Disorders of Glyoxylate and Oxalate Metabolism

name: Disorders of Glyoxylate and Oxalate Metabolism
display_name: Disorders of Glyoxylate and Oxalate Metabolism
creation_date: "2026-07-06T06:09:44Z"
description: >-
  An auditable grouping of distinct DisMech disease entries whose defining
  defect disrupts glyoxylate, glycolate, oxalate, or calcium oxalate handling.
  Members include hepatic enzyme deficiencies that overproduce oxalate,
  HAO1/glycolate oxidase deficiency upstream of glyoxylate production,
  transporter defects that alter oxalate handling and calcium oxalate stone
  risk, and the classic acquired toxic disorder in which ethylene glycol is
  metabolized through glycolate and glyoxylate to oxalate and floods the same
  pathway.
grouping_basis:
- SHARED_PATHWAY
- SHARED_MECHANISM
grouping_rationale: >-
  The members are kept as separate Disease entries because their proximal
  mechanisms differ: AGXT (PH1), GRHPR (PH2), and HOGA1 (PH3) are hepatic
  glyoxylate-metabolism enzyme defects with endogenous oxalate overproduction;
  HAO1 deficiency is a glycolate oxidase defect that primarily causes
  hyperglycolic aciduria; SLC26A1/SLC26A6 are oxalate/anion transporter
  disorders; and ethylene glycol poisoning is an acquired toxicity in which
  ethylene glycol is oxidized through glycolaldehyde, glycolate, and glyoxylate
  to oxalate, producing acute calcium oxalate crystal deposition. A grouping is
  useful because all belong to the same glyoxylate-and-oxalate pathway (the
  ICIMD inborn-error bucket plus its acquired phenocopy) and share downstream
  concern for oxalate or calcium oxalate handling. CAT catalase deficiency is
  intentionally excluded because it disrupts hydrogen peroxide metabolism
  instead, and secondary enteric hyperoxaluria complicating an unrelated primary
  disease (for example Crohn disease) is excluded because oxalate handling is a
  complication rather than that entry's defining mechanism.
membership_criteria:
- description: >-
    A member's defining mechanism disrupts the glyoxylate/glycolate/oxalate
    pathway or oxalate handling: either a primary genetic defect in a
    glyoxylate/glycolate metabolic enzyme or an oxalate/anion transporter, or an
    acquired toxic exposure whose metabolism floods the pathway with oxalate —
    in either case materially changing oxalate, glycolate, glyoxylate, or
    calcium oxalate handling.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: AGXT
        term:
          id: hgnc:341
          label: AGXT
      description: AGXT/alanine-glyoxylate aminotransferase defect.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: GRHPR
        term:
          id: hgnc:4570
          label: GRHPR
      description: GRHPR/glyoxylate reductase-hydroxypyruvate reductase defect.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: HOGA1
        term:
          id: hgnc:25155
          label: HOGA1
      description: HOGA1/4-hydroxy-2-oxoglutarate aldolase defect.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: HAO1
        term:
          id: hgnc:4809
          label: HAO1
      description: HAO1/glycolate oxidase defect.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: SLC26A1
        term:
          id: hgnc:10993
          label: SLC26A1
      description: SLC26A1/SAT1 anion transporter defect.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: SLC26A6
        term:
          id: hgnc:14472
          label: SLC26A6
      description: SLC26A6 epithelial oxalate transporter defect.
    - criterion_predicate: HAS_PHENOTYPE
      phenotype_term:
        preferred_term: Hyperoxaluria
        term:
          id: HP:0003159
          label: Hyperoxaluria
      description: >-
        Hyperoxaluria driven by acquired toxic conversion into the oxalate
        pathway (ethylene glycol metabolized through glyoxylate to oxalate),
        the non-genetic route into this pathway family.
members:
- member: Primary Hyperoxaluria Type 1
  member_type: DISEASE
  disease_term:
    preferred_term: primary hyperoxaluria type 1
    term:
      id: MONDO:0009823
      label: primary hyperoxaluria type 1
  differentiating_mechanisms:
  - description: >-
      AGXT deficiency blocks hepatic peroxisomal glyoxylate-to-glycine
      transamination, diverting glyoxylate to oxalate and causing severe
      endogenous hyperoxaluria.
    gene:
      preferred_term: AGXT
      term:
        id: hgnc:341
        label: AGXT
    biological_processes:
    - preferred_term: glyoxylate metabolic process
      term:
        id: GO:0046487
        label: glyoxylate metabolic process
      modifier: DYSREGULATED
- member: Primary Hyperoxaluria Type 2
  member_type: DISEASE
  disease_term:
    preferred_term: primary hyperoxaluria type 2
    term:
      id: MONDO:0009824
      label: primary hyperoxaluria type 2
  differentiating_mechanisms:
  - description: >-
      GRHPR deficiency impairs glyoxylate-to-glycolate and
      hydroxypyruvate-to-D-glycerate flux, producing increased urinary oxalate
      and L-glycerate.
    gene:
      preferred_term: GRHPR
      term:
        id: hgnc:4570
        label: GRHPR
    biological_processes:
    - preferred_term: glyoxylate metabolic process
      term:
        id: GO:0046487
        label: glyoxylate metabolic process
      modifier: DYSREGULATED
- member: Primary Hyperoxaluria Type 3
  member_type: DISEASE
  disease_term:
    preferred_term: primary hyperoxaluria type 3
    term:
      id: MONDO:0013327
      label: primary hyperoxaluria type 3
  differentiating_mechanisms:
  - description: >-
      HOGA1 deficiency blocks the final mitochondrial step of hepatic
      hydroxyproline degradation (4-hydroxy-2-oxoglutarate aldolase), causing
      accumulation of 4-hydroxy-2-oxoglutarate and increased endogenous oxalate;
      PH3 is generally the mildest primary hyperoxaluria with rare progression
      to kidney failure.
    gene:
      preferred_term: HOGA1
      term:
        id: hgnc:25155
        label: HOGA1
    biological_processes:
    - preferred_term: glyoxylate metabolic process
      term:
        id: GO:0046487
        label: glyoxylate metabolic process
      modifier: DYSREGULATED
- member: HAO1-Related Glycolate Oxidase Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      HAO1/glycolate oxidase deficiency reduces glycolate oxidation to
      glyoxylate, causing isolated hyperglycolic aciduria and generally benign
      biochemical disease rather than established recurrent calcium oxalate
      nephrolithiasis.
    gene:
      preferred_term: HAO1
      term:
        id: hgnc:4809
        label: HAO1
    biological_processes:
    - preferred_term: glyoxylate metabolic process
      term:
        id: GO:0046487
        label: glyoxylate metabolic process
      modifier: DECREASED
- member: SLC26A1-Related Oxalate Transporter Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SLC26A1/SAT1 variants reduce anion transporter activity and
      cause a recessive Mendelian calcium oxalate nephrolithiasis phenotype.
    gene:
      preferred_term: SLC26A1
      term:
        id: hgnc:10993
        label: SLC26A1
    biological_processes:
    - preferred_term: oxalate transport
      term:
        id: GO:0019532
        label: oxalate transport
      modifier: DECREASED
- member: SLC26A6-Related Hyperoxaluria and Nephrolithiasis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A rare dominant-negative SLC26A6 variant reduces epithelial oxalate
      transport, causing enteric hyperoxaluria and calcium oxalate
      nephrolithiasis in the reported family.
    gene:
      preferred_term: SLC26A6
      term:
        id: hgnc:14472
        label: SLC26A6
    biological_processes:
    - preferred_term: oxalate transport
      term:
        id: GO:0019532
        label: oxalate transport
      modifier: DECREASED
- member: Ethylene Glycol Poisoning
  member_type: DISEASE
  disease_term:
    preferred_term: ethylene glycol poisoning
    term:
      id: MONDO:0017861
      label: ethylene glycol poisoning
  differentiating_mechanisms:
  - description: >-
      Ethylene glycol poisoning is the acquired, non-genetic member: alcohol
      dehydrogenase oxidizes ethylene glycol through glycolaldehyde and glycolate
      to glyoxylate and finally to oxalate, so oxalate overproduction is driven by
      exogenous toxic substrate rather than an enzyme or transporter defect. The
      result is acute calcium oxalate crystal deposition and kidney injury, and
      the treatment (an alcohol dehydrogenase inhibitor) blocks the pathway
      upstream rather than replacing a missing function.
    biological_processes:
    - preferred_term: glyoxylate metabolic process
      term:
        id: GO:0046487
        label: glyoxylate metabolic process
      modifier: INCREASED
notes: >-
  Created for WP-032 to make the package boundary auditable without lumping
  distinct enzyme and transporter defects into one Disease entry.