Disorders of Copper Metabolism

name: Disorders of Copper Metabolism
display_name: Disorders of Copper Metabolism
creation_date: "2026-08-16T15:30:00Z"
description: >-
  An auditable grouping of distinct DisMech disease entries whose primary
  genetic defect disrupts cellular copper transport, trafficking, or delivery.
  Members span the two paralogous copper-transporting P-type ATPases — ATP7B
  (Wilson disease, copper OVERLOAD from failed biliary excretion) and ATP7A
  (Menkes disease, systemic copper DEFICIENCY from failed intestinal export) —
  plus secretory-pathway/trafficking defects that impair copper delivery and
  lower serum copper and ceruloplasmin (AP1S1 / MEDNIK syndrome and SLC33A1 /
  Huppke-Brendel syndrome).
grouping_basis:
- SHARED_PATHWAY
grouping_rationale: >-
  The members are kept as separate Disease entries because their proximal
  mechanisms differ. ATP7B and ATP7A are direct paralogs from the same family
  of copper-transporting P-type ATPases, acting in opposite directions: ATP7B loss
  causes hepatic copper overload and toxic systemic accumulation, while ATP7A
  loss causes failed intestinal copper export and systemic copper deficiency
  (X-linked Menkes disease). AP1S1 encodes an adaptor-protein-1 (AP-1) complex
  sigma subunit whose loss disrupts intracellular trafficking of the copper
  pumps; and SLC33A1 encodes the ER acetyl-CoA transporter AT-1, whose
  deficiency lowers serum copper and ceruloplasmin. A grouping is useful because
  all four fall in the ICIMD "Copper" group (Disorders of trace elements and
  metals) and converge on disrupted copper homeostasis. Iron-primary disorders
  such as aceruloplasminemia (CP / ferroxidase deficiency) are intentionally
  excluded because their proximal lesion is iron export, not copper handling,
  despite the shared ceruloplasmin connection. Occipital horn syndrome is
  allelic to Menkes (also ATP7A) and is not separately modeled in the KB, so it
  is represented here through the Menkes entry rather than as its own member.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017762
      label: disorder of copper metabolism
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch rather than exactMatch: this grouping is a curated union of the
      four copper-metabolism Disease entries currently in the KB, whereas
      MONDO:0017762 is the full ontology class of disorders of copper metabolism
      (which subsumes further entities, including ATP7A-allelic occipital horn
      syndrome). Same concept, curated subset extension.
membership_criteria:
- description: >-
    A member has a primary genetic defect in a gene required for cellular copper
    transport, trafficking, or delivery.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: ATP7B
        term:
          id: hgnc:870
          label: ATP7B
      description: ATP7B copper-transporting P-type ATPase defect (Wilson disease).
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: ATP7A
        term:
          id: hgnc:869
          label: ATP7A
      description: >-
        ATP7A copper-transporting P-type ATPase defect (Menkes disease) — the
        ATP7B paralog acting in the opposite direction.
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: AP1S1
        term:
          id: hgnc:559
          label: AP1S1
      description: >-
        AP1S1 adaptor-protein-1 complex subunit defect disrupting copper
        trafficking (MEDNIK syndrome).
    - criterion_predicate: HAS_GENE
      gene:
        preferred_term: SLC33A1
        term:
          id: hgnc:95
          label: SLC33A1
      description: >-
        SLC33A1 / AT-1 ER acetyl-CoA transporter defect lowering serum copper
        and ceruloplasmin (Huppke-Brendel syndrome).
members:
- member: Wilson Disease
  member_type: DISEASE
  disease_term:
    preferred_term: Wilson disease
    term:
      id: MONDO:0010200
      label: Wilson disease
  differentiating_mechanisms:
  - description: >-
      ATP7B loss impairs biliary copper excretion and ceruloplasmin loading,
      causing hepatic copper overload with toxic systemic (hepatic and
      neurologic) copper accumulation — copper OVERLOAD.
    gene:
      preferred_term: ATP7B
      term:
        id: hgnc:870
        label: ATP7B
- member: Menkes Disease
  member_type: DISEASE
  disease_term:
    preferred_term: Menkes disease
    term:
      id: MONDO:0010651
      label: Menkes disease
  differentiating_mechanisms:
  - description: >-
      ATP7A loss impairs intestinal copper export and delivery of copper to
      cuproenzymes, causing systemic copper DEFICIENCY with neurodegeneration
      and connective-tissue disease — the opposite-direction paralog of the
      ATP7B defect, and X-linked rather than autosomal recessive.
    gene:
      preferred_term: ATP7A
      term:
        id: hgnc:869
        label: ATP7A
- member: MEDNIK syndrome
  member_type: DISEASE
  disease_term:
    preferred_term: MEDNIK syndrome
    term:
      id: MONDO:0012251
      label: MEDNIK syndrome
  differentiating_mechanisms:
  - description: >-
      AP1S1 loss of function disrupts AP-1-dependent intracellular trafficking
      of copper pumps, producing a mixed copper-metabolism and general
      trafficking phenotype (enteropathy, deafness, neuropathy, ichthyosis,
      keratoderma).
    gene:
      preferred_term: AP1S1
      term:
        id: hgnc:559
        label: AP1S1
- member: Huppke-Brendel syndrome
  member_type: DISEASE
  disease_term:
    preferred_term: Huppke-Brendel syndrome
    term:
      id: MONDO:0013772
      label: Huppke-Brendel syndrome
  differentiating_mechanisms:
  - description: >-
      SLC33A1 / AT-1 ER acetyl-CoA transporter deficiency lowers serum copper
      and ceruloplasmin with congenital cataracts, hearing loss, and severe
      developmental delay — a low-copper delivery phenotype.
    gene:
      preferred_term: SLC33A1
      term:
        id: hgnc:95
        label: SLC33A1