Macroautophagy Deficiency Disorders (Disabled Macroautophagy)

name: Macroautophagy Deficiency Disorders
display_name: Macroautophagy Deficiency Disorders (Disabled Macroautophagy)
creation_date: "2026-08-02T01:01:07Z"
description: >-
  The macroautophagy deficiency disorders are diseases in which decline or
  disruption of the macroautophagy machinery impairs lysosomal sequestration and
  recycling of dysfunctional organelles and aggregated proteins. Loss of this
  cytoplasmic quality-control function allows damaged cargo to accumulate,
  driving cellular dysfunction in long-lived post-mitotic cells — neurons and
  myofibres in particular. Macroautophagy is the clearance arm of proteostasis
  and its progressive failure is a designated hallmark of aging.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared degradative machine rather than a shared aggregating
  substrate. This is the deliberate complement of the substrate-defined
  proteostasis groupings — MONDO's `proteostasis deficiencies` class names
  "degradation or clearance of misfolded proteins" in its own definition, yet all
  four of its children (synucleinopathy, amyloidosis, TDP-43 proteinopathy,
  SQSTM1 multisystem proteinopathy) are defined by *what accumulates* rather than
  by *what failed to clear it*. This grouping supplies the machinery side.
  Members are kept as separate Disease entries because they differ in which step
  of the pathway is hit — autophagosome maturation and clearance (VCP), selective
  cargo receptor function, or mitophagy (PINK1/PRKN) — and in the affected
  tissue.

  Criteria are NECESSARY and the grouping is explicitly provisional. Scope
  caveat, recorded rather than hidden: several listed members are common complex
  diseases in which impaired autophagy is one contributing mechanism among many
  rather than the defining lesion. Amyotrophic Lateral Sclerosis and Parkinson's
  Disease are both genetically and mechanistically heterogeneous, and only a
  subset of their genetic causes act primarily through autophagy. The class would
  be sounder if narrowed to the monogenic autophagy-machinery disorders — EPG5
  (Vici syndrome), WDR45 (BPAN), VCP, SQSTM1, ATG7 — with the complex diseases
  related by a weaker "contributes to" link rather than full membership. Those
  monogenic entries are not yet curated in dismech, which is the only reason the
  narrow version is not the one written here. Treat this grouping as a scaffold
  to be tightened, not as a settled boundary.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0021179
      label: proteostasis deficiencies
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      broadMatch: this grouping is the clearance-machinery subset of the MONDO
      proteostasis deficiencies class. MONDO has no macroautophagy-defined
      disease class — searches of labels, synonyms, and definition text for
      "macroautophagy" and "autophagy disorder" return zero hits, and the three
      "autophagy" label matches are individual myopathies with EXCESSIVE
      autophagy, the opposite direction. broadMatch is therefore the closest
      available alignment.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO:0021179's four current children are all substrate-defined
        (synucleinopathy, amyloidosis, TDP-43 proteinopathy, SQSTM1 multisystem
        proteinopathy), so its descendant set does not overlap this grouping's
        intent and must not be treated as a curation-gap list. See
        docs/reports/mondo-mechanism-classification-proposal-2026-08-01.md §3.9.
membership_criteria:
- description: >-
    Every member's pathophysiology conforms to the disabled macroautophagy module
    — decline of the autophagy machinery leading to failure of cytoplasmic
    quality control and accumulation of undegraded cellular damage.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: disabled_macroautophagy
    description: >-
      Conforms to the disabled_macroautophagy module at one or more nodes.
members:
- member: VCP-Associated Multisystem Proteinopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The cleanest monogenic member and the anchor of the class: VCP/p97 is the
      AAA-ATPase that extracts ubiquitinated substrates and drives autophagosome
      maturation, so disease-causing variants disable the machinery directly
      rather than merely overwhelming it. The multisystem phenotype — myopathy,
      Paget disease of bone, frontotemporal dementia, and ALS in varying
      combination within one family — is itself evidence that the lesion is in a
      general-purpose clearance pathway rather than a tissue-specific one.
    gene:
      preferred_term: VCP
      term:
        id: hgnc:12666
        label: VCP
    module: disabled_macroautophagy#Autophagy Machinery Decline
- member: Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The classically-named form of the VCP phenotype, retained as a distinct
      dismech entry; it additionally admits the hnRNPA2B1 and hnRNPA1
      prion-like-domain variants, which impair clearance of stress granules
      rather than of organelles, and so represent a distinct cargo route into the
      same machinery failure.
    gene:
      preferred_term: HNRNPA2B1
      term:
        id: hgnc:5033
        label: HNRNPA2B1
    module: disabled_macroautophagy#Autophagy Machinery Decline
  notes: >-
    Substantially overlapping with the VCP-Associated Multisystem Proteinopathy
    member above (both are VCP-driven; MONDO:0000507 vs MONDO:0008178). Retained
    as separate members because dismech curates them as separate Disease entries,
    but this pair should be reviewed for a lump/split decision independently of
    this grouping.
- member: Bethlem myopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The extracellular-matrix member, and the mechanistically most surprising
      one: collagen VI deficiency causes failure of autophagosome formation in
      muscle, so the autophagy block is a downstream consequence of an ECM defect
      rather than a primary lesion in the machinery. Notable as the member with
      the clearest therapeutic proof of concept — dietary and pharmacological
      autophagy reactivation improved muscle pathology in collagen VI deficiency.
    gene:
      preferred_term: COL6A1
      term:
        id: hgnc:2211
        label: COL6A1
    module: disabled_macroautophagy#Failure of Cytoplasmic Quality Control
- member: Parkinson's Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The lysosome-weighted member: GBA, LRRK2, VPS35, and ATP13A2 variants impair
      autophagic-lysosomal flux, while PINK1 and PRKN act in selective clearance
      of damaged mitochondria, so the autophagy arm here is organelle- and
      lysosome-directed rather than general. Impaired clearance also feeds
      alpha-synuclein accumulation, linking this member to the substrate-defined
      synucleinopathy class.
    gene:
      preferred_term: GBA1
      term:
        id: hgnc:4177
        label: GBA
    module: disabled_macroautophagy#Failure of Cytoplasmic Quality Control
  notes: >-
    Partial-mechanism member — see the scope caveat in grouping_rationale.
    Autophagy failure is one contributing mechanism among several in a genetically
    heterogeneous disease, not its defining lesion.
- member: Amyotrophic Lateral Sclerosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The autophagy-receptor member: SQSTM1/p62, OPTN, TBK1, and UBQLN2 variants
      disrupt selective cargo recognition rather than the core machinery, so
      damaged cargo is not delivered for degradation even where autophagy itself
      is intact — a distinct failure point from the VCP maturation block.
    gene:
      preferred_term: SQSTM1
      term:
        id: hgnc:11280
        label: SQSTM1
    module: disabled_macroautophagy#Failure of Cytoplasmic Quality Control
  notes: >-
    Partial-mechanism member — see the scope caveat in grouping_rationale.
    Autophagy failure is one contributing mechanism among several in a genetically
    heterogeneous disease, not its defining lesion. The gene descriptor carries
    SQSTM1 as the representative autophagy-receptor gene; OPTN, TBK1, and UBQLN2
    are named in the description and are listed alongside it on the conforming
    node in the ALS entry. OPTN itself is now separately anchored by the
    OPTN-related Open Angle Glaucoma member below, which carries the same
    receptor lesion as its defining cause rather than as one contributor among
    many.
- member: OPTN-related Open Angle Glaucoma
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The OPTN-anchored autophagy-receptor member, and the tissue counterpart
      of the ALS entry above: the same gene, the same failure point in
      selective cargo recognition, but in retinal ganglion cells rather than
      motor neurons. Unlike the two partial-mechanism members, autophagy
      failure is not one contributing mechanism among several here - a
      heterozygous OPTN missense variant (classically E50K) is the whole
      cause of the disease, and impaired autophagic flux with impaired
      OPTN-dependent mitophagy is its defining lesion. Mutant optineurin binds
      TBK1 abnormally tightly, becomes insoluble, and blocks flux; forcing
      autophagy pharmacologically rescues retinal ganglion cells in mouse and
      human stem-cell models.
    gene:
      preferred_term: OPTN
      term:
        id: hgnc:17142
        label: OPTN
    module: disabled_macroautophagy#Failure of Cytoplasmic Quality Control
    biological_processes:
    - preferred_term: macroautophagy
      term:
        id: GO:0016236
        label: macroautophagy
      modifier: DECREASED
    - preferred_term: mitophagy
      term:
        id: GO:0000423
        label: mitophagy
      modifier: DECREASED
notes: >-
  Curated as the dismech-side counterpart of proposed MONDO node #9 in
  docs/reports/mondo-mechanism-classification-proposal-2026-08-01.md, which is
  the weakest-backed of the ten proposals and is flagged there as needing a
  scoping decision. This grouping is written to make that decision reviewable
  rather than to pre-empt it: the two partial-mechanism members carry explicit
  `notes` marking them as such, so a later narrowing of the class has an
  unambiguous starting point.

  Known membership gap, deliberately not closed here: `Ullrich Congenital
  Muscular Dystrophy` is the same COL6 mechanism as the Bethlem myopathy member
  (the Bethlem evidence cites both diseases together) but its dismech entry
  declares no `conforms_to: disabled_macroautophagy`, so it is not a member. The
  fix belongs on that disorder entry, not here — adding it is a `kb/disorders/`
  change with its own history record, out of scope for the PR that introduced
  this grouping. Revisit alongside the tight-scoping decision above, which would
  drop the COL6 members entirely and make the question moot.