Hereditary Systemic Amyloidoses

name: Hereditary Systemic Amyloidoses
display_name: Hereditary Systemic Amyloidoses
creation_date: "2026-08-17T00:00:00Z"
description: >-
  The hereditary systemic amyloidoses are a group of Mendelian diseases in which
  a germline variant in a precursor protein renders that protein amyloidogenic,
  so that it misfolds, assembles into beta-sheet fibrils, and deposits as
  extracellular amyloid in multiple organs (characteristically peripheral and
  autonomic nerve, heart, kidney, and gastrointestinal tract). The members
  differ in the precursor protein, causal gene, proximal misfolding event, and
  organ tropism, but converge downstream on amyloid fibril formation and
  progressive tissue amyloid accumulation. This grouping is deliberately scoped
  to the SYSTEMIC hereditary amyloidoses; the hereditary CEREBRAL/localized
  amyloidoses (e.g. cerebral amyloid angiopathy, ADan/ABri ITM2B amyloidosis,
  the ABeta and cystatin-C forms, localized cutaneous amyloidosis) are out of
  scope even though they share the same downstream amyloidogenesis mechanism.
grouping_basis:
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared downstream mechanism: every member is an inherited
  (germline) amyloidosis whose disease-causing precursor protein misfolds and
  deposits as systemic amyloid, conforming to the amyloidogenesis module
  (amyloidogenic precursor -> protein misfolding/beta-sheet oligomerization ->
  amyloid fibril formation and extracellular deposition -> progressive tissue
  amyloid accumulation -> organ dysfunction). The members are kept as SEPARATE
  Disease entries rather than folded into one umbrella Disease, because they are
  genuinely distinct diseases: they differ in precursor protein and causal gene
  (transthyretin/TTR, apolipoprotein A-I/APOA1, apolipoprotein A-II/APOA2,
  gelsolin/GSN, fibrinogen A alpha-chain/FGA, lysozyme/LYZ), in the proximal
  molecular defect, in organ tropism, and in treatment. Sharing the
  amyloidogenesis module is not a reason to merge them; the module IS the shared
  convergence, and the grouping is a labeled union that points down at the
  discrete Disease entries. This mirrors the modeling of the acquired
  amyloidoses and follows the maintainer directive on issue #8655 (do NOT create
  an umbrella kb/disorders/Hereditary_Amyloidosis.yaml; represent this concept as
  a grouping; do not treat the dashboard action code CURATE_ROOT_WITH_SUBTYPES as
  a has_subtypes ruling).

  Current members: Hereditary Transthyretin Amyloidosis (ATTRv), the classic
  neuropathic/cardiac precursor form, and Familial Visceral Amyloidosis
  (MONDO:0007099), the Ostertag-type non-neuropathic visceral concept, which is
  curated as one Disease entry carrying the four precursor-defined forms
  (AApoAI/APOA1 MONDO:0019731, AApoAII/APOA2 MONDO:0016533, AFib/FGA
  MONDO:0019733, ALys/LYZ MONDO:0019732) as has_subtypes. That entry is
  MONDO:0007099's own MONDO subtree, so listing it here covers four of the five
  intended precursor members at once without inventing member foreign keys.

  Still TODO: AGel/Finnish-type gelsolin amyloidosis (GSN; MONDO:0007097) is
  curated as kb/disorders/Finnish_Type_Amyloidosis.yaml but is not yet listed as
  a member of this grouping. The four visceral precursor forms may later be split
  out as discrete Disease entries; if they are, they should be added here as
  members in their own right and the Familial Visceral Amyloidosis membership
  revisited.

  ADan amyloidosis (kb/disorders/ADan_amyloidosis.yaml, MONDO:0007297) is
  deliberately EXCLUDED. It is a descendant of the broad hereditary amyloidosis
  class (MONDO:0018634) and shares the amyloidogenesis convergence, but its
  direct MONDO parents are cerebral amyloid angiopathy (MONDO:0005620) and ITM2B
  amyloidosis (MONDO:0018591): it is a hereditary CEREBRAL amyloidosis whose
  precursor is the ITM2B/BRI2-derived ADan peptide (ITM2B, HGNC:6174), a
  different precursor family from the classic systemic precursors and a
  CNS-restricted deposition pattern rather than a systemic one. It therefore
  falls outside this grouping's systemic scope. This exclusion is exactly the
  MONDO:0018634 scope mismatch flagged on issue #8655: the MONDO class is broader
  than "hereditary systemic amyloidosis" because it also subsumes the
  cerebral/localized forms.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018634
      label: hereditary amyloidosis
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      broadMatch (NOT exactMatch): MONDO:0018634 (hereditary amyloidosis) is
      BROADER than this grouping. This grouping is scoped to the hereditary
      SYSTEMIC amyloidoses, whereas MONDO:0018634 also subsumes the hereditary
      CEREBRAL and localized forms among its children (cerebral amyloid
      angiopathy MONDO:0005620, Alzheimer disease type 1, ACys/ACys amyloidosis,
      ADan/ABri ITM2B amyloidosis, the ABeta Dutch/Iowa/Italian/Arctic variants,
      and primary localized cutaneous amyloidosis 1/2/3). The grouping is
      therefore a narrower concept than this MONDO class, so an exact mapping
      would over-claim scope.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        The single listed member, Hereditary Transthyretin Amyloidosis
        (disease_term MONDO:0007100, familial amyloid neuropathy), is an is-a
        descendant of MONDO:0018634, so it is consistent with the mapped class.
        The CONSISTENT verdict speaks only to member is-a placement; the
        broadMatch (rather than exactMatch) predicate records that the grouping
        CONCEPT is narrower than MONDO:0018634 (systemic-only), independent of
        current member coverage. The systemic precursor MONDO children not yet
        curated as Disease entries (AApoAI MONDO:0019731, AApoAII MONDO:0016533,
        AGel/Finnish MONDO:0007097, AFib MONDO:0019733, ALys MONDO:0019732) are
        curation gaps to be added as members later.
membership_criteria:
- description: >-
    A disorder belongs to the hereditary systemic amyloidoses if it is an
    inherited (germline) systemic amyloidosis: it conforms to the amyloidogenesis
    module (its disease-causing precursor protein misfolds and deposits as
    extracellular amyloid) AND its causation is a germline/hereditary variant in
    that precursor protein. The cerebral/localized hereditary amyloidoses satisfy
    the amyloidogenesis criterion but are excluded by scope.
  criteria_semantics: NECESSARY
  logic:
    operator: AND
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition
      description: >-
        Has a pathophysiology node conforming to the amyloidogenesis module's
        amyloid fibril formation and extracellular deposition node (the module's
        key conformance target).
    - criterion_predicate: HAS_INHERITANCE
      description: >-
        Hereditary: caused by a germline variant in the amyloidogenic precursor
        protein (most classic forms are autosomal dominant). This distinguishes
        the members from the acquired amyloidoses (AL, AA), which are out of
        scope.
members:
- member: Hereditary Transthyretin Amyloidosis
  member_type: DISEASE
  display_name: Hereditary Transthyretin Amyloidosis (ATTRv)
  differentiating_mechanisms:
  - description: >-
      Autosomal dominant, caused by pathogenic germline variants in TTR. The
      precursor protein is transthyretin, synthesized mainly by the liver and
      circulating as a tetramer; variant TTR tetramers destabilize and
      dissociate into aggregation-prone monomers that misfold and deposit as
      systemic amyloid. Organ tropism is characteristically peripheral and
      autonomic nerve and heart (a sensorimotor/autonomic polyneuropathy, an
      infiltrative cardiomyopathy, or a mixed phenotype), with gastrointestinal,
      ocular, and renal involvement varying by genotype. Distinctively treatable
      with TTR kinetic stabilizers (e.g. tafamidis) that hold the native
      tetramer together, and with TTR gene-silencing therapies; this
      precursor-directed treatment is specific to ATTRv and is not shared with
      the other precursor-defined members.
    gene:
      preferred_term: TTR
      term:
        id: hgnc:12405
        label: TTR
- member: Familial Visceral Amyloidosis
  member_type: DISEASE
  display_name: Familial Visceral Amyloidosis (Ostertag type)
  disease_term:
    preferred_term: familial visceral amyloidosis
    term:
      id: MONDO:0007099
      label: familial visceral amyloidosis
  differentiating_mechanisms:
  - description: >-
      Autosomal dominant, and the non-neuropathic visceral half of this grouping.
      Four different hepatically synthesised plasma proteins act as the
      amyloidogenic precursor - apolipoprotein A-I (APOA1), apolipoprotein A-II
      (APOA2), fibrinogen A alpha-chain (FGA) and lysozyme (LYZ) - and the
      precursor's identity, not anything downstream, sets which viscera are
      affected. What separates this member from ATTRv is organ tropism: amyloid
      deposits in kidney above all, and in liver, spleen, adrenal and gut, while
      peripheral nerve and myocardium are largely spared, so the presentation is
      proteinuria progressing to end-stage renal disease rather than a
      polyneuropathy or an infiltrative cardiomyopathy. It also differs
      therapeutically: no precursor-directed pharmacotherapy exists, and the only
      disease-modifying intervention is removal of the hepatic source of the
      variant protein by liver (or combined liver-kidney) transplantation.
    gene:
      preferred_term: FGA
      term:
        id: hgnc:3661
        label: FGA
  - description: >-
      Apolipoprotein A-I is the most clinically heterogeneous precursor of the
      four, involving kidney, liver and heart, and the only one in this grouping
      whose renal deposit is medullary and tubulointerstitial rather than
      glomerular. It is also the single exception to the non-neuropathic
      character of the visceral forms: the Gly26Arg allele can cause peripheral
      neuropathy in some kindreds.
    gene:
      preferred_term: APOA1
      term:
        id: hgnc:600
        label: APOA1
  - description: >-
      Lysozyme is the one precursor in this grouping that is not made
      exclusively by the liver - neutrophils and macrophages also synthesise it -
      and the ALys form is the one whose dominant organ can be the
      gastrointestinal tract rather than the kidney, with hepatic amyloid
      extensive enough to cause spontaneous liver rupture.
    gene:
      preferred_term: LYZ
      term:
        id: hgnc:6740
        label: LYZ
  - description: >-
      Apolipoprotein A-II is amyloidogenic by a mechanism found nowhere else in
      this grouping: stop-codon read-through appends a 21-residue C-terminal
      extension to the mature protein, rather than a missense substitution
      destabilising a native fold.
    gene:
      preferred_term: APOA2
      term:
        id: hgnc:601
        label: APOA2
notes: >-
  Scope and mapping caveat: this grouping is the hereditary SYSTEMIC amyloidoses
  only. It maps to MONDO:0018634 (hereditary amyloidosis) with skos:broadMatch,
  not skos:exactMatch, because that MONDO class is broader — it also includes the
  hereditary cerebral and localized amyloidoses. Distinct-precursor systemic
  forms (AApoAI/APOA1, AApoAII/APOA2, AGel/GSN, AFib/FGA, ALys/LYZ) are intended
  members. Four of them (AApoAI/APOA1, AApoAII/APOA2, AFib/FGA, ALys/LYZ) are now
  reached through the Familial Visceral Amyloidosis member, which curates
  MONDO:0007099 with those four as has_subtypes; AGel/GSN is curated as
  Finnish_Type_Amyloidosis but is not yet listed as a member here.
  ADan amyloidosis is excluded as a
  hereditary cerebral (ITM2B/BRI2) amyloidosis outside the systemic scope. See
  issue #8655 (maintainer directive) and #8727 (CURATE_ROOT_WITH_SUBTYPES is a
  priority hint, not a lump-vs-split ruling). The shared downstream mechanism is
  modeled once in kb/modules/amyloidogenesis.yaml.