED
  - preferred_term: glycerate
    term:
      id: CHEBI:33871
      label: glycerate
    modifier: INCREASED
  - preferred_term: glycolate
    term:
      id: CHEBI:29805
      label: glycolate
    modifier: DECREASED
  evidence:
  - reference: PMID:10484776
    reference_title: "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate."
    explanation: Supports the defining biochemical profile.
  downstream:
  - target: Urinary Calcium Oxalate Supersaturation
    causal_link_type: DIRECT
    description: Increased urinary oxalate raises calcium oxalate supersaturation.
- name: Urinary Calcium Oxalate Supersaturation
  conforms_to: "nephrolithiasis_crystal_nucleation#Urinary Supersaturation"
  description: >-
    Increased urinary oxalate raises the calcium oxalate crystallization burden
    in PH2, specializing the nephrolithiasis supersaturation module to GRHPR
    deficiency.
  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:10484776
    reference_title: "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The increased oxalate excretion can cause nephrolithiasis"
    explanation: Supports oxalate excretion as the upstream cause of stone formation.
  downstream:
  - target: Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
    causal_link_type: DIRECT
    description: Calcium oxalate supersaturation leads to stones and parenchymal calcification.
- name: Calcium Oxalate Nephrolithiasis and Nephrocalcinosis
  conforms_to: "nephrolithiasis_crystal_nucleation#Symptomatic Kidney Stones"
  description: >-
    PH2 commonly presents with recurrent calcium oxalate nephrolithiasis and
    nephrocalcinosis; severe disease can progress to end-stage kidney disease
    and systemic oxalate deposition.
  role: consequence
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PH2, caused by deficiency of the enzyme glyoxylate reductase/hydroxypyruvate reductase (GR/HPR), is characterized by recurrent nephrolithiasis"
    explanation: Supports recurrent nephrolithiasis in PH2.
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), and end-stage kidney disease (ESKD)."
    explanation: Supports nephrocalcinosis and severe kidney outcome in PH2.
  downstream:
  - target: Systemic Oxalate Deposition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: After advanced kidney failure, calcium oxalate can deposit systemically.
- name: Systemic Oxalate Deposition
  description: >-
    With end-stage kidney disease, PH2 can progress to oxalosis, with widespread
    tissue calcium oxalate deposition.
  role: consequence
  chemical_entities:
  - preferred_term: calcium oxalate
    term:
      id: CHEBI:60579
      label: calcium oxalate
    modifier: INCREASED
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "After ESKD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops."
    explanation: Supports systemic oxalate deposition after kidney failure.
phenotypes:
- category: Biochemical
  name: Hyperoxaluria
  description: PH2 is characterized by increased urinary oxalate.
  phenotype_term:
    preferred_term: Hyperoxaluria
    term:
      id: HP:0003159
      label: Hyperoxaluria
  evidence:
  - reference: PMID:10484776
    reference_title: "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate."
    explanation: Supports hyperoxaluria as a biochemical feature.
- category: Clinical
  name: Calcium oxalate nephrolithiasis
  description: Recurrent calcium oxalate stones are a core PH2 manifestation.
  phenotype_term:
    preferred_term: Calcium oxalate nephrolithiasis
    term:
      id: HP:0008672
      label: Calcium oxalate nephrolithiasis
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis"
    explanation: Supports recurrent calcium oxalate nephrolithiasis.
- category: Clinical
  name: Nephrocalcinosis
  description: Calcium oxalate deposition in renal parenchyma is a PH2 feature.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma)"
    explanation: Supports nephrocalcinosis in PH2.
- category: Clinical
  name: Stage 5 chronic kidney disease
  description: Severe PH2 can progress to ESKD.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:20301742
    reference_title: "Primary Hyperoxaluria Type 2."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "and end-stage kidney disease (ESKD)."
    explanation: Supports ESKD as a severe PH2 outcome.
notes: >-
  Package seed 13.1.01.01; OMIM:260000. MONDO provides an exact disease term
  for PH2, so this is curated as a separate Disease entry rather than only a
  subtype of a broad primary hyperoxaluria grouping.