Charcot-Marie-Tooth Disease Type 1

Mendelian MONDO:0019011 Pathograph 13 Show in embeddings browser Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease type 1 (CMT1) is the demyelinating compartment of Charcot-Marie-Tooth disease: a group of inherited peripheral neuropathies in which the primary lesion lies in the myelinating Schwann cell rather than the axon. Motor nerve conduction velocities are uniformly slowed (classically <38 m/s in the median nerve), reflecting dysmyelination and demyelination, and the characteristic clinical phenotype — slowly progressive distal weakness, sensory loss, pes cavus, and depressed reflexes — emerges from secondary, length-dependent axonal loss that follows the primary myelin defect. This entry collects the Schwann-cell / myelin mechanisms that converge on a single shared terminal node (demyelination with secondary axonal degeneration), distinct from the neuron-primary axonal mechanisms curated under Charcot-Marie-Tooth disease type 2. The dominant subtype is CMT1A, caused by a 1.4 Mb duplication on chromosome 17p11.2 containing PMP22; CMT1B is caused by MPZ mutations. The X-linked form CMTX1 (GJB1 / connexin-32) is electrophysiologically intermediate but is grouped here because its primary lesion is a Schwann-cell gap-junction defect; it forms the glia-axon bridge between the demyelinating and axonal compartments.

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4
Pathophys.
6
Phenotypes
13
Pathograph
4
Genes
4
Medical Actions
4
Subtypes
1
References
1
Deep Research
◆

Subtypes

4
CMT1A (PMP22 duplication)
The most common CMT subtype overall, caused by a 1.4 Mb tandem duplication of chromosome 17p11.2 containing PMP22. PMP22 overexpression destabilizes compact myelin, producing dysmyelination, demyelination, and onion-bulb formation.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
Establishes PMP22 duplication / CMT1A as the dominant genetic cause within the demyelinating compartment.
CMT1B (MPZ-related)
Caused by mutations in MPZ encoding myelin protein zero, the most abundant peripheral myelin protein. Many MPZ variants trigger protein misfolding, the unfolded protein response, and chronic Schwann-cell ER stress.
Show evidence (1 reference)
DOI:10.3390/ijms25179227 SUPPORT Other
"Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
Establishes UPR / ER stress as the canonical CMT1B (MPZ) Schwann-cell mechanism.
CMTX1 (GJB1 / connexin-32, X-linked intermediate bridge)
X-linked form caused by mutations in GJB1 encoding connexin-32, a Schwann-cell gap-junction protein at the paranodes and Schmidt-Lanterman incisures. Grouped in the demyelinating compartment because the primary lesion is a Schwann-cell gap-junction defect, though its electrophysiology is intermediate and its pathology shows both demyelination and axon loss — the glia-axon bridge between the CMT1 and CMT2 compartments.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"then GJB1 (CMTX1; 151/1165, 13.0%)"
GJB1 / CMTX1 is the second most common genetically resolved CMT subtype.
CMT1D (EGR2-related)
Demyelinating CMT caused by mutations in EGR2 (Krox20), a transcription factor required for Schwann-cell myelination. The same gene also causes congenital hypomyelinating neuropathy and Dejerine-Sottas neuropathy at the severe end of the spectrum.
Show evidence (1 reference)
PMID:9537424 SUPPORT Human Clinical
"we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)."
Establishes EGR2 mutations as a cause of demyelinating CMT1 (CMT1D).
⚙

Pathophysiology

4
PMP22 Overexpression and Dysmyelination
The most common cause of CMT (CMT1A) is a 1.4 Mb tandem duplication of chromosome 17p11.2 containing the peripheral myelin protein 22 (PMP22) gene. PMP22 overexpression destabilizes compact myelin and disrupts the structural organization of the myelin sheath, causing dysmyelination, demyelination, and characteristic onion-bulb formation from repeated Schwann-cell remyelination attempts. Slowed nerve conduction follows, and chronic secondary axonal loss eventually drives the clinical phenotype.
Schwann cell CL:0002573
PMP22 hgnc:9118
Myelination in the peripheral nervous system GO:0022011 ↓ DECREASED
Downstream
Demyelination and Secondary Axonal Loss PMP22-dosage-driven dysmyelination produces demyelination and, over time, length-dependent secondary axonal degeneration.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
Establishes PMP22 duplication / CMT1A as the dominant genetic cause of demyelinating CMT.
MPZ Misfolding and Schwann Cell ER Stress
MPZ (myelin protein zero) mutations cause CMT1B. Many MPZ variants produce protein misfolding that triggers the unfolded protein response (UPR) and chronic endoplasmic reticulum (ER) stress in Schwann cells, or cause mistrafficking of the mutant protein. The resulting myelin instability drives the demyelinating CMT1B phenotype.
Schwann cell CL:0002573
MPZ hgnc:7225
Endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED
Downstream
Demyelination and Secondary Axonal Loss Misfolded-MPZ-driven Schwann-cell ER stress destabilizes myelin, producing demyelination and secondary axonal degeneration.
Show evidence (1 reference)
DOI:10.3390/ijms25179227 SUPPORT Other
"Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
Establishes UPR / ER stress as the canonical CMT1B disease mechanism.
Connexin-32 Gap Junction Failure in CMTX1
GJB1 mutations cause loss of function of connexin-32, which forms reflexive gap-junction channels across the non-compact myelin of the paranodes and Schmidt-Lanterman incisures, shortening the radial diffusion pathway between the Schwann-cell body and the adaxonal cytoplasm. Loss of these channels impairs Schwann-cell homeostasis and myelin maintenance, producing the X-linked demyelinating-spectrum neuropathy CMTX1.
Schwann cell CL:0002573
GJB1 hgnc:4283
Gap junction assembly GO:0016264 ⚠ ABNORMAL
Downstream
Demyelination and Secondary Axonal Loss Connexin-32 gap-junction failure impairs Schwann-cell homeostasis, producing demyelination together with axon loss in CMTX1.
Show evidence (1 reference)
PMID:30881289 SUPPORT Other
"Most GJB1 mutations cause disability through the loss of function of Cx32"
Establishes loss of function of connexin-32 (Cx32) as the dominant CMTX1 disease mechanism.
Demyelination and Secondary Axonal Loss
The shared terminal node of the demyelinating compartment. Primary Schwann-cell and myelin defects (PMP22 dosage, MPZ misfolding, connexin-32 gap-junction failure) converge on segmental demyelination and repeated remyelination (onion-bulb formation), which over time produces length-dependent secondary axonal degeneration. It is this secondary axonal loss, affecting the longest motor and sensory fibers first, that determines the progressive clinical deficit shared with the axonal compartment.
Schwann cell CL:0002573 Sensory neuron of peripheral nervous system CL:0000101
Myelination in the peripheral nervous system GO:0022011 ↓ DECREASED
Downstream
Decreased Nerve Conduction Velocity Segmental demyelination slows saltatory conduction across peripheral nerves.
Distal Muscle Weakness Length-dependent secondary axonal loss in motor fibers produces distal lower-limb weakness and wasting.
Pes Cavus Chronic distal motor imbalance from hereditary peripheral neuropathy produces cavus foot deformity.
Decreased Tendon Reflexes Peripheral demyelinating neuropathy and secondary axonal dysfunction reduce ankle tendon reflexes.
Distal Sensory Loss Sensory fiber involvement in the demyelinating neuropathy produces distal sensory impairment.
Show evidence (1 reference)
PMID:30881289 SUPPORT Other
"Typically, the pathophysiology of CMTX1 includes features of both demyelination and axon loss"
Supports the convergence of demyelinating CMT mechanisms on combined demyelination and secondary axonal loss.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Charcot-Marie-Tooth Disease Type 1 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

6
Limbs 1
Pes Cavus Pes cavus HP:0001761
Show evidence (1 reference)
PMID:9183252 SUPPORT Human Clinical
"None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
In a 119-case CMT1A cohort, every patient had at least pes cavus or ankle areflexia on examination.
Musculoskeletal 1
Distal Muscle Weakness Distal muscle weakness HP:0002460
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:9183252 SUPPORT Human Clinical
"The predominant clinical signs were muscle weakness and wasting in the lower limbs."
119-case CMT1A study identifies distal lower-limb muscle weakness as the predominant clinical sign.
Other 4
Onion Bulb Formation Onion bulb formation HP:0003383
Decreased Tendon Reflexes Hyporeflexia HP:0001265
Show evidence (1 reference)
PMID:9183252 SUPPORT Human Clinical
"None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
Ankle-jerk areflexia was a near-universal examination finding in this CMT1A cohort.
Distal Sensory Loss Distal sensory impairment HP:0002936
Show evidence (1 reference)
PMID:9183252 SUPPORT Human Clinical
"Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss."
Sensory nerve potentials were abnormal in all CMT1A cases, evidencing the sensory component of the neuropathy.
Decreased Nerve Conduction Velocity Decreased nerve conduction velocity HP:0000762
Show evidence (1 reference)
PMID:9183252 SUPPORT Human Clinical
"Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients."
A 119-case CMT1A cohort directly reports uniformly reduced motor nerve conduction velocity.
🧬

Genetic Associations

4
PMP22 (Causal)
Gene: PMP22 hgnc:9118
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
PMP22 duplication is the dominant genetic cause of demyelinating CMT.
MPZ (Causal)
Gene: MPZ hgnc:7225
Show evidence (1 reference)
DOI:10.3390/ijms25179227 SUPPORT Other
"Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
Establishes the MPZ misfolding / ER-stress mechanism in CMT1B.
GJB1 (Causal)
Gene: GJB1 hgnc:4283
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"then GJB1 (CMTX1; 151/1165, 13.0%)"
GJB1 / CMTX1 is the second most common genetically resolved CMT subtype.
EGR2 (Causal)
Gene: EGR2 hgnc:3239
Show evidence (1 reference)
PMID:9537424 SUPPORT Human Clinical
"Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS)."
Establishes EGR2 (Krox20) as a Schwann-cell transcription factor controlling PNS myelination, the process disrupted in demyelinating CMT1D.
💊

Medical Actions

4
Physical and Occupational Therapy
Action: physical therapy MAXO:0000011
Mainstay of supportive care to maintain mobility and function.
Orthotic Bracing
Action: supportive care MAXO:0000950
Ankle-foot orthoses to compensate for foot drop and improve gait.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
Counseling for affected individuals and families.
PXT3003
Action: Pharmacotherapy NCIT:C15986
Oral fixed-dose combination of low-dose baclofen, naltrexone, and sorbitol designed to lower PMP22 expression and improve axonal function in CMT1A. Phase III trials (PLEO-CMT NCT02579759 completed, PREMIER NCT04762758).
Mechanism Target:
PMP22 Overexpression and Dysmyelination — PXT3003 is designed to lower PMP22 expression, targeting the primary dysmyelinating lesion of CMT1A.
Show evidence (1 reference)
DOI:10.3390/genes14071391 SUPPORT Other
"Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed."
Establishes PXT3003 as an active clinical/preclinical therapeutic candidate for CMT1A.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Type 1
creation_date: "2026-06-11T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 1 (CMT1) is the demyelinating compartment of
  Charcot-Marie-Tooth disease: a group of inherited peripheral neuropathies in
  which the primary lesion lies in the myelinating Schwann cell rather than the
  axon. Motor nerve conduction velocities are uniformly slowed (classically
  <38 m/s in the median nerve), reflecting dysmyelination and demyelination, and
  the characteristic clinical phenotype — slowly progressive distal weakness,
  sensory loss, pes cavus, and depressed reflexes — emerges from secondary,
  length-dependent axonal loss that follows the primary myelin defect. This entry
  collects the Schwann-cell / myelin mechanisms that converge on a single shared
  terminal node (demyelination with secondary axonal degeneration), distinct from
  the neuron-primary axonal mechanisms curated under Charcot-Marie-Tooth disease
  type 2. The dominant subtype is CMT1A, caused by a 1.4 Mb duplication on
  chromosome 17p11.2 containing PMP22; CMT1B is caused by MPZ mutations. The
  X-linked form CMTX1 (GJB1 / connexin-32) is electrophysiologically intermediate
  but is grouped here because its primary lesion is a Schwann-cell gap-junction
  defect; it forms the glia-axon bridge between the demyelinating and axonal
  compartments.
disease_term:
  preferred_term: Demyelinating Charcot-Marie-Tooth disease (CMT1)
  term:
    id: MONDO:0019011
    label: Charcot-Marie-Tooth disease type 1
parents:
- Charcot-Marie-Tooth disease
has_subtypes:
- name: CMT1A
  display_name: CMT1A (PMP22 duplication)
  description: >-
    The most common CMT subtype overall, caused by a 1.4 Mb tandem duplication of
    chromosome 17p11.2 containing PMP22. PMP22 overexpression destabilizes compact
    myelin, producing dysmyelination, demyelination, and onion-bulb formation.
  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: "The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
    explanation: Establishes PMP22 duplication / CMT1A as the dominant genetic cause within the demyelinating compartment.
- name: CMT1B
  display_name: CMT1B (MPZ-related)
  description: >-
    Caused by mutations in MPZ encoding myelin protein zero, the most abundant
    peripheral myelin protein. Many MPZ variants trigger protein misfolding, the
    unfolded protein response, and chronic Schwann-cell ER stress.
  evidence:
  - reference: DOI:10.3390/ijms25179227
    reference_title: "Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
    explanation: Establishes UPR / ER stress as the canonical CMT1B (MPZ) Schwann-cell mechanism.
- name: CMTX1
  display_name: CMTX1 (GJB1 / connexin-32, X-linked intermediate bridge)
  description: >-
    X-linked form caused by mutations in GJB1 encoding connexin-32, a Schwann-cell
    gap-junction protein at the paranodes and Schmidt-Lanterman incisures. Grouped
    in the demyelinating compartment because the primary lesion is a Schwann-cell
    gap-junction defect, though its electrophysiology is intermediate and its
    pathology shows both demyelination and axon loss — the glia-axon bridge between
    the CMT1 and CMT2 compartments.
  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: "then GJB1 (CMTX1; 151/1165, 13.0%)"
    explanation: GJB1 / CMTX1 is the second most common genetically resolved CMT subtype.
- name: CMT1D
  display_name: CMT1D (EGR2-related)
  description: >-
    Demyelinating CMT caused by mutations in EGR2 (Krox20), a transcription
    factor required for Schwann-cell myelination. The same gene also causes
    congenital hypomyelinating neuropathy and Dejerine-Sottas neuropathy at the
    severe end of the spectrum.
  evidence:
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified one recessive and two dominant missense mutations in EGR2 (within regions encoding conserved functional domains) in patients with congenital hypomyelinating neuropathy (CHN) and a family with Charcot-Marie-Tooth type 1 (CMT1)."
    explanation: Establishes EGR2 mutations as a cause of demyelinating CMT1 (CMT1D).
pathophysiology:
- name: PMP22 Overexpression and Dysmyelination
  description: >-
    The most common cause of CMT (CMT1A) is a 1.4 Mb tandem duplication of
    chromosome 17p11.2 containing the peripheral myelin protein 22 (PMP22) gene.
    PMP22 overexpression destabilizes compact myelin and disrupts the structural
    organization of the myelin sheath, causing dysmyelination, demyelination, and
    characteristic onion-bulb formation from repeated Schwann-cell remyelination
    attempts. Slowed nerve conduction follows, and chronic secondary axonal loss
    eventually drives the clinical phenotype.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Myelination in the peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  genes:
  - preferred_term: PMP22
    term:
      id: hgnc:9118
      label: PMP22
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      PMP22-dosage-driven dysmyelination produces demyelination and, over time,
      length-dependent secondary axonal degeneration.
  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: "The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
    explanation: Establishes PMP22 duplication / CMT1A as the dominant genetic cause of demyelinating CMT.
- name: MPZ Misfolding and Schwann Cell ER Stress
  description: >-
    MPZ (myelin protein zero) mutations cause CMT1B. Many MPZ variants produce
    protein misfolding that triggers the unfolded protein response (UPR) and
    chronic endoplasmic reticulum (ER) stress in Schwann cells, or cause
    mistrafficking of the mutant protein. The resulting myelin instability drives
    the demyelinating CMT1B phenotype.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  genes:
  - preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Misfolded-MPZ-driven Schwann-cell ER stress destabilizes myelin, producing
      demyelination and secondary axonal degeneration.
  evidence:
  - reference: DOI:10.3390/ijms25179227
    reference_title: "Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
    explanation: Establishes UPR / ER stress as the canonical CMT1B disease mechanism.
- name: Connexin-32 Gap Junction Failure in CMTX1
  description: >-
    GJB1 mutations cause loss of function of connexin-32, which forms reflexive
    gap-junction channels across the non-compact myelin of the paranodes and
    Schmidt-Lanterman incisures, shortening the radial diffusion pathway between
    the Schwann-cell body and the adaxonal cytoplasm. Loss of these channels
    impairs Schwann-cell homeostasis and myelin maintenance, producing the
    X-linked demyelinating-spectrum neuropathy CMTX1.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Gap junction assembly
    term:
      id: GO:0016264
      label: gap junction assembly
    modifier: ABNORMAL
  genes:
  - preferred_term: GJB1
    term:
      id: hgnc:4283
      label: GJB1
  downstream:
  - target: Demyelination and Secondary Axonal Loss
    description: >-
      Connexin-32 gap-junction failure impairs Schwann-cell homeostasis, producing
      demyelination together with axon loss in CMTX1.
  evidence:
  - reference: PMID:30881289
    reference_title: "Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most GJB1 mutations cause disability through the loss of function of Cx32"
    explanation: Establishes loss of function of connexin-32 (Cx32) as the dominant CMTX1 disease mechanism.
- name: Demyelination and Secondary Axonal Loss
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    The shared terminal node of the demyelinating compartment. Primary Schwann-cell
    and myelin defects (PMP22 dosage, MPZ misfolding, connexin-32 gap-junction
    failure) converge on segmental demyelination and repeated remyelination
    (onion-bulb formation), which over time produces length-dependent secondary
    axonal degeneration. It is this secondary axonal loss, affecting the longest
    motor and sensory fibers first, that determines the progressive clinical
    deficit shared with the axonal compartment.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Sensory neuron of peripheral nervous system
    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: DECREASED
  downstream:
  - target: Decreased Nerve Conduction Velocity
    description: >
      Segmental demyelination slows saltatory conduction across peripheral
      nerves.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9183252
      reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients."
      explanation: >
        The CMT1A cohort directly supports slowed motor nerve conduction as the
        electrophysiologic consequence of the demyelinating CMT1 lesion.
  - target: Distal Muscle Weakness
    description: >
      Length-dependent secondary axonal loss in motor fibers produces distal
      lower-limb weakness and wasting.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9183252
      reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The predominant clinical signs were muscle weakness and wasting in the lower limbs."
      explanation: >
        The 119-case CMT1A cohort identifies distal lower-limb weakness and
        wasting as predominant clinical signs.
  - target: Pes Cavus
    description: >
      Chronic distal motor imbalance from hereditary peripheral neuropathy
      produces cavus foot deformity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:9183252
      reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
      explanation: >
        The cohort supports pes cavus as a common examination finding in CMT1A.
  - target: Decreased Tendon Reflexes
    description: >
      Peripheral demyelinating neuropathy and secondary axonal dysfunction
      reduce ankle tendon reflexes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9183252
      reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
      explanation: >
        The cohort supports ankle-jerk areflexia as a CMT1A examination
        finding.
  - target: Distal Sensory Loss
    description: >
      Sensory fiber involvement in the demyelinating neuropathy produces distal
      sensory impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9183252
      reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss."
      explanation: >
        Abnormal sensory potentials in all cases support sensory-fiber
        involvement in CMT1A.
  evidence:
  - reference: PMID:30881289
    reference_title: "Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Typically, the pathophysiology of CMTX1 includes features of both demyelination and axon loss"
    explanation: Supports the convergence of demyelinating CMT mechanisms on combined demyelination and secondary axonal loss.
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:9183252
    reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant clinical signs were muscle weakness and wasting in the lower limbs."
    explanation: 119-case CMT1A study identifies distal lower-limb muscle weakness as the predominant clinical sign.
- category: Neurologic
  name: Onion Bulb Formation
  description: >-
    Concentric Schwann-cell and fibroblast processes around demyelinated and
    remyelinated axons on nerve biopsy, the histological hallmark of chronic
    demyelinating neuropathy and a feature that distinguishes CMT1 from axonal CMT2.
  phenotype_term:
    preferred_term: Onion bulb formation
    term:
      id: HP:0003383
      label: Onion bulb formation
- category: Musculoskeletal
  name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:9183252
    reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
    explanation: In a 119-case CMT1A cohort, every patient had at least pes cavus or ankle areflexia on examination.
- category: Neurologic
  name: Decreased Tendon Reflexes
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:9183252
    reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients was normal on clinical examination and all presented at least pes cavus or ankle jerk areflexia."
    explanation: Ankle-jerk areflexia was a near-universal examination finding in this CMT1A cohort.
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:9183252
    reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensory potentials were abnormal in all cases, even where there was no clinical sensory loss."
    explanation: Sensory nerve potentials were abnormal in all CMT1A cases, evidencing the sensory component of the neuropathy.
- category: Neurophysiologic
  name: Decreased Nerve Conduction Velocity
  description: >-
    Uniformly slowed motor nerve conduction is the defining electrophysiologic
    feature of the demyelinating CMT1 compartment.
  phenotype_term:
    preferred_term: Decreased nerve conduction velocity
    term:
      id: HP:0000762
      label: Decreased nerve conduction velocity
  evidence:
  - reference: PMID:9183252
    reference_title: "Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor nerve conduction velocity (MNCV) was uniformly reduced in all nerves, and was < or = 33 m/s in the median nerve for all patients."
    explanation: >
      A 119-case CMT1A cohort directly reports uniformly reduced motor nerve
      conduction velocity.
genetic:
- name: PMP22
  gene_term:
    preferred_term: PMP22
    term:
      id: hgnc:9118
      label: PMP22
  association: Causal
  subtype: CMT1A
  notes: >-
    A 1.4 Mb tandem duplication of 17p11.2 containing PMP22 causes CMT1A, the
    single most common CMT genotype. PMP22 point mutations cause rarer
    demyelinating forms; the reciprocal deletion causes HNPP (curated separately).
  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: "The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
    explanation: PMP22 duplication is the dominant genetic cause of demyelinating CMT.
- name: MPZ
  gene_term:
    preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  association: Causal
  subtype: CMT1B
  notes: >-
    MPZ (myelin protein zero) is the most abundant peripheral myelin protein.
    Mutations cause CMT1B; many trigger protein misfolding, UPR, and chronic ER
    stress in Schwann cells.
  evidence:
  - reference: DOI:10.3390/ijms25179227
    reference_title: "Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the MPZ gene can lead to protein misfolding, unfolded protein response (UPR), endoplasmic reticulum (ER) stress, or protein mistrafficking."
    explanation: Establishes the MPZ misfolding / ER-stress mechanism in CMT1B.
- name: GJB1
  gene_term:
    preferred_term: GJB1
    term:
      id: hgnc:4283
      label: GJB1
  association: Causal
  subtype: CMTX1
  notes: >-
    GJB1 encodes connexin-32, expressed in Schwann cells at the paranodal gap
    junctions and Schmidt-Lanterman incisures. X-linked (CMTX1), the second most
    common genetic cause of CMT.
  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: "then GJB1 (CMTX1; 151/1165, 13.0%)"
    explanation: GJB1 / CMTX1 is the second most common genetically resolved CMT subtype.
- name: EGR2
  gene_term:
    preferred_term: EGR2
    term:
      id: hgnc:3239
      label: EGR2
  association: Causal
  subtype: CMT1D
  notes: >-
    EGR2 (Krox20) is a transcription factor required for Schwann-cell
    myelination. Dominant mutations cause demyelinating CMT1D; recessive and
    other variants cause congenital hypomyelinating neuropathy and
    Dejerine-Sottas neuropathy.
  evidence:
  - reference: PMID:9537424
    reference_title: "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stable expression of Egr2 is specifically associated with the onset of myelination in the peripheral nervous system (PNS)."
    explanation: Establishes EGR2 (Krox20) as a Schwann-cell transcription factor controlling PNS myelination, the process disrupted in demyelinating CMT1D.
treatments:
- name: Physical and Occupational Therapy
  description: Mainstay of supportive care to maintain mobility and function.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      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: MAXO:0000950
      label: supportive care
- name: Genetic Counseling
  description: Counseling for affected individuals and families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: PXT3003
  description: >-
    Oral fixed-dose combination of low-dose baclofen, naltrexone, and sorbitol
    designed to lower PMP22 expression and improve axonal function in CMT1A.
    Phase III trials (PLEO-CMT NCT02579759 completed, PREMIER NCT04762758).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: PMP22 Overexpression and Dysmyelination
    description: >-
      PXT3003 is designed to lower PMP22 expression, targeting the primary
      dysmyelinating lesion of CMT1A.
  evidence:
  - reference: DOI:10.3390/genes14071391
    reference_title: "Therapeutic Strategies in Charcot-Marie-Tooth Disease"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed."
    explanation: Establishes PXT3003 as an active clinical/preclinical therapeutic candidate for CMT1A.
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
datasets: []
📚

References & Deep Research

References

1
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-06-11T23:04:21.124821

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Charcot-Marie-Tooth Disease Type 1
  • MONDO ID: MONDO:0019011 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Charcot-Marie-Tooth Disease Type 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: Charcot–Marie–Tooth Disease Type 1 (CMT1)

Scope and evidence note

This report synthesizes information retrieved from peer‑reviewed reviews and cohort studies (2022–2024 prioritized), ClinicalTrials.gov registry records for ongoing/completed interventional studies, and Open Targets disease–gene association data. Some identifier fields (OMIM, Orphanet, ICD-10/ICD-11, MeSH) were not directly present in the retrieved full texts; these gaps are explicitly labeled as “not retrieved in tool context” rather than inferred.

Item Evidence-backed statement/data Source (first author, journal, year) PMID/DOI/URL Notes for ontology mapping
Disease definition CMT1 is the demyelinating form of Charcot-Marie-Tooth disease, an inherited peripheral neuropathy affecting peripheral nerves/Schwann cells with slowly progressive distal weakness, sensory loss, and foot deformities (okamoto2023thecurrentstate pages 1-2, dong2024currenttreatmentmethods pages 1-2) Okamoto, Genes, 2023; Dong, Biomolecules, 2024 DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 MONDO:0019011; UBERON:0000010 peripheral nervous system; CL:0002573 myelinating Schwann cell; HPO: HP:0003401 distal muscle weakness, HP:0009836 peripheral neuropathy
Electrophysiologic classification In one recent treatment review, demyelinating CMT1 is defined by upper-limb MNCV <38 m/s, axonal CMT2 by >38 m/s, and intermediate forms by 25–45 m/s (okamoto2023thecurrentstate pages 1-2, estevezarias2022geneticapproachesand pages 1-3) Okamoto, Genes, 2023; Estévez-Arias, J Transl Genet Genom, 2022 DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 HPO support: HP:0003448 reduced nerve conduction velocity
Electrophysiologic subclassification Another 2024 review gives forearm ulnar motor NCV ranges: very slow <15 m/s; slow 15–35 m/s; intermediate 35–45 m/s; normal >45 m/s (dong2024currenttreatmentmethods pages 1-2) Dong, Biomolecules, 2024 DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 Useful for phenotype annotation and diagnostic rule representation
Cohort-specific strict CMT1 cutoff In the large UK diagnostic cohort, CMT1 was operationally defined as demyelinating neuropathy with upper-limb MNCV <25 m/s (record2024wholegenomesequencing pages 2-3, record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Note cohort definition differs from broader review cutoffs; encode as study-specific diagnostic criterion
Prevalence estimate Recent reviews report CMT prevalence ranging from 1 in 2,500 to 1 in 10,000 individuals (record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Disease-level epidemiology; aggregated resource, not individual EHR-derived
General prevalence estimate Other recent reviews summarize CMT prevalence as approximately 1:2,500 (estevezarias2022geneticapproachesand pages 1-3, dong2024currenttreatmentmethods pages 1-2) Estévez-Arias, J Transl Genet Genom, 2022; Dong, Biomolecules, 2024 DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04; DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 Supports common “most prevalent inherited neuropathy” statement
Major causal architecture CMT1A is caused by a recurrent chromosome 17 duplication containing PMP22; the canonical lesion is described as a 1.4 Mbp duplication in recent literature (estevezarias2022geneticapproachesand pages 3-5, record2024wholegenomesequencing pages 2-3) Estévez-Arias, J Transl Genet Genom, 2022; Record, Brain, 2024 DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04; DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 MONDO:0007309 CMT1A; gene: PMP22; structural variant/CNV annotation
PMP22 share of all CMT PMP22 duplication/CMT1A accounts for about 50% of all CMT cases in one review (estevezarias2022geneticapproachesand pages 3-5) Estévez-Arias, J Transl Genet Genom, 2022 DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 Genetic epidemiology fact; useful for testing prioritization
PMP22 share of demyelinating CMT The same review states PMP22 duplication accounts for about 70.7% of demyelinating CMT (estevezarias2022geneticapproachesand pages 3-5) Estévez-Arias, J Transl Genet Genom, 2022 DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 Apply specifically to CMT1/demyelinating subgroup
PMP22 share of solved cases In the UK specialist cohort, PMP22 duplication = 505/1165 solved cases (43.3%) (record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 High-value disease-gene frequency datum
PMP22 share within CMT1 In the same cohort, 505/621 CMT1 cases (82.3%) had PMP22 duplication; among solved CMT1, this was 84.0% (record2024wholegenomesequencing pages 3-5) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Supports first-line PMP22 CNV testing in CMT1 phenotype
CMT1 diagnostic rate In the large UK cohort, genetic diagnosis was achieved in 601/621 CMT1 cases (96.8%) (record2024wholegenomesequencing pages 3-5, record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Disease subclass-specific diagnostic performance metric
Overall diagnostic yield Across 1,515 patients with CMT/related disorders, overall genetic diagnosis was 76.9% (1165/1515) (record2024wholegenomesequencing pages 2-3, record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Real-world implementation metric for specialist inherited neuropathy service
Preferred first-line CNV test The 2024 Brain cohort paper states MLPA remains the preferred test for CMT1A (record2024wholegenomesequencing pages 2-3) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Diagnostic ontology note: CNV assay; consider MAXO-like testing action mapping externally
WGS diagnostic uplift In the UK cohort, WGS provided an overall diagnostic uplift of 3.5% across the whole cohort (record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Implementation metric for genome sequencing in unsolved neuropathy
WGS yield in 100KGP subset In the UK 100,000 Genomes subset, the “true” WGS diagnostic rate was 19.7% (46/233) after excluding diagnoses obtained by other means (record2024wholegenomesequencing pages 1-2) Record, Brain, 2024 DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 Useful for expectations after prior routine testing
PMP22 overexpression mechanism PMP22 overexpression in CMT1A leads to protein aggregates, reduced proteasome activity, accumulation of insoluble ubiquitinated substrates, and Schwann-cell apoptosis (dong2024currenttreatmentmethods pages 2-4) Dong, Biomolecules, 2024 DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 GO: protein aggregation, proteasome-mediated ubiquitin-dependent protein catabolic process, apoptotic process; CL: myelinating Schwann cell
MPZ/UPR mechanism For CMT1B, MPZ mutations can cause ER retention, activation of the unfolded protein response (UPR), and disruption of myelin compaction (dong2024currenttreatmentmethods pages 2-4) Dong, Biomolecules, 2024 DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 GO: response to endoplasmic reticulum stress, unfolded protein response, myelination; UBERON: peripheral nerve
Pathobiology theme Recent mechanistic reviews emphasize Schwann-cell/myelin dysfunction as central to demyelinating CMT, linking dysfunctional myelin to secondary axonal damage and disability (okamoto2023thecurrentstate pages 1-2, estevezarias2022geneticapproachesand pages 3-5) Okamoto, Genes, 2023; Estévez-Arias, J Transl Genet Genom, 2022 DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 GO: myelination, axon ensheathment; CL: Schwann cell; UBERON: peripheral nerve
Outcome measure validation sample The validated CMT-FOM was tested in 214 adults with CMT1A, ages 18–75, 58% female, across US/UK/Italy sites (mandarakas2024multicentervalidationof pages 1-2) Mandarakas, Neurology, 2024 DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 Clinical outcome assessment for trials; supportive of endpoint ontology mapping
CMT-FOM structure The CMT-FOM was validated as a 12-item unidimensional interval scale with a 0–100 scoring system covering strength, upper/lower limb function, balance, and mobility (mandarakas2024multicentervalidationof pages 1-2) Mandarakas, Neurology, 2024 DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 Functional phenotype capture: gait/balance/hand weakness/falls
CMT-FOM psychometric correlation 1 CMT-FOM correlated with the CMT Examination Score at r = 0.643; p < 0.001 (mandarakas2024multicentervalidationof pages 1-2) Mandarakas, Neurology, 2024 DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 Trial-readiness metric
CMT-FOM psychometric correlation 2 CMT-FOM correlated with the Overall Neuropathy Limitation Scale at r = 0.516; p < 0.001 (mandarakas2024multicentervalidationof pages 1-2) Mandarakas, Neurology, 2024 DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 Endpoint harmonization with prior CMT trials
PXT3003 Phase III design (PLEO-CMT) NCT02579759 enrolled 323 patients in a randomized, double-blind, placebo-controlled phase III trial; primary endpoint was ONLS total score averaged from months 12 and 15 (NCT02579759 chunk 1) ClinicalTrials.gov NCT02579759, 2015 registration https://clinicaltrials.gov/study/NCT02579759 MAXO suggestion: combination pharmacotherapy; disease-modifying investigational treatment
PXT3003 Phase III secondary endpoints (PLEO-CMT) PLEO-CMT key secondary endpoints included 10MWT, CMTNS-v2 sensory/exam scores, 9-HPT, plus safety outcomes (TEAEs, withdrawals, SAEs) (NCT02579759 chunk 1) ClinicalTrials.gov NCT02579759, 2015 registration https://clinicaltrials.gov/study/NCT02579759 Endpoint catalog for trial knowledge base
PLEO-CMT notable event In PLEO-CMT, the high-dose arm was prematurely discontinued on 18 Sep 2017 because of a product quality/stability issue; the DSMC had not identified safety concerns (NCT02579759 chunk 1) ClinicalTrials.gov NCT02579759, 2015 registration https://clinicaltrials.gov/study/NCT02579759 Important for interpreting phase III efficacy evidence
PXT3003 Phase III design (PREMIER) NCT04762758 is a multicenter randomized placebo-controlled phase III study planning about 350 subjects, with mONLS and 10-Meter Walk Test as primary outcomes at Month 15 (NCT04762758 chunk 1) ClinicalTrials.gov NCT04762758, 2021 registration https://clinicaltrials.gov/study/NCT04762758 MAXO suggestion: oral combination drug therapy
PXT3003 Phase III dosing (PREMIER) In PREMIER, PXT3003 is given 10 mL twice daily for 15 months after a 2-week half-dose titration (5 mL BID) (NCT04762758 chunk 1) ClinicalTrials.gov NCT04762758, 2021 registration https://clinicaltrials.gov/study/NCT04762758 Administration detail for intervention annotation
PXT3003 phase III status PREMIER was reported as ACTIVE_NOT_RECRUITING at last update in the registry excerpt (NCT04762758 chunk 1) ClinicalTrials.gov NCT04762758, 2021 registration https://clinicaltrials.gov/study/NCT04762758 Current implementation status; check registry for latest changes
Additional phase III registry A separate phase III PXT3003 study, NCT05092841, is listed in trial search results as completed with 176 participants (OpenTargets Search: Charcot-Marie-Tooth disease type 1,Charcot-Marie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B) ClinicalTrials.gov search results, 2024 retrieval https://clinicaltrials.gov/study/NCT05092841 Registry-level fact only from retrieved trial metadata
Visual diagnostic aid A recent review contains a figure showing typical CMT phenotypes (claw hands, pes cavus) and a table classifying demyelinating/intermediate/axonal CMT by NCV thresholds (dong2024currenttreatmentmethods media 041cb15e) Dong, Biomolecules, 2024 DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 HPO: HP:0001761 pes cavus, HP:0001159 syndactyl? not applicable; prioritize HP:0001765 hammer toe, HP:0009467 claw hand if used in KB

Table: This table compiles compact, citation-backed facts on Charcot-Marie-Tooth disease type 1 and CMT1A for knowledge-base use, spanning classification, epidemiology, genetics, mechanisms, outcomes, and current phase III therapeutic trials.

1. Disease Information

Definition and overview. Charcot–Marie–Tooth disease (CMT) comprises inherited peripheral neuropathies; CMT1 refers to demyelinating forms, with typical clinical findings of slowly progressive distal weakness/atrophy, reduced reflexes, distal sensory loss, and foot deformities such as pes cavus. (okamoto2023thecurrentstate pages 1-2, dong2024currenttreatmentmethods pages 1-2)

Classification by electrophysiology. A widely used scheme distinguishes demyelinating CMT1 versus axonal CMT2 using upper-limb motor nerve conduction velocities (MNCV). A recent 2023 review states <38 m/s is consistent with demyelinating CMT1 and >38 m/s with axonal CMT2, with intermediate ranges (e.g., 25–45 m/s) in some subtypes such as CMTX1. (okamoto2023thecurrentstate pages 1-2, estevezarias2022geneticapproachesand pages 1-3)

Study‑specific definition used in a large diagnostic cohort. A 2024 Brain specialist-center cohort operationalized CMT1 as upper-limb MNCV <25 m/s, CMT2 as >45 m/s, and intermediate CMT as 25–45 m/s, illustrating that thresholds vary by study/clinic and should be stored as provenance‑linked criteria. (record2024wholegenomesequencing pages 2-3, record2024wholegenomesequencing pages 3-5)

Key identifiers. - MONDO: MONDO:0019011 (Charcot–Marie–Tooth disease type 1) is supported in Open Targets disease–gene association outputs. (OpenTargets Search: Charcot-Marie-Tooth disease type 1,Charcot-Marie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B) - OMIM/Orphanet/ICD/MeSH: not retrieved in the current tool context.

Common synonyms/alternative names. “Charcot–Marie–Tooth disease” is also used interchangeably with “hereditary motor and sensory neuropathy” (HMSN) in the reviewed literature. (estevezarias2022geneticapproachesand pages 3-5)

Evidence source type. The information above is primarily from aggregated disease-level resources (reviews/cohorts) rather than individual EHR records. (okamoto2023thecurrentstate pages 1-2, record2024wholegenomesequencing pages 3-5)

2. Etiology

Primary causal factors (genetic). CMT1 is a Mendelian disorder family dominated by pathogenic variation in genes essential for peripheral myelin structure/function. Reviews emphasize PMP22, MPZ, and GJB1 as major causes of demyelinating/dysmyelinating CMT forms, with CMT1A caused by PMP22 copy‑number gain. (estevezarias2022geneticapproachesand pages 3-5, jacob2023mechanismsandtreatment pages 1-2)

CMT1A (major subtype). CMT1A arises from a recurrent tandem duplication spanning ~1.4–1.5 Mb containing PMP22, causing PMP22 overexpression (gene-dosage). (record2024wholegenomesequencing pages 2-3, jacob2023mechanismsandtreatment pages 1-2)

Inheritance. Many CMT1 subtypes (including CMT1A) are typically autosomal dominant in clinical descriptions of major demyelinating forms; pathogenic CNVs and dominant missense/truncating variants are recurrently discussed in the literature base. (estevezarias2022geneticapproachesand pages 3-5, jacob2023mechanismsandtreatment pages 1-2)

Risk factors / protective factors. For CMT1 (Mendelian), the principal “risk factor” is carrying the causal germline variant/CNV. Environmental protective factors or variant-defined “protective alleles” were not identified in the retrieved texts.

Gene–environment interactions. Not specifically addressed in the retrieved sources.

3. Phenotypes (clinical spectrum)

Core clinical features (symptoms/signs). Reviews describe length‑dependent, slowly progressive distal muscle atrophy/weakness (often feet/ankles first), sensory loss, diminished reflexes, and characteristic foot/hand deformities (e.g., pes cavus; claw hands). (okamoto2023thecurrentstate pages 1-2, dong2024currenttreatmentmethods pages 1-2)

Visual evidence of phenotype. A 2024 review includes a figure depicting typical manifestations such as claw hands and pes cavus/hammer toes; and a table classifying CMT by nerve conduction velocities. (dong2024currenttreatmentmethods media 041cb15e, dong2024currenttreatmentmethods media 8b0c7523)

Onset and progression. Reviews commonly place CMT onset in childhood through early adulthood (first to third decade) with slow progression. (estevezarias2022geneticapproachesand pages 1-3)

Phenotype frequencies / patient-reported burdens. In an Italian registry study on sleep metrics across CMT (mixed genotypes), poor sleep quality (PSQI >5) occurred in 56% and abnormal daytime somnolence (ESS >10) in 23%; poor sleep quality correlated with fatigue/anxiety/depression and with higher disease severity by CMTES. (cesaroni2025pmp22relatedneuropathiesa pages 12-13)

Suggested HPO terms (examples). - Peripheral neuropathy (HP:0009830) - Pes cavus (HP:0001761) - Hammer toe (HP:0001765) - Distal muscle weakness (HP:0003401) - Areflexia / decreased deep tendon reflexes (HP:0001284) - Reduced nerve conduction velocity (HP:0003448) - Foot drop (HP:0001760)

4. Genetic/Molecular Information

Causal genes (CMT1 focus). Open Targets and reviews support strong disease–gene associations for PMP22, MPZ, and EGR2 in CMT1; additional curated associations include SH3TC2 and others depending on subtype definition and curation source. (OpenTargets Search: Charcot-Marie-Tooth disease type 1,Charcot-Marie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B)

Variant classes and functional consequences. - PMP22 duplication (CNV): gene-dosage gain causing overexpression in Schwann cells; dominant demyelinating neuropathy. (jacob2023mechanismsandtreatment pages 1-2) - MPZ variants: can cause ER retention and activation of the unfolded protein response (UPR), disrupting myelin compaction. (dong2024currenttreatmentmethods pages 2-4)

Allele frequencies / population database frequencies. Not retrieved in the current tool context.

Modifier genes. Not explicitly identified in retrieved texts.

Epigenetic information. Not retrieved.

Chromosomal abnormalities. The principal structural abnormality for CMT1A is the recurrent ~1.4–1.5 Mb duplication on chromosome 17p containing PMP22. (record2024wholegenomesequencing pages 2-3)

5. Environmental Information

No CMT1‑specific toxins, lifestyle exposures, or infectious triggers were identified in the retrieved sources as causal contributors.

6. Mechanism / Pathophysiology

Causal chain (CMT1A, gene dosage). PMP22 copy-number gain → PMP22 overexpression in myelinating Schwann cells → destabilized myelin structure leading to demyelination/dysmyelination → secondary axonal loss → distal weakness/sensory loss and disability. (jacob2023mechanismsandtreatment pages 1-2)

Protein homeostasis and cell stress mechanisms. A 2024 review describes PMP22 overexpression leading to protein aggregates, reduced proteasome activity, accumulation of ubiquitinated substrates, and apoptosis in Schwann cells. (dong2024currenttreatmentmethods pages 2-4)

ER stress/UPR. Mechanistic review text reports PMP22 aggregates in ER/cytoplasm/lysosomes and links these to ER stress and activation of UPR pathways in CMT1A models; MPZ mutations (CMT1B) are also tied to ER retention and UPR activation. (jacob2023mechanismsandtreatment pages 1-2, dong2024currenttreatmentmethods pages 2-4)

Dysregulated signaling (axon–glia). In CMT1A rodent models, altered axon–Schwann signaling (NRG1/ErbB2/3) and downstream PI3K/AKT reduction with MEK/ERK hyperactivation are described as correlates of impaired Schwann differentiation and abnormal myelination. (jacob2023mechanismsandtreatment pages 1-2)

Inflammation as a possible modifier/comorbidity. A 2024 perspective review argues inflammation can coexist with hereditary neuropathy and that some CMT patients have shown responses to anti‑inflammatory therapy, challenging strict separation of inherited vs inflammatory neuropathies. (bamaga2025abriefreview pages 2-4)

Cell types (CL suggestions). - Myelinating Schwann cell (CL:0002573) - Peripheral nervous system neuron / motor neuron (CL:0000740 broadly; more specific motor neuron CL terms may be used depending on KB conventions) - Macrophage (CL:0000235) as a candidate immune effector cell type in inflammatory components (supported indirectly via inflammatory pathway discussion). (bamaga2025abriefreview pages 2-4)

GO biological process suggestions. - Myelination (GO:0042552) - Axon ensheathment (GO:0008366) - Response to endoplasmic reticulum stress (GO:0034976) - Unfolded protein response (GO:0030968) - Protein aggregation (GO:0070841) - Apoptotic process (GO:0006915)

GO cellular component suggestions. - Myelin sheath (GO:0043209) - Endoplasmic reticulum (GO:0005783) - Lysosome (GO:0005764)

Molecular profiling / biomarkers. A 2023 review emphasizes the need for sensitive endpoints and notes candidate biomarkers such as muscle MRI and plasma neurofilament light chain. (okamoto2023thecurrentstate pages 12-14)

7. Anatomical Structures Affected

Primary system. Peripheral nervous system and peripheral nerves (UBERON:0000010). (dong2024currenttreatmentmethods pages 1-2)

Tissue/cell level. Peripheral nerve myelin (Schwann cells; myelin sheath). (jacob2023mechanismsandtreatment pages 1-2)

Distal musculoskeletal manifestations. Foot deformities (pes cavus/hammer toes) and hand deformities (clawing) reflect chronic denervation and imbalance. Visual depiction available. (dong2024currenttreatmentmethods media 041cb15e)

8. Temporal Development

Onset. Commonly described as beginning in the first to third decade, though pediatric onset occurs. (estevezarias2022geneticapproachesand pages 1-3)

Course. Chronic, slowly progressive length‑dependent neuropathy. (estevezarias2022geneticapproachesand pages 1-3, okamoto2023thecurrentstate pages 1-2)

9. Inheritance and Population

Prevalence. A 2024 Brain paper states CMT prevalence is estimated 1 in 2,500 to 1 in 10,000. (record2024wholegenomesequencing pages 1-2)

Genetic distribution (CMT1). In a large specialist cohort (n=1515), CMT1 comprised 41.0% (621/1515) and had a very high molecular diagnostic rate (96.8%). PMP22 duplication accounted for 505 cases and dominated CMT1 genetic architecture. (record2024wholegenomesequencing pages 3-5)

Sex ratio and demographics. Not systematically extracted for CMT1 specifically in the retrieved sources.

10. Diagnostics

Electrophysiology. Demyelinating vs axonal classification relies on upper-limb MNCV thresholds; different sources use different cutoffs (e.g., <38 m/s vs <25 m/s for “CMT1” depending on context). This should be represented as multiple rule sets with provenance. (okamoto2023thecurrentstate pages 1-2, record2024wholegenomesequencing pages 2-3)

Genetic testing strategy (evidence-backed). - First line (CMT1 phenotype): test for PMP22 duplication using MLPA; a large diagnostic cohort explicitly states “MLPA remains the preferred test for CMT1A.” (record2024wholegenomesequencing pages 2-3) - Second line: gene panels / WES / WGS as costs fell and for non-PMP22 cases; interpretation complexity includes VUS per ACMG/AMP. (estevezarias2022geneticapproachesand pages 3-5)

Real-world diagnostic yield (WGS and overall). In the UK specialist cohort (2009–2023), overall genetic diagnosis was 76.9%, and CMT1 had 96.8% diagnostic success. WGS increased the overall diagnostic rate with a reported 3.5% uplift; in a UK 100,000 Genomes subset, “true” WGS diagnostic rate was 19.7% (46/233) after removing diagnoses made otherwise. (record2024wholegenomesequencing pages 1-2)

Differential diagnosis. Not comprehensively retrieved; however, clinical distinction from acquired inflammatory neuropathies is discussed as potentially complicated by inflammatory components in some hereditary cases. (bamaga2025abriefreview pages 2-4)

11. Outcome/Prognosis

Disability and functional endpoints. Slow progression complicates trial sensitivity; a 2024 validation study established the CMT-Functional Outcome Measure (CMT-FOM) as a disease-specific functional COA for adults with CMT1A. (mandarakas2024multicentervalidationof pages 1-2)

Validated outcome measure (CMT-FOM). Multicenter validation included 214 adults (18–75 years) with CMT1A and supported a 12-item unidimensional 0–100 scale; it correlated with CMT Examination Score (r=0.643) and ONLS (r=0.516), and discriminated patient-reported problems such as daily trips/falls and hand weakness. (mandarakas2024multicentervalidationof pages 1-2)

Quality of life–adjacent outcomes. Sleep disturbance is common and associated with fatigue and anxiety/depression in a large registry-based questionnaire study. (cesaroni2025pmp22relatedneuropathiesa pages 12-13)

12. Treatment

Current standard of care (real-world implementation). Reviews emphasize that there is no established pharmacologic disease-modifying therapy, and management is multidisciplinary supportive care including rehabilitation, orthotics, and surgery for deformities. (estevezarias2022geneticapproachesand pages 3-5, dong2024currenttreatmentmethods pages 1-2)

Investigational pharmacotherapy: PXT3003 (baclofen + naltrexone + D-sorbitol). - PLEO-CMT (NCT02579759; Phase III, completed; n=323): primary endpoint ONLS (mean of months 12 and 15). A product quality/stability issue led to premature discontinuation of one dose arm; DSMC did not identify safety concerns. (NCT02579759 chunk 1) - PREMIER (NCT04762758; Phase III; planned ~350; active not recruiting per registry excerpt): primary outcomes include modified ONLS and 10‑meter walk test at month 15. (NCT04762758 chunk 1) - A separate Phase III PXT3003 study NCT05092841 is listed as completed with 176 participants in retrieved trial metadata (results not extracted in the available text chunks). (OpenTargets Search: Charcot-Marie-Tooth disease type 1,Charcot-Marie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B)

Gene therapy / genome editing (recent developments). - iPSC Schwann cell genome editing: A 2023 Communications Medicine study used an AAV2‑SaCas9 strategy designed to excise the duplication junction; the abstract reports decreasing PMP22 gene duplication by ~20–40% in edited iPSCs and normalization of PMP22 expression with improved apoptosis/myelination phenotypes in patient‑derived Schwann cell models. (yoshioka2023aavmediatededitingof pages 13-14) - Neurotrophin‑3 (NT‑3) approaches: Reviews summarize evidence that NT‑3 delivery promotes nerve regeneration/myelination in CMT1A models and has been explored clinically; an scAAV1.tMCK.NT3 program reached a Phase I/IIa trial but was suspended due to vector manufacturing complications. (okamoto2023thecurrentstate pages 16-17, stavrou2023charcot–marie–toothneuropathiescurrentgene pages 9-10) - Targeting purinergic/inflammatory pathways: Gene-therapy review notes P2X7 receptor silencing/antagonism improving Schwann-cell co-culture properties and myelin-related protein expression in CMT1A models, suggesting immuno-metabolic pathways as adjunct targets. (stavrou2023charcot–marie–toothneuropathiescurrentgene pages 9-10)

MAXO (treatment ontology) suggestions (examples). - Physical therapy / rehabilitation therapy (MAXO term family for rehabilitation) - Orthotic device therapy (e.g., ankle-foot orthosis) - Surgical correction of foot deformity - Combination drug therapy (PXT3003) - Gene therapy / AAV-mediated gene therapy - Genome editing therapy (CRISPR-based)

13. Prevention

Primary prevention. Not applicable in the classical sense for Mendelian CMT1; prevention focuses on reproductive counseling.

Secondary/tertiary prevention. Early diagnosis enables specialist follow‑up, orthotics/rehabilitation, and management of complications (e.g., deformities, falls). (estevezarias2022geneticapproachesand pages 3-5)

Genetic counseling. Reviews emphasize genetic counseling as part of current management; preimplantation genetic diagnosis approaches for CMT1A are referenced (microsatellite-based segregation analysis) though detailed guidelines were not extracted in available chunks. (estevezarias2022geneticapproachesand pages 3-5)

14. Other Species / Natural Disease

Not addressed in retrieved texts.

15. Model Organisms

Rodent models (CMT1A). A mechanistic review lists commonly used PMP22-overexpression models (e.g., C22, C61, C3‑PMP) that recapitulate variable severities depending on PMP22 copy number. (jacob2023mechanismsandtreatment pages 1-2)

Human cellular models. Patient-derived iPSC Schwann cell models are used to study duplication correction and myelination phenotypes, supporting translational genome editing pipelines. (yoshioka2023aavmediatededitingof pages 13-14)

Recent developments (2023–2024) highlighted

  1. Clinical genomics implementation: WGS in routine pathways adds incremental diagnostic yield (3.5% uplift) but PMP22 CNV testing remains essential first-line for CMT1A. (record2024wholegenomesequencing pages 2-3, record2024wholegenomesequencing pages 1-2)
  2. Trial readiness improvements: CMT‑FOM validated as a robust functional endpoint for adult CMT1A trials (n=214). (mandarakas2024multicentervalidationof pages 1-2)
  3. Therapeutic pipeline maturation: Multiple Phase III PXT3003 trials have been conducted/are ongoing, with clearly defined functional endpoints (ONLS, walking tests) in registries. (NCT04762758 chunk 1, NCT02579759 chunk 1)
  4. Gene editing in human Schwann cells: AAV‑CRISPR editing of PMP22 duplication junctions demonstrated partial duplication reduction and phenotype rescue in patient-derived Schwann cells. (yoshioka2023aavmediatededitingof pages 13-14)

Key statistics (recent cohort and trials)

  • CMT prevalence estimate: 1:2,500 to 1:10,000. (record2024wholegenomesequencing pages 1-2)
  • Large specialist cohort (n=1515): overall molecular diagnosis 76.9%; CMT1 diagnosis 96.8%; PMP22dup 43.3% of solved cases and 82.3% of CMT1. (record2024wholegenomesequencing pages 3-5, record2024wholegenomesequencing pages 1-2)
  • WGS: overall diagnostic uplift 3.5% in that cohort; “true” WGS diagnostic rate 19.7% (46/233) in 100KGP subset after adjustment. (record2024wholegenomesequencing pages 1-2)
  • CMT-FOM validation cohort: 214 adults with CMT1A; correlation with CMTES r=0.643 and ONLS r=0.516. (mandarakas2024multicentervalidationof pages 1-2)
  • PXT3003 Phase III: PLEO‑CMT n=323, ONLS primary endpoint; PREMIER planned ~350 with mONLS and 10mWT primary outcomes at month 15. (NCT04762758 chunk 1, NCT02579759 chunk 1)

Limitations and missing fields

  • OMIM/Orphanet/ICD/MeSH identifiers were not present in retrieved tool context; they should be added via direct database queries (OMIM/Orphanet/WHO ICD/MeSH) in a subsequent pass.
  • Population-specific variant frequencies, penetrance, founder effects, and protective factors were not available in the retrieved evidence.
  • Published Phase III efficacy results for PXT3003 were not extracted from peer‑reviewed publications in the retrieved chunks; registry endpoints and notable trial events were extracted. (NCT02579759 chunk 1)

References

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Artifacts