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 four compartment-level entries curated so
  far — type 1 (dominant demyelinating), type 2 (predominantly dominant axonal),
  type 4 (autosomal-recessive demyelinating) and type X (X-linked) — 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 four curated compartment-level entries (types 1, 2, 4 and X), and the
  gene-anchored standalone subtype entries CMT2W (HARS1) and CMT2JJ (BAG3). The
  compartments are separated by the cell-biological level of the lesion
  (demyelinating versus axonal) and, incompletely, by inheritance rather than by
  the terminal node, which they share. Inheritance separates type X from the
  autosomal compartments and type 4 from type 1, but it does not cleanly separate
  type 2: recessive axonal forms such as SORD-CMT2 and CMT2B1/LMNA are curated
  under type 2, not type 4. The members list is therefore expected to carry all
  four compartments alongside the umbrella entry; that expectation is over the
  compartments, not over CMT entries generally — the notes below record fourteen
  further curated CMT entries this list deliberately does not carry. The X-linked
  connexin-32 mechanism belongs to the type X row rather than to type 1.
  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 umbrella
        entry and its four compartment-level entries — Charcot-Marie-Tooth
        Disease Type 1, Type 2, Type 4 and Type X — 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: >-
      Dominantly inherited demyelinating CMT dominated by Schwann-cell and
      compact-myelin pathology, commonly involving PMP22 dosage gain in CMT1A,
      MPZ myelin protein defects, and EGR2 transcriptional regulation defects.
      The GJB1 connexin-32 gap-junction lesion is not a CMT1 mechanism and is
      carried by the Charcot-Marie-Tooth Disease Type X member row.
    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: Charcot-Marie-Tooth Disease Type 4
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The autosomal-recessive demyelinating compartment; recessive axonal forms
      such as SORD-CMT2 and CMT2B1/LMNA are curated under type 2. Biallelic loss
      of a Schwann-cell or
      neuronal gene produces demyelination that is generally earlier in onset
      and more severe than the dominant forms, with redundant myelin
      outfoldings or onion bulbs on nerve biopsy in several subtypes. Separated
      from CMT1 by inheritance and by the loci involved — GDAP1 (CMT4A,
      mitochondrial dynamics), MTMR2 and SBF2/MTMR13 (CMT4B1/B2, myotubularin
      phosphoinositide phosphatases), SH3TC2 (CMT4C, the most common CMT4
      subtype and a cause of early-onset scoliosis), NDRG1 (CMT4D / HMSN-Lom),
      PRX/periaxin (CMT4F) and FIG4 (CMT4J) — rather than by the terminal node,
      which is the same demyelination with secondary length-dependent axonal
      degeneration.
    gene:
      preferred_term: SH3TC2
      term:
        id: hgnc:29427
        label: SH3TC2
  - description: >-
      The myotubularin arm is mechanistically distinct from the other recessive
      loci: MTMR2 and its catalytically inactive binding partner SBF2/MTMR13 are
      phosphoinositide phosphatases rather than structural myelin or
      mitochondrial proteins, and their loss produces the focally folded myelin
      that is the recognizable morphological signature of CMT4B1/B2.
    gene:
      preferred_term: MTMR2
      term:
        id: hgnc:7450
        label: MTMR2
- member: Charcot-Marie-Tooth Disease Type X
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The X-linked compartment, overwhelmingly dominated by CMTX1.
      Loss-of-function GJB1 variants remove the connexin-32 reflexive gap
      junctions that connect the abaxonal and adaxonal cytoplasm of a
      myelinating Schwann cell across its own non-compact myelin, abolishing the
      short radial diffusion path for ions and small metabolites. That is a
      gap-junction coupling lesion rather than the compact-myelin dosage or
      structural lesions of CMT1, and it yields intermediate conduction
      velocities — slowed beyond pure axonal disease but not into the uniformly
      demyelinating range. X-linkage also sets the inheritance pattern apart
      from every other member: hemizygous males are consistently and more
      severely affected than heterozygous females. Connexin-32 is expressed by
      oligodendrocytes as well, so this compartment alone carries a recognized
      CNS phenotype of transient, reversible white-matter dysfunction.
    gene:
      preferred_term: GJB1
      term:
        id: hgnc:4283
        label: GJB1
  - description: >-
      The remaining CMTX loci are individually rare and unrelated to connexin
      biology, each reaching the shared peripheral-nerve endpoint by a different
      route: AIFM1 (CMTX4 / Cowchock syndrome) and PDK3 (CMTX6) through
      mitochondrial bioenergetic failure, PRPS1 (CMTX5) through impaired purine
      nucleotide biosynthesis, and CMTX3 through a non-coding interchromosomal
      insertion at Xq27.1 whose transcriptional consequence is unresolved.
      Several carry syndromic sensorineural hearing loss or optic atrophy that a
      pure CMTX1 picture does not.
    gene:
      preferred_term: AIFM1
      term:
        id: hgnc:8768
        label: AIFM1
- 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.

  Known incompleteness, recorded rather than left implicit (#10915). Adding the
  type 4 and type X compartments completes the compartment level, but fourteen
  further curated CMT Disease entries are still not listed: the axonal types 2C,
  2P, 2S and 2T; types 4B3, 4D and 4K; dominant intermediate B, E and G;
  recessive intermediate D; X-linked recessive 4 (CMTX4 / Cowchock syndrome,
  which is also carried as a has_subtypes record inside type X); Intermediate
  Charcot-Marie-Tooth Disease; and Charcot-Marie-Tooth Disease-Hearing
  Loss-Intellectual Disability Syndrome. Each is a candidate gene-anchored
  member on the same footing as CMT2W and CMT2JJ and needs its own
  differentiating_mechanisms text rather than a bare name, and the intermediate
  and X-linked-recessive entries additionally overlap compartment members, so
  that sweep is a separate curation decision from the compartment-level addition
  made here.