Intermediate Charcot-Marie-Tooth Disease

Mendelian MONDO:0018778 Pathograph 13 Show in embeddings browser Charcot-Marie-Tooth disease

Intermediate Charcot-Marie-Tooth disease (intermediate CMT / CMTi) is the compartment of Charcot-Marie-Tooth disease that sits electrophysiologically and pathologically between the demyelinating (CMT1) and axonal (CMT2) compartments. It is defined by upper-limb motor nerve conduction velocities in an intermediate range (classically ~25–45 m/s, overlapping the CMT1 and CMT2 cut-offs) and by nerve pathology that combines features of both demyelination and axonal degeneration — sometimes varying between affected members of a single family. Intermediate CMT is not a trivial category: in a 1,515-patient specialist cohort it comprised 13.5% of all CMT presentations, more than the axonal-optic and HNPP groups combined. It occurs in dominant-intermediate (DI-CMT) and recessive-intermediate (RI-CMT) forms. The dominant-intermediate subtypes include DI-CMTB (DNM2 / dynamin-2, a membrane-remodelling large GTPase), DI-CMTC (YARS1 / tyrosyl-tRNA synthetase), and DI-CMTF (GNB4 / G-protein beta-4); the aminoacyl-tRNA-synthetase mechanism recurs in the recessive-intermediate form RI-CMTB (KARS1 / lysyl-tRNA synthetase). Several intermediate-CMT genes are pleiotropic — DNM2, for example, also causes centronuclear myopathy. Whatever the gene, the subtypes converge on the shared CMT terminal node — combined demyelination and length-dependent axonal degeneration — producing the uniform clinical picture of distal weakness, wasting, sensory loss, foot deformity, and depressed reflexes.

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2
Inheritance
4
Pathophys.
5
Phenotypes
13
Pathograph
4
Genes
3
Medical Actions
4
Subtypes
2
References
👪

Inheritance

2
Autosomal Dominant HP:0000006
The dominant-intermediate CMT subtypes — DI-CMTB (DNM2), DI-CMTC (YARS1), and DI-CMTF (GNB4) — are inherited in an autosomal dominant manner.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
Documents autosomal dominant inheritance of the dominant-intermediate CMT subtypes.
Autosomal Recessive HP:0000007
Recessive-intermediate CMT (RI-CMT) subtypes, including RI-CMTB (KARS1), are inherited in an autosomal recessive manner, requiring biallelic (compound-heterozygous or homozygous) loss-of-function variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Documents compound-heterozygous (autosomal recessive) inheritance for RI-CMTB.
◆

Subtypes

4
DI-CMTB (DNM2 / dynamin-2)
Dominant-intermediate CMT type B, caused by mutations in DNM2 encoding dynamin-2, a large GTPase of the cellular membrane fission-fusion apparatus. DNM2 is pleiotropic — other DNM2 mutations cause centronuclear myopathy.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 mutations as the cause of dominant-intermediate CMT (DI-CMTB).
DI-CMTC (YARS1 / tyrosyl-tRNA synthetase)
Dominant-intermediate CMT type C, caused by mutations in YARS1 (YARS) encoding tyrosyl-tRNA synthetase — the first aminoacyl-tRNA synthetase linked to CMT, mislocalizing to axonal termini and partially losing aminoacylation activity.
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
Establishes YARS1 (YARS) mutations as the cause of dominant-intermediate CMT (DI-CMTC).
DI-CMTF (GNB4 / G-protein beta-4)
Dominant-intermediate CMT type F, caused by mutations in GNB4 encoding the G-protein beta-4 subunit, implicating G-protein-coupled receptor signaling in peripheral-nerve function.
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
Establishes GNB4 mutations as the cause of dominant-intermediate CMT (DI-CMTF).
RI-CMTB (KARS1 / lysyl-tRNA synthetase)
Recessive-intermediate CMT type B, caused by biallelic loss-of-function mutations in KARS1 (KARS) encoding lysyl-tRNA synthetase — a second aminoacyl-tRNA synthetase implicated in CMT, here acting recessively.
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Establishes compound-heterozygous KARS1 (KARS) loss-of-function variants as a cause of recessive-intermediate CMT (RI-CMTB).
⚙

Pathophysiology

4
DNM2 Membrane Remodeling Defect
Mutations in DNM2 (DI-CMTB) impair dynamin-2, a large GTPase of the membrane fission-fusion machinery that mediates membrane scission during endocytosis and vesicle trafficking. Disrupted DNM2-dependent membrane remodeling in Schwann cells and neurons produces a mixed demyelinating-and-axonal (intermediate) neuropathy.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
Endocytosis GO:0006897 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Endocytosis (GO:0006897). GO:0006897 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Combined Demyelinating and Axonal Degeneration DNM2-dependent membrane-trafficking failure impairs both Schwann-cell and axonal homeostasis, converging on the mixed intermediate lesion.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 (a membrane fission-fusion GTPase) as the DI-CMTB gene.
Aminoacyl-tRNA Synthetase Dysfunction
Mutations in the aminoacyl-tRNA synthetases YARS1 (tyrosyl-tRNA synthetase, DI-CMTC) and KARS1 (lysyl-tRNA synthetase, RI-CMTB) partially impair tRNA-charging (aminoacylation) activity and, for YARS1, mislocalize the enzyme within the axon. Aminoacyl-tRNA synthetase impairment is a recurrent CMT mechanism, predominantly producing axonal pathology, and here yields the intermediate phenotype.
Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
YARS1 hgnc:12840 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves YARS1 (hgnc:12840). hgnc:12840 is a gene from the HUGO Gene Nomenclature Committee. KARS1 hgnc:6215 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KARS1 (hgnc:6215). hgnc:6215 is a gene from the HUGO Gene Nomenclature Committee.
tRNA aminoacylation for protein translation GO:0006418 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased tRNA aminoacylation for protein translation (GO:0006418). GO:0006418 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Combined Demyelinating and Axonal Degeneration Impaired tRNA aminoacylation compromises protein synthesis in long peripheral neurons, converging on the intermediate demyelinating-and-axonal lesion.
Show evidence (2 references)
PMID:16429158 SUPPORT In Vitro
"Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins"
Demonstrates partial loss of aminoacylation activity for DI-CMTC YARS1 mutants.
PMID:20920668 SUPPORT Human Clinical
"Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology."
Establishes aminoacyl-tRNA synthetase dysfunction (including KARS1) as a recurrent CMT mechanism.
GNB4 G-Protein Signaling Defect
Mutations in GNB4 (DI-CMTF) disrupt the G-protein beta-4 subunit, which is expressed in axons and Schwann cells of peripheral nerve, implicating G-protein-coupled receptor signaling in the maintenance of peripheral-nerve function.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
GNB4 hgnc:20731 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GNB4 (hgnc:20731). hgnc:20731 is a gene from the HUGO Gene Nomenclature Committee.
G protein-coupled receptor signaling pathway GO:0007186 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal G protein-coupled receptor signaling pathway (GO:0007186). GO:0007186 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Combined Demyelinating and Axonal Degeneration Disrupted Gβ4-related GPCR signaling in peripheral nerve converges on the mixed intermediate lesion.
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
Establishes GNB4 (G-protein beta-4) as the DI-CMTF gene.
Combined Demyelinating and Axonal Degeneration
The shared terminal node of the intermediate CMT compartment. The diverse upstream lesions (DNM2 membrane-remodelling failure, aminoacyl-tRNA synthetase dysfunction, GNB4 signaling defect) converge on peripheral nerve pathology that combines demyelination and length-dependent axonal degeneration — the combination that produces the intermediate nerve conduction velocities defining this compartment and the progressive distal deficit shared with the CMT1 and CMT2 compartments.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Sensory neuron CL:0000101 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology.
Myelination in the peripheral nervous system GO:0022011 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Myelination in the peripheral nervous system, annotated with myelination in peripheral nervous system (GO:0022011). GO:0022011 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Distal Muscle Weakness
Distal Sensory Loss
Pes Cavus
Decreased Tendon Reflexes
Decreased Nerve Conduction Velocity
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features."
Supports the combined demyelinating-and-axonal pathology that underlies the intermediate CMT compartment.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intermediate Charcot-Marie-Tooth Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Limbs 1
Pes Cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Musculoskeletal 1
Distal Muscle Weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as course progressive. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
Supports impaired distal motor function as a core CMT phenotype shared by the intermediate forms.
Other 3
Distal Sensory Loss Distal sensory impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
Supports impaired distal sensory function as a core CMT phenotype shared by the intermediate forms.
Decreased Tendon Reflexes Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Decreased Nerve Conduction Velocity HP:0000762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased nerve conduction velocity (HP:0000762). HP:0000762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
Establishes the 'intermediate' electrophysiologic category of CMT that this entry models.
🧬

Genetic Associations

4
DNM2 (Causal)
Gene: DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:15731758 SUPPORT Human Clinical
"we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
Establishes DNM2 as the DI-CMTB gene.
YARS1 (Causal)
Gene: YARS1 hgnc:12840 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is YARS1 (hgnc:12840). hgnc:12840 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:16429158 SUPPORT Human Clinical
"we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
Establishes YARS1 as the DI-CMTC gene.
GNB4 (Causal)
Gene: GNB4 hgnc:20731 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNB4 (hgnc:20731). hgnc:20731 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:23434117 SUPPORT Human Clinical
"we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29."
Establishes the dominant-intermediate CMT locus (3q28-q29) subsequently attributed to GNB4 (DI-CMTF).
KARS1 (Causal)
Gene: KARS1 hgnc:6215 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KARS1 (hgnc:6215). hgnc:6215 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:20920668 SUPPORT Human Clinical
"we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
Establishes KARS1 as the RI-CMTB gene.
💊

Medical Actions

3
Physical and Occupational Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Mainstay of supportive care to maintain mobility and function.
Orthotic Bracing
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Ankle-foot orthoses to compensate for foot drop and improve gait.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for affected individuals and families, addressing the mixed dominant and recessive inheritance across intermediate-CMT subtypes.
🔬

Diagnosis

1
Intermediate Nerve Conduction Velocities
The defining diagnostic feature of intermediate CMT is upper-limb motor nerve conduction velocities in an intermediate range that overlaps the CMT1 (<38 m/s) and CMT2 (>38 m/s) cut-offs, with nerve biopsy showing both demyelinating and axonal features. Intermediate CMT is a substantial fraction of all CMT: it comprised 13.5% of a large single-centre specialist cohort.
Distinguishes the intermediate compartment from demyelinating CMT1 and axonal CMT2.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"205 intermediate CMT (CMTi, 13.5%)"
Intermediate CMT comprised 13.5% (205/1515) of a specialist CMT cohort, quantifying the size of this compartment.
{ }

Source YAML

click to show 
name: Intermediate Charcot-Marie-Tooth Disease
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Intermediate Charcot-Marie-Tooth disease (intermediate CMT / CMTi) is the
  compartment of Charcot-Marie-Tooth disease that sits electrophysiologically and
  pathologically between the demyelinating (CMT1) and axonal (CMT2) compartments.
  It is defined by upper-limb motor nerve conduction velocities in an intermediate
  range (classically ~25–45 m/s, overlapping the CMT1 and CMT2 cut-offs) and by
  nerve pathology that combines features of both demyelination and axonal
  degeneration — sometimes varying between affected members of a single family.
  Intermediate CMT is not a trivial category: in a 1,515-patient specialist
  cohort it comprised 13.5% of all CMT presentations, more than the axonal-optic
  and HNPP groups combined. It occurs in dominant-intermediate (DI-CMT) and
  recessive-intermediate (RI-CMT) forms. The dominant-intermediate subtypes
  include DI-CMTB (DNM2 / dynamin-2, a membrane-remodelling large GTPase),
  DI-CMTC (YARS1 / tyrosyl-tRNA synthetase), and DI-CMTF (GNB4 / G-protein
  beta-4); the aminoacyl-tRNA-synthetase mechanism recurs in the
  recessive-intermediate form RI-CMTB (KARS1 / lysyl-tRNA synthetase). Several
  intermediate-CMT genes are pleiotropic — DNM2, for example, also causes
  centronuclear myopathy. Whatever the gene, the subtypes converge on the shared CMT
  terminal node — combined demyelination and length-dependent axonal
  degeneration — producing the uniform clinical picture of distal weakness,
  wasting, sensory loss, foot deformity, and depressed reflexes.
disease_term:
  preferred_term: Intermediate Charcot-Marie-Tooth disease (CMTi)
  term:
    id: MONDO:0018778
    label: intermediate Charcot-Marie-Tooth disease
parents:
- Charcot-Marie-Tooth disease
has_subtypes:
- name: DI-CMTB
  display_name: DI-CMTB (DNM2 / dynamin-2)
  description: >-
    Dominant-intermediate CMT type B, caused by mutations in DNM2 encoding
    dynamin-2, a large GTPase of the cellular membrane fission-fusion apparatus.
    DNM2 is pleiotropic — other DNM2 mutations cause centronuclear myopathy.
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 mutations as the cause of dominant-intermediate CMT (DI-CMTB).
- name: DI-CMTC
  display_name: DI-CMTC (YARS1 / tyrosyl-tRNA synthetase)
  description: >-
    Dominant-intermediate CMT type C, caused by mutations in YARS1 (YARS)
    encoding tyrosyl-tRNA synthetase — the first aminoacyl-tRNA synthetase linked
    to CMT, mislocalizing to axonal termini and partially losing aminoacylation
    activity.
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
    explanation: Establishes YARS1 (YARS) mutations as the cause of dominant-intermediate CMT (DI-CMTC).
- name: DI-CMTF
  display_name: DI-CMTF (GNB4 / G-protein beta-4)
  description: >-
    Dominant-intermediate CMT type F, caused by mutations in GNB4 encoding the
    G-protein beta-4 subunit, implicating G-protein-coupled receptor signaling in
    peripheral-nerve function.
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
    explanation: Establishes GNB4 mutations as the cause of dominant-intermediate CMT (DI-CMTF).
- name: RI-CMTB
  display_name: RI-CMTB (KARS1 / lysyl-tRNA synthetase)
  description: >-
    Recessive-intermediate CMT type B, caused by biallelic loss-of-function
    mutations in KARS1 (KARS) encoding lysyl-tRNA synthetase — a second
    aminoacyl-tRNA synthetase implicated in CMT, here acting recessively.
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Establishes compound-heterozygous KARS1 (KARS) loss-of-function variants as a cause of recessive-intermediate CMT (RI-CMTB).
pathophysiology:
- name: DNM2 Membrane Remodeling Defect
  description: >-
    Mutations in DNM2 (DI-CMTB) impair dynamin-2, a large GTPase of the membrane
    fission-fusion machinery that mediates membrane scission during endocytosis
    and vesicle trafficking. Disrupted DNM2-dependent membrane remodeling in
    Schwann cells and neurons produces a mixed demyelinating-and-axonal
    (intermediate) neuropathy.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: Endocytosis
    term:
      id: GO:0006897
      label: endocytosis
    modifier: ABNORMAL
  genes:
  - preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      DNM2-dependent membrane-trafficking failure impairs both Schwann-cell and
      axonal homeostasis, converging on the mixed intermediate lesion.
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 (a membrane fission-fusion GTPase) as the DI-CMTB gene.
- name: Aminoacyl-tRNA Synthetase Dysfunction
  description: >-
    Mutations in the aminoacyl-tRNA synthetases YARS1 (tyrosyl-tRNA synthetase,
    DI-CMTC) and KARS1 (lysyl-tRNA synthetase, RI-CMTB) partially impair
    tRNA-charging (aminoacylation) activity and, for YARS1, mislocalize the
    enzyme within the axon. Aminoacyl-tRNA synthetase impairment is a recurrent
    CMT mechanism, predominantly producing axonal pathology, and here yields the
    intermediate phenotype.
  cell_types:
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: tRNA aminoacylation for protein translation
    term:
      id: GO:0006418
      label: tRNA aminoacylation for protein translation
    modifier: DECREASED
  genes:
  - preferred_term: YARS1
    term:
      id: hgnc:12840
      label: YARS1
  - preferred_term: KARS1
    term:
      id: hgnc:6215
      label: KARS1
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Impaired tRNA aminoacylation compromises protein synthesis in long
      peripheral neurons, converging on the intermediate demyelinating-and-axonal
      lesion.
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical experiments and genetic complementation in yeast show partial loss of aminoacylation activity of the mutant proteins"
    explanation: Demonstrates partial loss of aminoacylation activity for DI-CMTC YARS1 mutants.
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in three genes encoding aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT disease primarily associated with an axonal pathology."
    explanation: Establishes aminoacyl-tRNA synthetase dysfunction (including KARS1) as a recurrent CMT mechanism.
- name: GNB4 G-Protein Signaling Defect
  description: >-
    Mutations in GNB4 (DI-CMTF) disrupt the G-protein beta-4 subunit, which is
    expressed in axons and Schwann cells of peripheral nerve, implicating
    G-protein-coupled receptor signaling in the maintenance of peripheral-nerve
    function.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  biological_processes:
  - preferred_term: G protein-coupled receptor signaling pathway
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
    modifier: ABNORMAL
  genes:
  - preferred_term: GNB4
    term:
      id: hgnc:20731
      label: GNB4
  downstream:
  - target: Combined Demyelinating and Axonal Degeneration
    description: >-
      Disrupted Gβ4-related GPCR signaling in peripheral nerve converges on the
      mixed intermediate lesion.
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed heterozygous mutation c.158G>A (p.Gly53Asp) in GNB4, encoding guanine-nucleotide-binding protein subunit beta-4"
    explanation: Establishes GNB4 (G-protein beta-4) as the DI-CMTF gene.
- name: Combined Demyelinating and Axonal Degeneration
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The shared terminal node of the intermediate CMT compartment. The diverse
    upstream lesions (DNM2 membrane-remodelling failure, aminoacyl-tRNA
    synthetase dysfunction, GNB4 signaling defect) converge on peripheral nerve
    pathology that combines demyelination and length-dependent axonal
    degeneration — the combination that produces the intermediate nerve
    conduction velocities defining this compartment and the progressive distal
    deficit shared with the CMT1 and CMT2 compartments.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: ABNORMAL
  downstream:
  - target: Distal Muscle Weakness
  - target: Distal Sensory Loss
  - target: Pes Cavus
  - target: Decreased Tendon Reflexes
  - target: Decreased Nerve Conduction Velocity
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) neuropathies are common disorders of the peripheral nervous system caused by demyelination or axonal degeneration, or a combination of both features."
    explanation: Supports the combined demyelinating-and-axonal pathology that underlies the intermediate CMT compartment.
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  diagnostic: true
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
    explanation: Supports impaired distal motor function as a core CMT phenotype shared by the intermediate forms.
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Charcot-Marie-Tooth (CMT) disease comprises a genetically and clinically heterogeneous group of peripheral nerve disorders characterized by impaired distal motor and sensory function."
    explanation: Supports impaired distal sensory function as a core CMT phenotype shared by the intermediate forms.
- category: Musculoskeletal
  name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
- category: Neurologic
  name: Decreased Tendon Reflexes
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
- category: Neurophysiologic
  name: Decreased Nerve Conduction Velocity
  description: >-
    Motor nerve conduction velocities fall in an intermediate range (classically
    ~25–45 m/s) that overlaps the demyelinating CMT1 (<38 m/s) and axonal CMT2
    (>38 m/s) cut-offs, reflecting the combined demyelinating-and-axonal
    pathology that defines this compartment.
  phenotype_term:
    preferred_term: Decreased nerve conduction velocity
    term:
      id: HP:0000762
      label: Decreased nerve conduction velocity
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
    explanation: Establishes the 'intermediate' electrophysiologic category of CMT that this entry models.
genetic:
- name: DNM2
  gene_term:
    preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  association: Causal
  subtype: DI-CMTB
  notes: >-
    Dynamin-2, a large GTPase of the membrane fission-fusion apparatus; dominant
    mutations cause DI-CMTB. The gene is pleiotropic (also centronuclear myopathy).
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified unique mutations in dynamin 2 (DNM2) in all families. DNM2 belongs to the family of large GTPases and is part of the cellular fusion-fission apparatus."
    explanation: Establishes DNM2 as the DI-CMTB gene.
- name: YARS1
  gene_term:
    preferred_term: YARS1
    term:
      id: hgnc:12840
      label: YARS1
  association: Causal
  subtype: DI-CMTC
  notes: >-
    Tyrosyl-tRNA synthetase; dominant mutations cause DI-CMTC (the first
    aminoacyl-tRNA synthetase linked to CMT).
  evidence:
  - reference: PMID:16429158
    reference_title: "Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify two heterozygous missense mutations (G41R and E196K) and one de novo deletion (153-156delVKQV) in tyrosyl-tRNA synthetase (YARS) in three unrelated families affected with DI-CMTC."
    explanation: Establishes YARS1 as the DI-CMTC gene.
- name: GNB4
  gene_term:
    preferred_term: GNB4
    term:
      id: hgnc:20731
      label: GNB4
  association: Causal
  subtype: DI-CMTF
  notes: >-
    G-protein beta-4 subunit expressed in axons and Schwann cells; dominant
    mutations cause DI-CMTF, implicating GPCR signaling in peripheral nerve.
  evidence:
  - reference: PMID:23434117
    reference_title: "Exome sequencing identifies GNB4 mutations as a cause of dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we previously mapped a dominant intermediate CMT to chromosomal region 3q28-q29."
    explanation: Establishes the dominant-intermediate CMT locus (3q28-q29) subsequently attributed to GNB4 (DI-CMTF).
- name: KARS1
  gene_term:
    preferred_term: KARS1
    term:
      id: hgnc:6215
      label: KARS1
  association: Causal
  subtype: RI-CMTB
  notes: >-
    Lysyl-tRNA synthetase; biallelic loss-of-function variants cause
    recessive-intermediate CMT (RI-CMTB), a second ARS implicated in CMT.
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Establishes KARS1 as the RI-CMTB gene.
inheritance:
- name: Autosomal Dominant
  description: >-
    The dominant-intermediate CMT subtypes — DI-CMTB (DNM2), DI-CMTC (YARS1),
    and DI-CMTF (GNB4) — are inherited in an autosomal dominant manner.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:15731758
    reference_title: "Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Different chromosomal loci have been linked with three autosomal dominant, 'intermediate' types of CMT: DI-CMTA, DI-CMTB and DI-CMTC."
    explanation: Documents autosomal dominant inheritance of the dominant-intermediate CMT subtypes.
- name: Autosomal Recessive
  description: >-
    Recessive-intermediate CMT (RI-CMT) subtypes, including RI-CMTB (KARS1),
    are inherited in an autosomal recessive manner, requiring biallelic
    (compound-heterozygous or homozygous) loss-of-function variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20920668
    reference_title: "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe three variants (p.Leu133His, p.Tyr173SerfsX7, and p.Ile302Met) in the lysyl-tRNA synthetase (KARS) gene in two patients from this cohort."
    explanation: Documents compound-heterozygous (autosomal recessive) inheritance for RI-CMTB.
diagnosis:
- name: Intermediate Nerve Conduction Velocities
  description: >-
    The defining diagnostic feature of intermediate CMT is upper-limb motor nerve
    conduction velocities in an intermediate range that overlaps the CMT1 (<38
    m/s) and CMT2 (>38 m/s) cut-offs, with nerve biopsy showing both
    demyelinating and axonal features. Intermediate CMT is a substantial fraction
    of all CMT: it comprised 13.5% of a large single-centre specialist cohort.
  notes: Distinguishes the intermediate compartment from demyelinating CMT1 and axonal CMT2.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "205 intermediate CMT (CMTi, 13.5%)"
    explanation: Intermediate CMT comprised 13.5% (205/1515) of a specialist CMT cohort, quantifying the size of this compartment.
treatments:
- name: Physical and Occupational Therapy
  description: Mainstay of supportive care to maintain mobility and function.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Orthotic Bracing
  description: Ankle-foot orthoses to compensate for foot drop and improve gait.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Counseling for affected individuals and families, addressing the mixed
    dominant and recessive inheritance across intermediate-CMT subtypes.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1093/brain/awae064
  title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
  findings: []
datasets: []
📚

References & Deep Research

References

2
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.
DOI:10.1093/brain/awae064
Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease
No top-level findings curated for this source.