Autosomal Dominant Cerebellar Ataxia

name: Autosomal Dominant Cerebellar Ataxia
creation_date: '2026-08-19T12:00:00Z'
category: Mendelian
description: >
  Autosomal dominant cerebellar ataxia (ADCA) is the family of dominantly inherited
  neurodegenerative disorders in which the cerebellum and its connections progressively
  degenerate. Every member presents with progressive ataxia as its cardinal feature,
  usually with dysarthria and oculomotor abnormalities; members differ in what else
  accompanies it and in how fast it advances.

  The family is described along two axes that do not coincide, and keeping them apart
  is the main curation problem this entry exists to solve. Harding's historical
  clinical axis divides ADCA into type I (ataxia with extracerebellar features), type
  II (ataxia with pigmentary retinopathy) and type III (essentially pure cerebellar
  ataxia). The modern axis is molecular, numbering loci as spinocerebellar ataxias
  (SCA1, SCA2, SCA3/Machado-Joseph disease, SCA6, SCA7, SCA17 and many more) plus
  dentatorubral-pallidoluysian atrophy. One Harding class contains several SCAs, and
  the classes are defined by phenotype rather than genotype, so a Roman numeral here
  never denotes a numbered SCA — ADCA-III is not SCA3.

  Mechanistically the largest single group is the polyglutamine SCAs, caused by CAG
  repeat expansions in the coding region of otherwise unrelated genes, which converge
  on Purkinje-cell proteotoxicity and degeneration. That convergence is what makes a
  shared pathograph meaningful at this level. It is not universal: the family also
  contains non-coding repeat expansions and conventional loss-of-function and
  missense alleles, whose routes to the same cerebellar endpoint differ. Subtype
  frequencies vary strikingly by population through founder effects, so the commonest
  ADCA in one country is not the commonest in another.

  This root entry carries only the family-level material — the two classification axes
  and their relationship, the shared convergence on Purkinje neuron degeneration, and
  the population structure of subtype frequency. Per-class and per-locus detail is not
  re-derived here: see `Autosomal_Dominant_Cerebellar_Ataxia_Type_I.yaml`,
  `Autosomal_Dominant_Cerebellar_Ataxia_Type_III.yaml`, `Machado_Joseph_Disease.yaml`,
  `Dentatorubral-Pallidoluysian_Atrophy.yaml`, `Spinocerebellar_Ataxia_Type_17.yaml`,
  `Spinocerebellar_Ataxia_Type_15_16.yaml`, `Spinocerebellar_Ataxia_27B.yaml` and
  `Spinocerebellar_Ataxia_43.yaml`.
disease_term:
  preferred_term: autosomal dominant cerebellar ataxia
  term:
    id: MONDO:0020380
    label: autosomal dominant cerebellar ataxia
synonyms:
- ADCA
- autosomal dominant spinocerebellar ataxia
categories:
- Neurodegenerative Disorder
- Hereditary Ataxia
parents:
- Hereditary ataxia
- Cerebellar degeneration

inheritance:
- name: Autosomal dominant
  description: >-
    Dominant transmission defines the family and separates it from the autosomal
    recessive cerebellar ataxias. In the polyglutamine members the expanded repeat is
    meiotically unstable and tends to lengthen on transmission, producing anticipation
    — earlier onset and more severe disease in successive generations — which is a
    property of the repeat-expansion branch rather than of ADCA as a whole.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance

has_subtypes:
- name: ADCA-I
  display_name: ADCA Type I (ataxia with extracerebellar features)
  classification: clinical
  description: >-
    Harding type I: progressive cerebellar ataxia accompanied by extracerebellar
    features, which may be pyramidal, extrapyramidal, bulbar, spinal, peripheral-nerve,
    cognitive, psychiatric or epileptic depending on the underlying locus. Contains
    SCA1, SCA2, SCA3 and SCA17 among others. Fully curated in
    `Autosomal_Dominant_Cerebellar_Ataxia_Type_I.yaml`.
- name: ADCA-II
  display_name: ADCA Type II (ataxia with pigmentary retinopathy)
  classification: clinical
  description: >-
    Harding type II: cerebellar ataxia with pigmentary macular degeneration, essentially
    synonymous with SCA7 (ATXN7 CAG expansion). The retinal involvement is what
    separates it from type I and makes it the most clinically distinctive of the three
    classes. No dismech entry yet.
- name: ADCA-III
  display_name: ADCA Type III (pure cerebellar ataxia)
  classification: clinical
  description: >-
    Harding type III: a largely pure, later-onset cerebellar syndrome comprising SCA5,
    SCA6, SCA11, SCA26, SCA30 and SCA31. Explicitly not SCA3. Fully curated in
    `Autosomal_Dominant_Cerebellar_Ataxia_Type_III.yaml`.

prevalence:
- population: Singapore (families ascertained through genetic testing)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.7
  notes: >-
    Reported as at least 1 in 27,000 Singaporean families, normalised here to 3.7 per
    100,000. A lower bound, since it counts only genetically confirmed families across
    the panel tested.
  evidence:
  - reference: PMID:12485197
    reference_title: >-
      Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in
      Singapore.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated prevalence of ADCA in Singaporean families was at least 1 : 27,000."
    explanation: >-
      Population-level prevalence estimate for ADCA as a class, stated as a lower bound
      by the authors.

pathophysiology:
- name: Dominantly Inherited Cerebellar Neuron Insult
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    A single dominant allele initiates the process. The largest mechanistic class is the
    polyglutamine SCAs, in which a CAG repeat expansion in the coding region of an
    otherwise unrelated gene produces an expanded polyglutamine tract in the encoded
    protein. The genes involved share no normal function — ATXN1, ATXN2, ATXN3, ATXN7,
    the CACNA1A calcium channel, the TBP general transcription factor and ATN1 — which
    is what identifies the expanded tract itself, rather than loss of the host protein's
    function, as the pathogenic element. Non-polyglutamine members of the family reach
    the same endpoint through non-coding repeat expansions or through conventional
    missense and loss-of-function alleles, and are not covered by this node's
    repeat-expansion claim.
  genes:
  - preferred_term: ATXN1
    term:
      id: hgnc:10548
      label: ATXN1
  - preferred_term: ATXN2
    term:
      id: hgnc:10555
      label: ATXN2
  - preferred_term: ATXN3
    term:
      id: hgnc:7106
      label: ATXN3
  - preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  - preferred_term: TBP
    term:
      id: hgnc:11588
      label: TBP
  - preferred_term: ATN1
    term:
      id: hgnc:3033
      label: ATN1
  evidence:
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These diseases are all caused by a CAG repeat expansion in the coding region of a gene."
    explanation: >-
      States that the polyglutamine SCAs are all caused by a coding-region CAG repeat
      expansion — the shared molecular lesion of the family's largest class.
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs."
    explanation: >-
      Establishes that the polyglutamine SCAs are the most common members, which is what
      justifies putting the repeat-expansion mechanism at the root rather than only on
      the individual entries.
  downstream:
  - target: Purkinje Neuron Degeneration and Loss of Cerebellar Output
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The expanded polyglutamine protein misfolds, aggregates into intranuclear and
      cytoplasmic inclusions, and dysregulates Purkinje-cell proteostasis and calcium
      handling, culminating in degeneration of the cerebellum and its connections. The
      intermediate steps are curated once in the `cerebellar_purkinje_degeneration`
      module and are not re-derived here.
    intermediate_mechanisms:
    - Polyglutamine protein misfolding and inclusion formation
    - Purkinje cell proteostasis and calcium dysregulation
    evidence:
    - reference: PMID:30607747
      reference_title: >-
        Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
        Ataxias.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections."
      explanation: >-
        Identifies degeneration of the cerebellum and its connections as the defining
        pathological endpoint shared by the whole ADCA family.

- name: Purkinje Neuron Degeneration and Loss of Cerebellar Output
  conforms_to: "cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration"
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The convergent node of the family. Whatever the initiating allele, the cerebellar
    cortex and its efferent connections degenerate, with Purkinje neurons the principal
    casualty. Loss of cerebellar cortical output produces the progressive ataxia,
    dysarthria and oculomotor disturbance common to every member; which additional
    systems degenerate alongside is what separates Harding's classes from one another.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
    modifier: INCREASED
  evidence:
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections."
    explanation: >-
      The defining statement that ADCAs are characterised by degeneration of the
      cerebellum and its connections.
  downstream:
  - target: Progressive Ataxic Syndrome
    causal_link_type: DIRECT
    description: >-
      Degeneration of cerebellar output manifests as the progressive clinical syndrome.
    evidence:
    - reference: PMID:30607747
      reference_title: >-
        Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
        Ataxias.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits."
      explanation: >-
        Names progressive ataxia with dysarthria and oculomotor deficits as the shared
        clinical expression across all ADCAs.

- name: Progressive Ataxic Syndrome
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Ataxia"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Progressive gait and limb ataxia with dysarthria and abnormal eye movements, on a
    background of radiological cerebellar atrophy. No disease-modifying therapy is
    established for any member; management is symptomatic and rehabilitative.
  evidence:
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits."
    explanation: >-
      The family-level clinical description.
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression."
    explanation: >-
      Records the absence of curative therapy across the polyglutamine SCAs, which is
      why the root carries no treatments section.

phenotypes:
- category: Neurologic
  name: Progressive Cerebellar Ataxia
  description: >-
    Progressive incoordination of gait and limbs, the cardinal and universal feature of
    the family.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
    clinical_course: PROGRESSIVE
- category: Neurologic
  name: Dysarthria
  description: Cerebellar dysarthria, present in most members.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
- category: Neurologic
  name: Nystagmus
  description: >-
    One of the oculomotor deficits that frequently accompany the ataxia; the specific
    oculomotor signature differs by subtype.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
- category: Imaging
  name: Cerebellar Atrophy
  description: >-
    Radiological correlate of the degeneration; predominantly cerebellar in ADCA-III and
    frequently accompanied by brainstem atrophy in ADCA-I subtypes such as SCA2.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy

discussions:
- discussion_id: adca_harding_vs_molecular_axis
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Dominantly Inherited Cerebellar Neuron Insult"
  prompt: >-
    Should ADCA be curated along Harding's clinical axis, along the molecular SCA
    numbering, or both — and what is the dismech entry for a given patient?
  rationale: >-
    The two classifications cross-cut. A Harding class is a phenotype grouping that
    contains several molecularly unrelated loci, while an SCA number denotes one locus
    whose phenotype may span classes. The KB currently holds entries on both axes —
    `Autosomal_Dominant_Cerebellar_Ataxia_Type_I` and `_Type_III` on the clinical axis,
    `Machado_Joseph_Disease`, `Spinocerebellar_Ataxia_Type_17` and others on the
    molecular axis — so the same patient can satisfy two entries that are not related as
    parent and child. This entry models the Harding axis in `has_subtypes` because those
    are the entries that exist and because MONDO's own ADCA descendants are the numbered
    SCAs rather than the Harding classes, but that is a pragmatic choice and not a
    resolution. Bears on issue #5121 (the dismech-entry to MONDO-term relationship
    should be 1:1).
  evidence:
  - reference: PMID:30607747
    reference_title: >-
      Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar
      Ataxias.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs."
    explanation: >-
      Shows the molecular axis in use as the primary organising principle in the current
      literature, alongside the ADCA family name that Harding's classes subdivide.

- discussion_id: adca_subtype_frequency_is_population_specific
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Dominantly Inherited Cerebellar Neuron Insult"
  prompt: >-
    Can any single subtype-frequency distribution be curated for ADCA, or is subtype
    frequency only meaningful per population?
  rationale: >-
    Reported subtype frequencies differ so sharply between populations that a global
    ranking would misrepresent every one of them. SCA3 accounts for just over half of
    genetically confirmed ADCA in Singapore, whereas in Aomori, Japan, SCA6 accounts for
    more than three quarters and SCA1 for a single patient out of eighty. Founder
    effects, not ascertainment artefact, appear to drive this. The practical consequence
    is that per-subtype `subtype_frequency` values on this entry would need to be
    population-scoped to be honest, and none are asserted here.
  evidence:
  - reference: PMID:12485197
    reference_title: >-
      Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in
      Singapore.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCA 3 was identified in 31 (53.4%) patients from 15 families, SCA 2 in 17 (29.3%) patients from 12 families and SCA 1 in four (6.9%) patients from four families."
    explanation: >-
      Gives the Singaporean subtype distribution, dominated by SCA3.
  - reference: PMID:21088341
    reference_title: >-
      Prevalence of autosomal dominant cerebellar ataxia in Aomori, the northernmost
      prefecture of Honshu, Japan.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinocerebellar ataxia (SCA) type 6 was often observed (77.7% of cases), with SCA2 (10.6% of cases) being the next most common form."
    explanation: >-
      The contrasting Japanese distribution, dominated by SCA6 — the direct comparison
      that makes a single global ranking untenable.

notes: >
  Scope. A thin root over a partially populated subtree. It binds MONDO:0020380 and
  carries the family-level convergence on Purkinje neuron degeneration once, conforming
  to the `cerebellar_purkinje_degeneration` module at three nodes. Per-class and
  per-locus mechanism stays in the existing entries.

  Subtype axis. `has_subtypes` follows Harding's clinical classes because two of the
  three already exist as curated entries and the third (ADCA-II) is a coherent
  clinical concept. No MONDO terms are bound to the Harding classes: MONDO's ADCA
  descendants are the numbered SCAs, and binding a Harding class to an SCA term would
  assert an equivalence that does not hold, except arguably for ADCA-II and SCA7. This
  is recorded as an open question rather than resolved.

  Mechanism scope. The repeat-expansion claim on the trigger node is explicitly scoped
  to the polyglutamine class and is not asserted of the family as a whole; the family
  also contains non-coding repeat expansions and conventional alleles. Anticipation is
  likewise scoped to the repeat-expansion branch in the inheritance block rather than
  claimed for ADCA generally.

  No treatments section. There is no established disease-modifying therapy for any
  member, and symptomatic management is not ADCA-specific, so nothing is curated here.