Charcot-Marie-Tooth Diseases

name: Charcot-Marie-Tooth Diseases
display_name: Charcot-Marie-Tooth Diseases
creation_date: "2026-06-14T00:00:00Z"
description: >-
  A curated grouping of explicit Charcot-Marie-Tooth disease entries spanning
  the broad CMT umbrella entry, the currently curated type 1 demyelinating and
  type 2 axonal CMT entries, and the gene-anchored standalone subtype entries
  curated so far (CMT2W/HARS1 and CMT2JJ/BAG3). Members share inherited
  length-dependent
  peripheral neuropathy with distal muscle weakness, distal sensory impairment,
  pes cavus, reduced reflexes, gait impairment, and progressive motor-sensory
  axon or Schwann-cell/myelin pathology.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as an explicit curated union of Disease entries named as
  Charcot-Marie-Tooth disease or major CMT type-level entries, not as all
  hereditary peripheral neuropathies. The shared boundary is inherited
  motor-sensory peripheral neuropathy with convergent distal axon degeneration
  and/or Schwann-cell demyelination. Current members are the umbrella CMT entry,
  the curated type 1 and type 2 entries, and the gene-anchored standalone
  subtype entries CMT2W (HARS1) and CMT2JJ (BAG3). Boundary entities such as
  hereditary neuropathy with liability to pressure palsies and PRPS1 deficiency
  spectrum are not included unless a standalone entry is explicitly curated as
  a CMT disease subtype.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015626
      label: Charcot-Marie-Tooth disease
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch: the grouping corresponds to the MONDO Charcot-Marie-Tooth
      disease class, but is implemented as an explicit curated subset of current
      dismech Disease entries rather than as an automatic MONDO subtree closure.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Listed members are the current KB Charcot-Marie-Tooth Disease,
        Charcot-Marie-Tooth Disease Type 1, and Charcot-Marie-Tooth Disease
        Type 2 umbrella entries, plus the two gene-anchored standalone subtype
        entries curated so far (CMT2W/HARS1 and CMT2JJ/BAG3). Additional CMT
        subtypes should be added only when standalone Disease entries are
        curated; subtypes carried inside another entry's `has_subtypes` list are
        deliberately not listed here.
membership_criteria:
- description: >-
    A member is an explicit Charcot-Marie-Tooth disease entry with inherited
    peripheral motor-sensory neuropathy and at least one characteristic shared
    CMT manifestation such as distal muscle weakness, distal sensory impairment,
    pes cavus, hyporeflexia, or areflexia.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Distal muscle weakness.
      phenotype_term:
        preferred_term: Distal muscle weakness
        term:
          id: HP:0002460
          label: Distal muscle weakness
    - criterion_predicate: HAS_PHENOTYPE
      description: Distal sensory impairment.
      phenotype_term:
        preferred_term: Distal sensory impairment
        term:
          id: HP:0002936
          label: Distal sensory impairment
    - criterion_predicate: HAS_PHENOTYPE
      description: Pes cavus.
      phenotype_term:
        preferred_term: Pes cavus
        term:
          id: HP:0001761
          label: Pes cavus
    - criterion_predicate: HAS_PHENOTYPE
      description: Hyporeflexia.
      phenotype_term:
        preferred_term: Hyporeflexia
        term:
          id: HP:0001265
          label: Hyporeflexia
    - criterion_predicate: HAS_PHENOTYPE
      description: Areflexia.
      phenotype_term:
        preferred_term: Areflexia
        term:
          id: HP:0001284
          label: Areflexia
members:
- member: Charcot-Marie-Tooth Disease
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Broad genetically heterogeneous CMT umbrella entry spanning demyelinating,
      axonal, intermediate, recessive, and X-linked inherited motor-sensory
      neuropathies that converge on distal peripheral nerve dysfunction with
      length-dependent weakness, sensory loss, pes cavus, and reduced reflexes.
- member: Charcot-Marie-Tooth Disease Type 1
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Demyelinating CMT dominated by Schwann-cell and peripheral myelin
      pathology, commonly involving PMP22 dosage gain in CMT1A, MPZ myelin
      protein defects, GJB1 connexin-32 dysfunction in overlapping X-linked or
      intermediate CMT, and EGR2 transcriptional regulation defects.
    gene:
      preferred_term: PMP22
      term:
        id: hgnc:9118
        label: PMP22
  - description: >-
      MPZ-related CMT1 disrupts myelin protein zero structure, trafficking, or
      unfolded-protein responses in Schwann cells, producing demyelinating
      peripheral neuropathy with slowed conduction and onion-bulb pathology.
    gene:
      preferred_term: MPZ
      term:
        id: hgnc:7225
        label: MPZ
- member: Charcot-Marie-Tooth Disease Type 2
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Axonal CMT with primary motor and sensory axon degeneration, including
      MFN2-related mitochondrial fusion and transport failure, NEFL
      neurofilament disruption, RAB7A endolysosomal trafficking defects, GARS1
      tRNA-synthetase-mediated axonal toxicity, and SORD sorbitol-pathway
      disease.
    gene:
      preferred_term: MFN2
      term:
        id: hgnc:16877
        label: MFN2
  - description: >-
      SORD-related recessive axonal CMT2 links sorbitol dehydrogenase loss to
      peripheral nerve metabolic stress and is mechanistically distinct from
      dominant MFN2, NEFL, RAB7A, and GARS1 forms while sharing the axonal CMT2
      phenotype.
    gene:
      preferred_term: SORD
      term:
        id: hgnc:11184
        label: SORD
- member: Autosomal dominant Charcot-Marie-Tooth disease type 2W
  member_type: DISEASE
  display_name: CMT2W (HARS1)
  differentiating_mechanisms:
  - description: >-
      Axonal CMT caused by heterozygous variants in the catalytic domain of
      HARS1, the cytoplasmic histidyl-tRNA synthetase. Distinguished within CMT2
      by a translation-machinery lesion rather than a myelin, transport or
      metabolic one, and by allele-specific biochemistry: some alleles
      mistranslate histidine while others reduce enzyme abundance, which splits
      them into histidine-rescued and histidine-harmed groups. Shares the
      aminoacyl-tRNA synthetase mechanism class with the GARS1 arm curated inside
      Charcot-Marie-Tooth Disease Type 2.
    gene:
      preferred_term: HARS1
      term:
        id: hgnc:4816
        label: HARS1
- member: Charcot-Marie-Tooth disease, axonal, type 2JJ
  member_type: DISEASE
  display_name: CMT2JJ (BAG3)
  differentiating_mechanisms:
  - description: >-
      Adult-onset axonal CMT caused by heterozygous BAG3 variants at the second
      conserved IPV motif, understood as a toxic gain of function that relocates
      chaperone-assisted selective autophagy components into insoluble
      aggresomes — shown in vitro for the Pro209 mutant class including the
      recurrent CMT2JJ allele p.Pro209Ser, though what makes Ser neuropathic and
      Leu myopathic is unexplained. Mechanistically a proteostasis disease rather
      than a myelin, transport or tRNA-charging defect; the nearest arm on that
      axis is CMT2F, curated inside Charcot-Marie-Tooth Disease Type 2, whose
      HSPB1/HSP27 lesion is also a small heat-shock protein (HSPB8 is BAG3's
      direct CASA partner) though that entry frames it through neurofilament and
      axonal-transport disruption. Separated from BAG3 myofibrillar myopathy 6
      by the substitution at codon 209 — Ser is the recurrent neuropathy allele
      and Leu the childhood myopathy allele — but the partition is not clean: a
      p.Pro209Leu patient has been reported with a CMT-like axonal polyneuropathy
      and no cardiomyopathy, so the two alleles may produce overlapping spectra
      with different centres of gravity rather than separate diseases.
    gene:
      preferred_term: BAG3
      term:
        id: hgnc:939
        label: BAG3
notes: >-
  Exclude hereditary neuropathy with liability to pressure palsies, isolated
  distal hereditary motor neuropathy, hereditary sensory and autonomic
  neuropathy, PRPS1 Deficiency Spectrum, mitochondrial trifunctional protein
  deficiency, and broad peripheral neuropathy entries unless a standalone
  Disease entry is explicitly curated as a Charcot-Marie-Tooth disease subtype.