GM2 gangliosidoses (Tay-Sachs, Sandhoff, and AB variant)

name: GM2 Gangliosidoses
display_name: GM2 gangliosidoses (Tay-Sachs, Sandhoff, and AB variant)
creation_date: "2026-08-28T00:00:00Z"
description: >-
  The GM2 gangliosidoses are the lysosomal storage diseases caused by failure
  to degrade GM2 ganglioside. Hydrolysis of GM2 requires three gene products
  acting at one enzymatic step: the beta-hexosaminidase A heterodimer (an
  alpha subunit encoded by HEXA and a beta subunit encoded by HEXB) and the
  GM2 activator protein (GM2A), which presents membrane-bound GM2 to the
  enzyme. Loss of any one of the three produces the same core disease -
  progressive neuronal GM2 storage with neurodegeneration, and in the classic
  infantile forms a cherry-red macular spot and death in early childhood -
  which is why the three diseases have historically been described as one
  clinical spectrum with biochemical variants (B, 0, and AB).
grouping_basis:
- SHARED_MECHANISM
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on a single shared mechanism at maximal resolution: every member
  inactivates one obligatory component of the same GM2-degrading enzyme
  system, and the downstream pathophysiology - lysosomal GM2 accumulation in
  neurons followed by neurodegeneration - is common to all three. The members
  are deliberately kept as separate Disease entries rather than merged,
  because the lesions are in three different genes with different biochemical
  signatures and diagnostic pitfalls: Tay-Sachs disease (HEXA) abolishes
  hexosaminidase A but spares hexosaminidase B; Sandhoff disease (HEXB)
  abolishes both hexosaminidase A and B and adds visceral involvement and
  globoside accumulation; and the AB variant (GM2A) shows entirely normal
  hexosaminidase activity on conventional synthetic-substrate assays, so it
  is missed by the standard enzymatic screen and requires activator or
  molecular testing. Age-of-onset forms (infantile, juvenile, adult) are
  clinical severity grades within each member, not additional members.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0017720
      label: GM2 gangliosidosis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      The grouping concept corresponds exactly to the MONDO GM2 gangliosidosis
      class. exactMatch records the intended conceptual alignment; the
      descendant accounting lives in the consistency block below.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        All three listed members are is-a descendants of MONDO:0017720. Of the
        remaining descendants, six are onset-based forms (infantile, juvenile,
        adult) of Tay-Sachs and Sandhoff disease, and one - Tay-Sachs disease
        B1 variant (MONDO:0017728) - is a biochemical variant of HEXA
        Tay-Sachs (active-site missense such as R178H), covered by the
        Tay-Sachs Disease member rather than a missing member. None is a
        curation gap for this grouping.
membership_criteria:
- description: >-
    A disease belongs to the GM2 gangliosidoses if and only if it is caused by
    loss of function of a component of the GM2 ganglioside degradation system:
    the hexosaminidase alpha subunit (HEXA), the hexosaminidase beta subunit
    (HEXB), or the GM2 activator protein (GM2A).
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_GENE
      description: Caused by pathogenic variants in HEXA.
      gene:
        preferred_term: HEXA
        term:
          id: hgnc:4878
          label: HEXA
    - criterion_predicate: HAS_GENE
      description: Caused by pathogenic variants in HEXB.
      gene:
        preferred_term: HEXB
        term:
          id: hgnc:4879
          label: HEXB
    - criterion_predicate: HAS_GENE
      description: Caused by pathogenic variants in GM2A.
      gene:
        preferred_term: GM2A
        term:
          id: hgnc:4367
          label: GM2A
- description: >-
    Every member conforms to the lysosomal substrate accumulation module: the
    stored substrate is GM2 ganglioside and the storage compartment is the
    neuronal lysosome.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: lysosomal_substrate_accumulation#Lysosomal Substrate Accumulation
    description: >-
      Has a pathophysiology node conforming to the lysosomal substrate
      accumulation module (lysosomal GM2 ganglioside storage).
members:
- member: Tay-Sachs Disease
  member_type: DISEASE
  display_name: Tay-Sachs disease (B variant, HEXA)
  differentiating_mechanisms:
  - description: >-
      Loss of the hexosaminidase alpha subunit abolishes hexosaminidase A
      (alpha-beta) while hexosaminidase B (beta-beta) remains intact - the
      biochemical "B variant". Storage is essentially confined to the nervous
      system, without the visceral involvement of Sandhoff disease, and
      carrier screening by hexosaminidase A assay works because the enzyme
      deficiency is detectable in serum and leukocytes - with the caveat
      that the B1 variant (an active-site HEXA missense) assays near-normal
      against the standard neutral substrate 4-MUG and is only unmasked by
      the sulfated substrate 4-MUGS.
    gene:
      preferred_term: HEXA
      term:
        id: hgnc:4878
        label: HEXA
- member: Sandhoff Disease
  member_type: DISEASE
  display_name: Sandhoff disease (0 variant, HEXB)
  differentiating_mechanisms:
  - description: >-
      Loss of the shared beta subunit abolishes both hexosaminidase A and
      hexosaminidase B - the "0 variant". In addition to neuronal GM2 storage
      it accumulates globoside in visceral organs, producing organomegaly and
      skeletal involvement absent from Tay-Sachs disease, and it is the only
      member whose total hexosaminidase activity is near zero.
    gene:
      preferred_term: HEXB
      term:
        id: hgnc:4879
        label: HEXB
- member: Tay-Sachs Disease AB Variant
  member_type: DISEASE
  display_name: AB variant (GM2 activator deficiency, GM2A)
  differentiating_mechanisms:
  - description: >-
      Loss of the GM2 activator protein leaves both hexosaminidase isozymes
      catalytically intact, so enzymatic assays on synthetic water-soluble
      substrates are normal - the classic diagnostic pitfall of this member.
      The block is in substrate presentation: without the activator,
      membrane-bound GM2 cannot be lifted and delivered to hexosaminidase A,
      so storage proceeds despite normal measured enzyme activity.
    gene:
      preferred_term: GM2A
      term:
        id: hgnc:4367
        label: GM2A
notes: >-
  Created from the stub-queue lump/split review: the seeded stub for
  MONDO:0017720 (GM2 gangliosidosis) resolved as entry_type GROUPING because
  all three constituent diseases are already curated as separate entries and
  the concept is their union, not a disease with one pathograph. The
  membership criteria are machine-checkable against each member's genetic:
  block (HAS_GENE is evaluated exactly) and lysosomal_substrate_accumulation
  conformance, which all three members already declare.