Cerebellar Ataxias (cerebellar ataxia syndrome group)

name: Cerebellar Ataxias
display_name: Cerebellar Ataxias (cerebellar ataxia syndrome group)
creation_date: "2026-08-19T00:00:00Z"
description: >-
  The cerebellar ataxias are the clinically recognized group of disorders whose
  cardinal manifestation is progressive incoordination of gait, limb, speech and
  eye movement arising from disease of the cerebellum and its afferent and
  efferent connections, or of the proprioceptive sensory pathways that feed
  them. The group is defined by a shared syndrome and a shared anatomical
  target, not by a shared molecular lesion: members reach the same clinical
  endpoint from polyglutamine and non-coding repeat expansions
  (SCA3/Machado-Joseph disease, SCA17, DRPLA, SCA27B, CANVAS, FXTAS),
  calcium- and ion-handling defects (SCA15/16, CAPOS), mitochondrial and coenzyme-Q
  bioenergetic failure (Friedreich ataxia, COQ8A ataxia, MTDPS7/IOSCA),
  DNA-damage-response failure (ataxia-telangiectasia), membrane-trafficking,
  autophagy and organelle-contact defects (ARSACS, CALFAN/SCYL1, SCAR15/RUBCN,
  SCAR20/SNX14, VPS13D), lipid, sterol and fat-soluble-vitamin handling defects
  (abetalipoproteinemia, AVED, cerebrotendinous xanthomatosis, GBA2 ataxia,
  peroxisome biogenesis disorder), and developmental cerebellar hypoplasia
  (CAMRQ). Members are kept as separate Disease entries because they differ in
  causal gene and inheritance, age and tempo of onset, the balance of cerebellar
  versus sensory/proprioceptive versus pyramidal involvement, and — critically
  for management — whether the disorder is treatable (vitamin E in AVED,
  chenodeoxycholic acid in cerebrotendinous xanthomatosis, coenzyme Q10 in
  COQ8A ataxia) or not.
grouping_basis:
- SHARED_PHENOTYPE
- SHARED_MECHANISM
grouping_rationale: >-
  Grouped on a shared clinical syndrome plus a shared anatomical-pathological
  target — the cerebellar cortex, its connections, and the proprioceptive
  afferents that serve cerebellar coordination — rather than on a single
  molecular mechanism, which is deliberately heterogeneous across the group.
  The mechanistic convergence that justifies lumping is captured separately and
  reusably as the `cerebellar_purkinje_degeneration` module: functionally
  diverse insults converge on Purkinje cell calcium/proteostasis dysregulation,
  Purkinje neuron loss, and failure of cerebellar cortical output. Members are
  kept as separate entries because the upstream lesion, the inheritance mode,
  the non-cerebellar accompaniments, and the therapeutic implications all
  differ; several members (the treatable metabolic ataxias) would be actively
  misrepresented by a blended umbrella graph.

  The boundary is drawn as NECESSARY rather than NECESSARY_AND_SUFFICIENT.
  Ataxia is a syndrome, not a disease: it occurs as a core feature in the
  members listed here, but also as a secondary or occasional feature of
  disorders no clinician would file under "the ataxias" — stroke, tumour,
  multiple sclerosis, alcohol-related and paraneoplastic cerebellar
  degeneration, multiple system atrophy, and a long tail of metabolic and
  mitochondrial multisystem diseases. Beaudin et al. make exactly this
  distinction, sorting candidate entities into primary ataxias, complex
  multisystem disorders with prominent ataxia, and disorders that may
  occasionally present with ataxia; encoding a SUFFICIENT criterion here would
  collapse those three tiers and pull the third tier in as candidate members.
  The tier boundary is recorded in this rationale and in the per-member
  differentiating mechanisms instead of as machine-checkable sufficiency.

  Scope note on nesting: three members (Autosomal Dominant Cerebellar Ataxia
  and Harding's classes ADCA type I and ADCA type III) are themselves
  umbrella-level Disease entries that sit above several other members of this
  grouping. They are listed as flat DISEASE members because that is what they
  are in the KB; the grouping is a union over curated entries, not a
  reconstruction of the MONDO hierarchy.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000437
      label: cerebellar ataxia
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      narrowMatch: this grouping is the curated subset of MONDO's cerebellar
      ataxia class that currently has dismech Disease entries. MONDO:0000437 is
      itself flagged `disease_grouping` / `ordo_group_of_disorders` and is
      logically defined as an atactic disorder located in the cerebellum
      (RO:0004020 UBERON:0002037), which is the same boundary this grouping
      draws; but the MONDO class has ~170 descendants against 32 curated
      members here, so the alignment is narrower rather than exact. MONDO
      descendants without dismech entries are curation gaps, not evidence that
      the grouping boundary is wrong.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO:0000437 is the correct and only alignment target; the dismech
        grouping deliberately covers fewer entities.
membership_criteria:
- description: >-
    Every member manifests ataxia — incoordination of gait, limb, speech, or
    eye movement — as a core, disease-defining feature rather than an
    incidental or late complication. Both arms of the OR are needed because
    HPO does not place sensory ataxia under HP:0001251: HP:0010871 descends
    from HP:0010831 (impaired proprioception) on the somatic-sensory branch,
    while MONDO's definition of cerebellar ataxia explicitly admits ataxia
    arising in the proprioceptive sensory pathways. A single HP:0001251 leaf
    would therefore falsely contradict the membership of the
    proprioceptive-route members.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: Ataxia of cerebellar and/or proprioceptive type.
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Ataxia (satisfied through the HPO closure by gait ataxia, limb ataxia,
        truncal ataxia, progressive cerebellar ataxia, and the other
        descendants of HP:0001251).
      phenotype_term:
        preferred_term: Ataxia
        term:
          id: HP:0001251
          label: Ataxia
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Sensory (proprioceptive) ataxia, which sits on a separate HPO branch
        from HP:0001251 but is the same clinical syndrome by a different
        route.
      phenotype_term:
        preferred_term: Sensory ataxia
        term:
          id: HP:0010871
          label: Sensory ataxia
- description: >-
    The ataxia is referable to the cerebellum, its afferent/efferent
    connections, or the proprioceptive sensory pathways serving cerebellar
    coordination — evidenced either by conformance to the shared Purkinje-cell
    degeneration mechanism, by a structural cerebellar abnormality, or by a
    documented proprioceptive/posterior-column lesion.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Cerebellar or proprioceptive localization of the ataxia (the shared
      anatomical lesion of the group).
    operands:
    - criterion_predicate: CONFORMS_TO_MODULE
      module: cerebellar_purkinje_degeneration
      description: >-
        Declares conformance to the conserved cerebellar Purkinje cell
        degeneration mechanism module.
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Structural cerebellar abnormality (satisfied through the HPO closure by
        cerebellar atrophy, cerebellar hypoplasia, vermis hypoplasia, and other
        descendants of HP:0001317).
      phenotype_term:
        preferred_term: Abnormal cerebellum morphology
        term:
          id: HP:0001317
          label: Abnormal cerebellum morphology
    - criterion_predicate: HAS_PHENOTYPE
      description: >-
        Sensory (proprioceptive) ataxia, the second localization admitted by
        the MONDO definition of cerebellar ataxia.
      phenotype_term:
        preferred_term: Sensory ataxia
        term:
          id: HP:0010871
          label: Sensory ataxia
    - criterion_predicate: OTHER
      description: >-
        Otherwise-documented pathology of the cerebellar afferent or efferent
        connections (spinocerebellar tracts, dentate nucleus, inferior olive,
        middle/superior cerebellar peduncles) without a curated structural
        cerebellar phenotype term. Not machine-evaluable; present so that this
        OR is not falsely reported as unsatisfied for a member whose lesion is
        in the connections rather than the cerebellar cortex.
members:
- member: Autosomal Dominant Cerebellar Ataxia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The dominant branch of the group as a whole, and the entry that carries
      the reconciliation of the two non-coincident axes used to describe it —
      Harding's clinical classes (types I, II, III) and the molecular SCA
      locus numbering. Included as a member despite sitting above several other
      members because it is a curated Disease entry in its own right; it is the
      place where the ADCA-vs-SCA nomenclature problem is modeled rather than a
      distinct molecular disease.
- member: Autosomal Dominant Cerebellar Ataxia Type I
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Harding's class of dominant progressive cerebellar ataxia WITH
      extracerebellar features (oculomotor, pyramidal, extrapyramidal, bulbar,
      spinal, peripheral-nerve, cognitive, psychiatric or seizure). Molecularly
      an umbrella spanning coding polyglutamine expansions (SCA1/2/3/17), other
      repeat disorders, and conventional sequence variants, so repeat
      instability and anticipation apply to particular branches rather than to
      the class.
- member: Autosomal Dominant Cerebellar Ataxia Type III
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Harding's class of dominant, essentially PURE cerebellar syndromes
      (SCA5, SCA6, SCA11, SCA26, SCA30, SCA31) — the phenotypic complement of
      ADCA type I within the same grouping. Explicitly not SCA3: the Roman
      numeral denotes Harding's class, not a numbered SCA locus. Mechanistically
      heterogeneous (SPTBN2 postsynaptic organization, CACNA1A polyglutamine,
      TTBK2 ciliary, EEF2 translational fidelity, BEAN1 repeat RNA).
- member: Machado-Joseph Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The most common dominant SCA worldwide. Polyglutamine-expanded ataxin-3
      (CAG expansion in ATXN3 exon 10) misfolds and aggregates, disrupting the
      ubiquitin-proteasome system, autophagy, transcription and mitochondrial
      function. Distinguished from the pure cerebellar members by prominent
      pyramidal, extrapyramidal, peripheral-nerve and oculomotor involvement and
      four recognized clinical subtypes graded by age at onset.
    gene:
      preferred_term: ATXN3
      term:
        id: hgnc:7106
        label: ATXN3
- member: Spinocerebellar ataxia type 17
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Polyglutamine SCA in which the expanded protein is a general
      transcription factor (TBP), so transcriptional dysregulation is the
      proximate mechanism. Distinguished within the group by the combination of
      ataxia with chorea, dystonia, parkinsonism, dementia and psychiatric
      features (a Huntington-disease phenocopy), and by CAA interruptions that
      partly stabilize the repeat and blunt anticipation.
    gene:
      preferred_term: TBP
      term:
        id: hgnc:11588
        label: TBP
- member: Dentatorubral-Pallidoluysian Atrophy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Polyglutamine expansion in ATN1; expanded atrophin-1 drives neuronal
      intranuclear inclusions and transcriptional dysregulation with selective
      degeneration of the dentatorubral and pallidoluysian systems — i.e. the
      cerebellar OUTFLOW tract rather than the Purkinje cell layer. Uniquely
      age-split within the group: juvenile onset presents as progressive
      myoclonus epilepsy, adult onset as ataxia with choreoathetosis and
      dementia.
    gene:
      preferred_term: ATN1
      term:
        id: hgnc:3033
        label: ATN1
- member: Spinocerebellar ataxia 27B
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Deep intronic (GAA) expansion in FGF14 intron 1 acting by loss of
      expression rather than by a toxic expanded protein. FGF14 binds
      voltage-gated sodium channels at the Purkinje axon initial segment, so the
      primary lesion is failure of Purkinje FIRING, with cell loss following —
      an electrophysiological rather than proteotoxic route into the shared
      module. One of the most common causes of late-onset ataxia (median onset
      ~57-60 years), frequently preceded for years by episodic ataxia and
      downbeat nystagmus.
    gene:
      preferred_term: FGF14
      term:
        id: hgnc:3671
        label: FGF14
- member: Spinocerebellar Ataxia Type 15/16
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      ITPR1 haploinsufficiency (most often heterozygous deletion) removing the
      principal ER calcium-release channel of the Purkinje cell — the most
      direct genetic instantiation of the calcium-dysregulation arm of the
      shared module. Phenotypically the near-pure, very slowly progressive
      dominant cerebellar ataxia of the group. SCA15 and SCA16 were separate
      loci until shown to be the same ITPR1 disorder.
    gene:
      preferred_term: ITPR1
      term:
        id: hgnc:6180
        label: ITPR1
- member: Spinocerebellar Ataxia 43
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous MME (neprilysin) variants; distinguished among the dominant
      ataxias by the obligate co-occurrence of a late-onset, motor-predominant
      axonal sensorimotor polyneuropathy with the cerebellar signs. Allelic
      dose matters directionally: RECESSIVE MME loss of function causes a purely
      peripheral CMT2T without cerebellar involvement, so the dominant,
      cerebellum-involving mechanism remains only partly understood.
    gene:
      preferred_term: MME
      term:
        id: hgnc:7154
        label: MME
- member: Autosomal Dominant Cerebellar Ataxia Deafness and Narcolepsy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous exon-21 DNMT1 variants in the replication-foci-targeting
      domain — the epigenetic-maintenance route into the group. Distinguished by
      the order of onset: narcolepsy with cataplexy and progressive
      sensorineural deafness precede the ataxia, which is followed by dementia.
      Allelic to HSAN1E, whose variants lie in exon 20 of the same domain.
    gene:
      preferred_term: DNMT1
      term:
        id: hgnc:2976
        label: DNMT1
- member: CAPOS Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      A single recurrent ATP1A3 variant (p.Glu818Lys) crippling the
      neuron-specific Na+/K+-ATPase alpha-3 subunit. Unique tempo within the
      group: not steadily progressive but stepwise, with a small number of
      febrile-illness-triggered episodes of acute cerebellar ataxia and
      encephalopathy in early childhood, each leaving incomplete recovery —
      ataxia, areflexia, pes cavus, optic atrophy and auditory neuropathy.
    gene:
      preferred_term: ATP1A3
      term:
        id: hgnc:801
        label: ATP1A3
- member: Fragile X-Associated Tremor Ataxia Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The premutation (55-200 CGG) disorder of FMR1, mechanistically the inverse
      of full-mutation fragile X syndrome: RNA toxic gain of function from
      elevated CGG-repeat FMR1 mRNA plus RAN translation of a polyglycine
      protein (FMRpolyG), not FMRP loss. Ubiquitin-positive intranuclear
      inclusions are the pathological hallmark and the middle cerebellar
      peduncle T2 sign the radiological one; intention tremor typically leads
      the ataxia.
    gene:
      preferred_term: FMR1
      term:
        id: hgnc:3775
        label: FMR1
- member: Friedreich Ataxia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The most common inherited ataxia. Homozygous GAA expansion in FXN intron 1
      silences frataxin, an iron-sulfur-cluster biogenesis protein; mitochondrial
      iron accumulation, impaired oxidative phosphorylation and oxidative stress
      follow. Distinguished from the cortical-cerebellar members by its
      dorsal-root-ganglion/posterior-column and dentate-nucleus predominance
      (areflexia with extensor plantars, sensory loss) and by systemic disease —
      hypertrophic cardiomyopathy, scoliosis and diabetes.
    gene:
      preferred_term: FXN
      term:
        id: hgnc:3951
        label: FXN
- member: Ataxia-telangiectasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic ATM loss disabling the DNA double-strand-break response — the
      genome-instability route into cerebellar degeneration. Unique in the group
      for its extraneurological burden: oculocutaneous telangiectasia,
      immunodeficiency, cellular radiosensitivity (which contraindicates
      diagnostic irradiation), elevated alpha-fetoprotein, and a high lifetime
      malignancy risk. The link from ATM loss to SELECTIVE Purkinje/granule cell
      death remains unresolved.
    gene:
      preferred_term: ATM
      term:
        id: hgnc:795
        label: ATM
- member: CANVAS
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic intronic (AAGGG)n expansion in RFC1. Distinguished by triple
      deafferentation — cerebellar degeneration PLUS bilateral vestibular
      areflexia PLUS a sensory ganglionopathy (loss of DRG cell bodies, not a
      dying-back axonopathy) — so imbalance exceeds what any single deficit
      would cause. Chronic dry cough often precedes neurological onset by
      decades. A leading identified cause of late-onset ataxia; the pathogenic
      mechanism of the expansion is genuinely unresolved.
    gene:
      preferred_term: RFC1
      term:
        id: hgnc:9969
        label: RFC1
- member: Charlevoix-Saguenay spastic ataxia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SACS loss of sacsin, a giant multidomain chaperone; childhood
      onset with the distinctive triad of cerebellar ataxia, lower-limb
      spasticity and peripheral neuropathy, plus a near-pathognomonic THICKENED
      retinal nerve fibre layer on OCT. Downstream defects span cytoskeletal
      (neurofilament/intermediate filament) organization, protein quality
      control and mitochondrial dynamics.
    gene:
      preferred_term: SACS
      term:
        id: hgnc:10519
        label: SACS
- member: Autosomal Recessive Ataxia Beauce Type
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SYNE1-related ARCA1/SCAR8, defined in French-Canadian founder families of
      the Beauce region. The reference example within the group of a relatively
      PURE, adult-onset, slowly progressive recessive cerebellar syndrome with
      diffuse cerebellar atrophy and no neuropathy and no effect on life
      expectancy; SYNE1 deficiency nonetheless spans a broader
      "cerebellar-plus" spectrum including motor neuron and childhood
      multisystem presentations.
    gene:
      preferred_term: SYNE1
      term:
        id: hgnc:17089
        label: SYNE1
- member: Autosomal Recessive Cerebellar Ataxia-Saccadic Intrusion Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic VPS13D (SCAR4). Distinguished among recessive ataxias by
      fixation-disrupting saccadic intrusions — macrosaccadic oscillations and
      hypermetric saccades — with pyramidal signs and axonal sensorimotor
      neuropathy. VPS13D acts at organelle contact sites in lipid transfer,
      mitochondrial fission and mitophagy; the steps connecting those cellular
      defects to the selective regional phenotype are unresolved.
    gene:
      preferred_term: VPS13D
      term:
        id: hgnc:23595
        label: VPS13D
- member: Autosomal Recessive Ataxia Due to Ubiquinone Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      COQ8A-related primary coenzyme Q10 deficiency (ARCA2/SCAR9): the atypical
      mitochondrial ATPase that stabilizes the CoQ biosynthesis complex fails,
      lowering CoQ10 and compromising respiratory-chain electron transfer. One
      of the potentially treatable members — oral CoQ10 is mechanistically
      rational and helps some patients — but response is variable and no
      randomized COQ8A-specific trial has established dosing.
    gene:
      preferred_term: COQ8A
      term:
        id: hgnc:16812
        label: COQ8A
- member: Mitochondrial DNA Depletion Syndrome 7
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic TWNK (Twinkle helicase) loss causing tissue-specific mtDNA
      depletion — the mtDNA-maintenance route into infantile-onset
      spinocerebellar ataxia (IOSCA). Distinguished by its very early onset
      after normal development to age one and by the breadth of the associated
      deficits (athetosis, ophthalmoplegia, sensorineural hearing loss, sensory
      neuropathy, optic atrophy, hypergonadotropic hypogonadism, epilepsy
      progressing to fatal encephalopathy).
    gene:
      preferred_term: TWNK
      term:
        id: hgnc:1160
        label: TWNK
- member: THG1L-Related Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic THG1L (SCAR28), a mitochondrial tRNA-histidine
      guanylyltransferase that also participates in mitochondrial fusion via
      MFN2. Distinguished by an early-onset, largely NON-progressive ataxia with
      cerebellar atrophy or hypoplasia — nearer the developmental than the
      degenerative end of the group. ClinGen gene-disease validity is only
      Limited, which is itself a differentiator worth preserving.
    gene:
      preferred_term: THG1L
      term:
        id: hgnc:26053
        label: THG1L
- member: Autosomal Recessive Spinocerebellar Ataxia 15
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic RUBCN (Rubicon) truncations — loss of a NEGATIVE regulator of
      macroautophagy and of LC3-associated phagocytosis at Rab7-positive late
      endosomes. Salih ataxia: early-onset, slowly progressive or relatively
      non-progressive ataxia combined with intellectual disability and epilepsy,
      with only mild superior vermian atrophy on MRI.
    gene:
      preferred_term: RUBCN
      term:
        id: hgnc:28991
        label: RUBCN
- member: Autosomal Recessive Spinocerebellar Ataxia 20
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SNX14 (sorting nexin 14). The most neurodevelopmentally weighted
      member: early-onset ataxia with severe-to-profound intellectual
      disability, absent expressive speech, hypotonia, progressively coarsening
      facies and relative macrocephaly, on a substrate of cerebellar
      atrophy/hypoplasia with progressive Purkinje cell loss.
    gene:
      preferred_term: SNX14
      term:
        id: hgnc:14977
        label: SNX14
- member: Lichtenstein-Knorr Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SLC9A1/NHE1 loss — the intracellular pH-homeostasis route into
      cerebellar degeneration. Defined by the pairing of progressive cerebellar
      ataxia with SEVERE progressive sensorineural hearing loss, reflecting
      shared NHE1 dependence of Purkinje neurons and cochlear hair cells. High
      named-entity-confusion risk: SCAR19/Lichtenstein-Knorr has been conflated
      in the literature with SNX14-related SCAR20, also a member here.
    gene:
      preferred_term: SLC9A1
      term:
        id: hgnc:11071
        label: SLC9A1
- member: CALFAN Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic SCYL1 (SCAR21): loss of a COPI scaffold pseudokinase in
      retrograde Golgi-to-ER trafficking. The only member whose presenting
      illness is hepatic — recurrent low-GGT cholestasis or infection-triggered
      acute liver failure in infancy — with the cerebellar ataxia and peripheral
      neuropathy appearing later, so it is typically diagnosed outside the
      ataxia clinic.
    gene:
      preferred_term: SCYL1
      term:
        id: hgnc:14372
        label: SCYL1
- member: Autosomal Recessive Cerebellar Ataxia With Late-Onset Spasticity
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic GBA2 loss of the NONlysosomal glucosylceramidase (contrast the
      lysosomal GBA1 of Gaucher disease), with glucosylceramide accumulation
      established in patient material. Sits on the ataxia/spastic-paraplegia
      boundary — the same allele series is labelled SPG46 — and the ataxia
      precedes the spasticity in this presentation.
    gene:
      preferred_term: GBA2
      term:
        id: hgnc:18986
        label: GBA2
- member: Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CAMRQ: the DEVELOPMENTAL rather than degenerative member — congenital,
      non-progressive ataxia on a substrate of cerebellar HYPOPLASIA (inferior
      cerebellum and vermis), with intellectual disability, severely delayed
      ambulation and, in a subset, quadrupedal locomotion. Four genetic
      subtypes: VLDLR (Reelin signalling), WDR81, CA8 and ATP8A2.
    gene:
      preferred_term: VLDLR
      term:
        id: hgnc:12698
        label: VLDLR
- member: Familial Isolated Vitamin E Deficiency
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      AVED: biallelic TTPA loss prevents hepatic incorporation of
      alpha-tocopherol into nascent VLDL, so systemic vitamin E deficiency
      develops despite normal intake and absorption, and lipid-soluble
      antioxidant protection of large myelinated sensory neurons, dorsal columns
      and cerebellar pathways fails. Phenotypically a Friedreich-ataxia mimic —
      and the most important treatable one, since lifelong high-dose vitamin E
      is disease-modifying and prevents disease if started presymptomatically.
    gene:
      preferred_term: TTPA
      term:
        id: hgnc:12404
        label: TTPA
- member: Abetalipoproteinemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic MTTP loss blocks assembly and secretion of apoB-containing
      lipoproteins, so the ataxia is a downstream consequence of fat
      malabsorption and secondary fat-soluble vitamin (especially vitamin E)
      deficiency rather than of a primary neuronal lesion. Distinguished from
      AVED by the gastrointestinal and haematological presentation in infancy —
      failure to thrive, steatorrhoea, acanthocytosis, very low cholesterol —
      and by retinal degeneration and coagulopathy.
    gene:
      preferred_term: MTTP
      term:
        id: hgnc:7467
        label: MTTP
- member: Cerebrotendinous xanthomatosis
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic CYP27A1 loss of mitochondrial sterol 27-hydroxylase diverts bile
      acid synthesis, and cholestanol and bile alcohols deposit in brain and
      tendon. Recognizable by its non-neurological signposts — infantile
      diarrhoea or neonatal cholestasis, juvenile cataracts, tendon xanthomas —
      which appear years before the cerebellar and pyramidal signs. The second
      major treatable member: chenodeoxycholic acid modifies disease when
      started early.
    gene:
      preferred_term: CYP27A1
      term:
        id: hgnc:2605
        label: CYP27A1
- member: Peroxisome Biogenesis Disorder 4B
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The milder, non-classic end of the PEX6 Zellweger spectrum, entering this
      grouping because it subsumes the entity formerly catalogued as SCAR3 —
      early-onset cerebellar ataxia with sensorineural hearing loss and visual
      loss. Residual peroxin function in the PEX1/PEX6 receptor-export AAA-ATPase
      shifts disease from lethal neonatal presentation to a slowly progressive
      degenerative course; peroxisomal matrix-protein import failure, not a
      cerebellum-specific lesion, is the primary defect.
    gene:
      preferred_term: PEX6
      term:
        id: hgnc:8859
        label: PEX6
- member: FLVCR1-Related Retinopathy with or without Ataxia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic FLVCR1 loss of the cytoplasmic heme exporter; misfolded
      transporter is retained and degraded, and intracellular heme toxicity
      selects the neurons with the highest FLVCR1 expression. The purest example
      in the group of the PROPRIOCEPTIVE (posterior-column) rather than
      cerebellar route to ataxia — classically posterior column ataxia with
      retinitis pigmentosa (PCARP) — with photoreceptors always affected and the
      posterior columns spared in a minority retaining partial function.
    gene:
      preferred_term: FLVCR1
      term:
        id: hgnc:24682
        label: FLVCR1
references:
- reference: PMID:29421540
  title: >-
    Why do so many genetic insults lead to Purkinje Cell degeneration and
    spinocerebellar ataxia?
  findings:
  - statement: >-
      The mechanistic convergence that licenses this grouping: functionally
      diverse genes converge on the same cerebellar target, which is why the
      shared chain is factored out into the cerebellar_purkinje_degeneration
      module rather than re-derived in each member entry.
    supporting_text: >-
      The genetically heterozygous spinocerebellar ataxias are all characterized
      by cerebellar atrophy and pervasive Purkinje Cell degeneration.
  - statement: >-
      The scale of the genetic heterogeneity the grouping has to absorb, and the
      reason membership is asserted per entry rather than inferred from a shared
      lesion.
    supporting_text: >-
      Up to date, more than 35 functionally diverse spinocerebellar ataxia genes
      have been identified.
- reference: PMID:28250961
  title: >-
    Systematic review of autosomal recessive ataxias and proposal for a
    classification.
  findings:
  - statement: >-
      Supports the NECESSARY (not NECESSARY_AND_SUFFICIENT) criteria semantics:
      published classification practice separates disorders in which ataxia is a
      core presenting feature from those with prominent ataxia in a multisystem
      context and those that merely may present with ataxia, so satisfying the
      ataxia criterion cannot by itself confer membership.
    supporting_text: >-
      Included disorders were classified as primary recessive ataxias, as other
      complex movement or multisystem disorders with prominent ataxia, or as
      disorders that may occasionally present with ataxia.
  - statement: >-
      Records why the group is lumped at the syndrome level rather than by
      mechanism, and why per-member differentiating mechanisms carry the
      discriminating detail.
    supporting_text: >-
      The classification of autosomal recessive ataxias represents a significant
      challenge because of high genetic heterogeneity and complex phenotypes.
notes: >-
  Scoping decision (issue #8941, CURATE_ROOT MONDO:0000437). MONDO:0000437
  "cerebellar ataxia" is curated as a Grouping, not as a broad Disease entry.
  Three facts drove that: MONDO itself flags the term `disease_grouping` and
  `ordo_group_of_disorders` and defines it logically as an atactic disorder
  located in the cerebellum rather than as a disease with its own mechanism; the
  conserved mechanism it would otherwise carry is ALREADY modeled, in
  `kb/modules/cerebellar_purkinje_degeneration.yaml`; and the KB already holds
  32 curated Disease entries that are MONDO is_a descendants of the term. A
  Disease entry here would have had to either duplicate the module or blend 32
  distinct pathographs into one umbrella graph. This follows the diabetes
  precedent recorded in CLAUDE.md — Grouping + module + per-type entries, not a
  blended umbrella Disease.

  Member selection. Members are exactly the intersection of (a)
  `kb/disorders/*.yaml` entries and (b) the MONDO is_a closure of
  MONDO:0000437, computed with `runoak -i sqlite:obo:mondo descendants -p i
  MONDO:0000437` — 32 of the ~170 descendants. Using the ontology closure rather
  than a name match keeps the boundary reproducible and auditable.

  Deliberate exclusions. Eight further KB entries whose names contain "ataxia"
  are NOT members because MONDO does not place them under MONDO:0000437:
  Episodic Ataxia (MONDO:0016227), Autosomal Dominant Sensory Ataxia 1
  (MONDO:0012166), Cerebellar Ataxia-Hypogonadism Syndrome (MONDO:0008935),
  Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine
  (MONDO:0032733), Proximal tubulopathy-diabetes mellitus-cerebellar ataxia
  syndrome (MONDO:0010798), SDHA-Related Neurodegeneration With Ataxia and
  Optic Atrophy (MONDO:0031006), Sensory Ataxic Neuropathy, Dysarthria, and
  Ophthalmoparesis (MONDO:0011835), and Spasticity-Ataxia-Gait Anomalies
  Syndrome (MONDO:0014803). Several of these are clinically defensible members
  (episodic ataxia is a CACNA1A/KCNA1 cerebellar channelopathy), but adding them
  would substitute curator judgement for the reproducible closure rule without
  recording which rule was actually applied. They are the first candidates to
  revisit if the boundary is widened, and widening it should be a deliberate,
  documented decision rather than drift.

  How the advisory evaluator reads these criteria. Both blocks are ORs. The
  first (ataxia) resolves SATISFIED for every current member; note it needs the
  HP:0010871 arm as well as the HP:0001251 arm, because HPO files sensory
  ataxia under impaired proprioception rather than under Ataxia, and a single
  HP:0001251 leaf reported FLVCR1-Related Retinopathy — a curated
  posterior-column ataxia — as a contradiction. The second block is an OR
  containing an `OTHER` leaf,
  so it can report SATISFIED (if any machine-evaluable arm holds) or UNKNOWN,
  but never a false NOT_SATISFIED for a member whose lesion lies in the
  cerebellar connections rather than the cerebellar cortex. Per-leaf
  NOT_SATISFIED lines on the unsatisfied arms of that OR are expected and are
  not violations. A member reported UNKNOWN is a curation gap in that member's
  phenotype annotation, not evidence against its membership.

  No SUFFICIENT block, deliberately — see `grouping_rationale`. Encoding "has
  ataxia + cerebellar localization" as sufficient would propose stroke, tumour,
  multiple sclerosis, paraneoplastic and toxic cerebellar degeneration, and a
  long tail of multisystem metabolic disease as candidate members. Acquired
  cerebellar ataxias are in scope for the CONCEPT but have no curated entries
  yet; when they are added they should be listed explicitly here rather than
  swept in by a classifier.