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.
Ask a research question about Primary Hyperoxaluria Type 2. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
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
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
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.
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
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
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
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
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
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
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
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
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
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
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.