Polyglutamine (CAG-Repeat) Expansion Disorders

name: Polyglutamine Disorders
display_name: Polyglutamine (CAG-Repeat) Expansion Disorders
creation_date: "2026-06-13T00:00:00Z"
description: >-
  The polyglutamine (polyQ) disorders are a group of dominantly inherited,
  adult-onset neurodegenerative diseases caused by expansion of a translated CAG
  trinucleotide repeat that encodes an elongated polyglutamine tract in the
  respective disease protein. The expanded protein misfolds and aggregates,
  overloading the proteostasis network, dysregulating transcription, and
  impairing mitochondrial function, culminating in selective, region-specific
  neuronal dysfunction and loss. The disorders share anticipation (earlier,
  more severe disease with longer repeats across generations) and a repeat-length
  threshold for pathogenicity.
grouping_basis:
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared proteotoxic mechanism: each member conforms to the
  polyglutamine_expansion_proteotoxicity module (translated CAG/polyQ expansion
  -> misfolded protein aggregation -> transcriptional and proteostasis
  dysregulation -> selective neuronal loss). Members are kept as separate
  Disease entries because they differ in the host gene carrying the repeat, the
  protein's normal function, and the regional neuronal vulnerability that
  determines the clinical phenotype (striatal, cerebellar, or pallidoluysian).
  The criteria are NECESSARY_AND_SUFFICIENT: a translated-CAG polyQ proteotoxic
  mechanism both characterizes every member and flags any further CAG-repeat
  disease (e.g., other SCAs, SBMA) as a candidate member.
membership_criteria:
- description: >-
    A disorder is a polyglutamine disease if and only if it conforms to the
    polyglutamine expansion proteotoxicity module (a translated CAG repeat
    encoding an aggregation-prone polyglutamine tract).
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: polyglutamine_expansion_proteotoxicity#Misfolded Polyglutamine Protein Aggregation
    description: >-
      Conforms to the polyglutamine aggregation node of the proteotoxicity
      module.
members:
- member: Huntington Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAG expansion in HTT (huntingtin) with predominant medium spiny neuron loss
      in the striatum, producing chorea, cognitive decline, and psychiatric
      features — the prototypical polyQ disease.
    gene:
      preferred_term: HTT
      term:
        id: hgnc:4851
        label: HTT
- member: Machado-Joseph Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAG expansion in ATXN3 (a deubiquitinating enzyme); spinocerebellar ataxia
      type 3, the most common dominant ataxia, with cerebellar, pyramidal, and
      extrapyramidal involvement.
    gene:
      preferred_term: ATXN3
      term:
        id: hgnc:7106
        label: ATXN3
- member: Spinocerebellar ataxia type 17
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAG/CAA expansion in TBP (TATA-box binding protein) directly couples the
      polyQ tract to a general transcription factor, producing ataxia with
      prominent cognitive and psychiatric features (a Huntington-like phenotype).
    gene:
      preferred_term: TBP
      term:
        id: hgnc:11588
        label: TBP
- member: Spinocerebellar Ataxia Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAG expansion in ATXN2, whose product is an RNA-binding translational
      regulator rather than a transcription factor - so the disease-relevant
      loss of function is translational. SCA2 is also the member that breaks the
      polyQ nuclear-inclusion stereotype: its microaggregates are cytoplasmic,
      and neither nuclear localization nor inclusion-body formation is necessary
      for pathogenesis. Regional vulnerability is olivopontocerebellar with
      early, marked saccade slowing, and the dentate nucleus is spared.
      Intermediate-length alleles at the same locus are separately a risk factor
      for ALS via modification of TDP-43 toxicity.
    gene:
      preferred_term: ATXN2
      term:
        id: hgnc:10555
        label: ATXN2
- member: Dentatorubral-Pallidoluysian Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAG expansion in ATN1 (atrophin-1) targeting the dentatorubral and
      pallidoluysian systems, producing a variable combination of ataxia,
      myoclonus, epilepsy, chorea, and dementia.
    gene:
      preferred_term: ATN1
      term:
        id: hgnc:3033
        label: ATN1
notes: >-
  As more CAG-repeat spinocerebellar ataxias and spinobulbar muscular atrophy are
  curated, the NECESSARY_AND_SUFFICIENT criterion will flag them as candidate
  members. The differentiating axis is the host gene and the regionally selective
  neuronal vulnerability.
  MONDO mapping: deliberately omitted. MONDO has no "polyglutamine disease" /
  repeat-expansion mechanism class; it classifies each member under its
  phenotype lineage (Huntington disease under basal-ganglia disease, the SCAs
  under hereditary ataxia, DRPLA separately). This grouping is defined by the
  shared CAG/polyQ proteotoxic mechanism, which crosscuts that taxonomy, so no
  single MONDO class applies.