CMT1E is demyelinating Charcot-Marie-Tooth neuropathy caused by coding point mutations and small indels in PMP22, frequently accompanied by sensorineural hearing loss. It is the third of three PMP22 diseases, and the one that is not about gene dosage. **The lesion is a misfolded protein, not a dose.** CMT1A arises from duplication of the 1.4 Mb region containing PMP22 and HNPP from its deletion; both are dosage diseases of a wild-type protein. CMT1E instead produces an abnormal protein. Disease-related missense mutations in the PMP22 transmembrane domains disturb intracellular trafficking, so the mutant accumulates in the endoplasmic reticulum and Golgi rather than reaching the Schwann cell surface. In Trembler-J nerve the retained protein has an extended half-life and forms aggresome-like structures ringed by chaperones and lysosomes, cleared by autophagy and accumulating when autophagy is blocked. **There is a second arm through lipid handling.** Cholesterol is an essential structural lipid of compact myelin. In Trembler-J Schwann cells, cholesterol is retained with the mutant protein in the Golgi and its plasma-membrane level falls correspondingly. So the same mis-trafficking event that creates the proteostatic burden also diverts a myelin building block, and the two arms converge on the failure to make and maintain myelin. **This distinction is not academic - it predicts therapy failure.** Expression profiling across Pmp22-null, Pmp22-overexpressing and Trembler mice found three distinct profiles, which is the direct evidence that dosage and point-mutation disease are different mechanisms rather than points on one severity scale. And the clinical history bears it out: ascorbic acid, which worked in the CMT1A transgenic dosage model, had no benefit across three one-year human trials. Extrapolating a CMT1A-directed therapy to CMT1E is therefore not conservative, it is unsupported. **The phenotype sits at the severe end, and deafness is the distinguishing feature.** In a Korean cohort of 850 duplication-negative CMT families, more than 40 percent of CMT1E patients had hearing loss, and both physical and electrophysiological severity exceeded CMT1A. But expressivity is wide: one Portuguese family carrying p.Trp28Cys ranged from asymptomatic to mild numbness with onset from the mid-twenties to the late sixties and no hearing loss at all, while the classic Trembler p.Gly150Asp substitution produces Dejerine-Sottas syndrome with deafness and cognitive impairment. Which variant, and where it sits in the protein, is a major determinant of severity.
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name: Charcot-Marie-Tooth Disease Type 1E
category: Mendelian
creation_date: "2026-09-22T13:35:00Z"
synonyms:
- CMT1E
- Charcot-Marie-Tooth disease, demyelinating, type 1E
- Charcot-Marie-Tooth disease and deafness
- autosomal dominant Charcot-Marie-Tooth neuropathy and deafness
description: >-
CMT1E is demyelinating Charcot-Marie-Tooth neuropathy caused by coding point
mutations and small indels in PMP22, frequently accompanied by sensorineural
hearing loss. It is the third of three PMP22 diseases, and the one that is not
about gene dosage.
**The lesion is a misfolded protein, not a dose.** CMT1A arises from duplication
of the 1.4 Mb region containing PMP22 and HNPP from its deletion; both are dosage
diseases of a wild-type protein. CMT1E instead produces an abnormal protein.
Disease-related missense mutations in the PMP22 transmembrane domains disturb
intracellular trafficking, so the mutant accumulates in the endoplasmic reticulum
and Golgi rather than reaching the Schwann cell surface. In Trembler-J nerve the
retained protein has an extended half-life and forms aggresome-like structures
ringed by chaperones and lysosomes, cleared by autophagy and accumulating when
autophagy is blocked.
**There is a second arm through lipid handling.** Cholesterol is an essential
structural lipid of compact myelin. In Trembler-J Schwann cells, cholesterol is
retained with the mutant protein in the Golgi and its plasma-membrane level falls
correspondingly. So the same mis-trafficking event that creates the proteostatic
burden also diverts a myelin building block, and the two arms converge on the
failure to make and maintain myelin.
**This distinction is not academic - it predicts therapy failure.** Expression
profiling across Pmp22-null, Pmp22-overexpressing and Trembler mice found three
distinct profiles, which is the direct evidence that dosage and point-mutation
disease are different mechanisms rather than points on one severity scale. And the
clinical history bears it out: ascorbic acid, which worked in the CMT1A transgenic
dosage model, had no benefit across three one-year human trials. Extrapolating a
CMT1A-directed therapy to CMT1E is therefore not conservative, it is unsupported.
**The phenotype sits at the severe end, and deafness is the distinguishing
feature.** In a Korean cohort of 850 duplication-negative CMT families, more than
40 percent of CMT1E patients had hearing loss, and both physical and
electrophysiological severity exceeded CMT1A. But expressivity is wide: one
Portuguese family carrying p.Trp28Cys ranged from asymptomatic to mild numbness
with onset from the mid-twenties to the late sixties and no hearing loss at all,
while the classic Trembler p.Gly150Asp substitution produces Dejerine-Sottas
syndrome with deafness and cognitive impairment. Which variant, and where it sits
in the protein, is a major determinant of severity.
disease_term:
preferred_term: Charcot-Marie-Tooth disease type 1E
term:
id: MONDO:0007311
label: Charcot-Marie-Tooth disease type 1E
parents:
- Charcot-Marie-Tooth Disease
references:
- reference: PMID:20301532
title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
tags:
- GeneReviews
- reference: PMID:35886002
title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
- reference: PMID:34332267
title: "Characterization of a Portuguese family with Charcot-Marie-Tooth disease type 1E due to a novel point mutation in the PMP22 gene."
- reference: PMID:10625337
title: "Tetraspan myelin protein PMP22 and demyelinating peripheral neuropathies: new facts and hypotheses."
- reference: PMID:14627652
title: "Emerging role for autophagy in the removal of aggresomes in Schwann cells."
- reference: PMID:32511821
title: "Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22."
- reference: PMID:17701891
title: "Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy."
- reference: PMID:15755691
title: "Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation."
- reference: PMID:35974257
title: "Expanding the phenotypic spectrum of Dejerine-Sottas syndrome caused by the trembler mutation."
- reference: PMID:21393063
title: "Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial."
- reference: PMID:41571707
title: "Charcot-Marie-Tooth disease and related neuropathies."
- reference: PMID:32506583
title: "Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies."
- reference: PMID:42563944
title: "Charcot-Marie-Tooth disease in children."
- reference: PMID:31213528
title: "Peripheral myelin protein 22 modulates store-operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology."
- reference: PMID:12421361
title: "Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves."
- reference: PMID:42105803
title: "Diaphragm hypertrophy and spinal stress response accompany phrenic myelin defects in a murine model of Charcot-Marie-Tooth Disease Type 1E."
inheritance:
- name: Autosomal dominant
description: >-
Heterozygous PMP22 point mutations. De novo mutations are frequent, and two
recurrent sites have been proposed as mutational hotspots, so a negative family
history does not argue against the diagnosis.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots"
explanation: >-
Records both the de novo rate and the recurrent sites in a cohort of 850 CMT
families.
genetic:
- name: PMP22
notes: >-
PMP22 encodes peripheral myelin protein 22, a tetraspan membrane protein of
compact PNS myelin. Three distinct diseases arise from it: duplication gives
CMT1A, deletion gives HNPP, and coding point mutations give CMT1E. Most CMT1E
mutations localize to the conserved transmembrane domains.
relationship_type: CAUSATIVE
gene_term:
preferred_term: PMP22
term:
id: hgnc:9118
label: PMP22
evidence:
- reference: PMID:34332267
reference_title: "Characterization of a Portuguese family with Charcot-Marie-Tooth disease type 1E due to a novel point mutation in the PMP22 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Point mutations in the Peripheral Myelin Protein 22 (PMP22) gene comprise less than 5% of the Charcot-Marie-Tooth (CMT) type 1 cases"
explanation: >-
Establishes that the point-mutation mechanism is a small minority of CMT1 and so
that CMT1E is rare relative to the dosage diseases of the same gene.
pathophysiology:
- name: PMP22 Transmembrane-Domain Missense Mutation
description: >-
A heterozygous coding point mutation or small indel, usually in one of the
conserved transmembrane domains, produces an abnormal PMP22 protein. This is the
point of departure from CMT1A and HNPP, both of which alter the amount of a
normal protein rather than its sequence.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
genes:
- preferred_term: PMP22
term:
id: hgnc:9118
label: PMP22
genetic_context:
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: DOMINANT_NEGATIVE
description: >-
Recorded as DOMINANT_NEGATIVE rather than LOSS_OF_FUNCTION because the disease
is more severe than the heterozygous deletion state, HNPP, which is the
comparison a true loss-of-function reading would have to survive. The mutant
protein is retained and aggregates rather than simply being absent.
downstream:
- target: ER and Golgi Retention of Misfolded PMP22
causal_link_type: DIRECT
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP"
explanation: >-
Defines the CMT1E lesion class as point mutations and indels, separating it from
the duplication that causes CMT1A.
- name: ER and Golgi Retention of Misfolded PMP22
description: >-
The mutant protein does not traffic to the Schwann cell plasma membrane. It
accumulates in the endoplasmic reticulum and Golgi compartment instead, and the
trafficking defect is attributable specifically to mutations within the
transmembrane domains.
biological_scale: MOLECULAR
mechanism_confidence: ESTABLISHED
cellular_components:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
- preferred_term: Golgi apparatus
term:
id: GO:0005794
label: Golgi apparatus
biological_processes:
- preferred_term: protein folding
modifier: DECREASED
term:
id: GO:0006457
label: protein folding
downstream:
- target: Aggresome Formation and Proteostatic Burden
causal_link_type: DIRECT
- target: Cholesterol Sequestration in the Golgi
causal_link_type: DIRECT
description: >-
The second arm. The same retained protein traps cholesterol with it, so one
trafficking failure has two separable consequences.
- target: Altered Store-Operated Calcium Handling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The third arm, and the least direct of them. Retained PMP22 alters store-operated
calcium entry in Schwann cells; the steps between the retained protein and the
altered flux are not established, which is what the link type records.
evidence:
- reference: PMID:10625337
reference_title: "Tetraspan myelin protein PMP22 and demyelinating peripheral neuropathies: new facts and hypotheses."
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: BACKGROUND
snippet: "disease-related missense mutations within transmembrane domains of PMP22 disturb intracellular protein trafficking leading to accumulation of the mutant protein in the endoplasmic reticulum/Golgi compartment"
explanation: >-
States the trafficking lesion and locates it to the transmembrane domains. This
paper's own subject is the PMP22-integrin complex and the basal lamina; the
quoted sentence is its framing of established PMP22 mutation biology, so it is
graded BACKGROUND rather than PRIMARY_RESULT.
- name: Aggresome Formation and Proteostatic Burden
description: >-
Retained PMP22 has an extended half-life and forms aggresome-like structures
surrounded by molecular chaperones and lysosomes. Clearance depends on autophagy:
it is enhanced when autophagy is activated and largely prevented when autophagy is
inhibited. The Schwann cell is therefore holding the mutant protein under a
disposal system that can be saturated.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: myelinating Schwann cell
term:
id: CL:0000218
label: myelinating Schwann cell
cellular_components:
- preferred_term: aggresome
term:
id: GO:0016235
label: aggresome
biological_processes:
- preferred_term: autophagy
modifier: INCREASED
term:
id: GO:0006914
label: autophagy
downstream:
- target: Schwann Cell Apoptosis and Failure of Myelination
causal_link_type: DIRECT
evidence:
- reference: PMID:14627652
reference_title: "Emerging role for autophagy in the removal of aggresomes in Schwann cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes"
explanation: >-
The observation in Trembler-J nerve that defines this node: not merely retained
protein but an organized aggresome under chaperone and lysosomal surveillance.
- name: Cholesterol Sequestration in the Golgi
description: >-
Cholesterol is retained with the mutant protein in the Golgi, and plasma-membrane
cholesterol falls correspondingly. Because cholesterol is a structural lipid of
compact myelin, this diverts a myelin building block away from the membrane where
it is needed.
Note the source paper contrasts this directly with the CMT1A mechanism in the same
experiments: PMP22 overexpression sequesters cholesterol to lysosomes instead. The
two PMP22 diseases therefore mis-route the same lipid to different compartments,
which is a sharper statement of "different mechanism" than a severity comparison
would be.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
cellular_components:
- preferred_term: Golgi apparatus
term:
id: GO:0005794
label: Golgi apparatus
biological_processes:
- preferred_term: cholesterol transport
modifier: DECREASED
term:
id: GO:0030301
label: cholesterol transport
downstream:
- target: Schwann Cell Apoptosis and Failure of Myelination
causal_link_type: DIRECT
evidence:
- reference: PMID:32511821
reference_title: "Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In Schwann cells from homozygous Trembler J (TrJ) mice carrying a Leu16Pro mutation, cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level."
explanation: >-
The measured cholesterol mis-localization in a cell model of the human Leu16Pro
allele, with the reciprocal fall at the plasma membrane.
- reference: PMID:32511821
reference_title: "Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "PMP22 overexpression, which models CMT1A caused by gene duplication, triggered cholesterol sequestration to lysosomes, and reduced ATP-binding cassette transporter-dependent cholesterol efflux."
explanation: >-
The CMT1A comparison from the same study. Quoted here because it is what makes
the Golgi localization specific to the point-mutation disease rather than a
generic PMP22 phenomenon.
- name: Schwann Cell Apoptosis and Failure of Myelination
description: >-
Proteostatic burden and diverted myelin lipid converge on the myelinating Schwann
cell, which undergoes apoptosis and fails to make and maintain normal compact
myelin. That apoptosis is the convergence point is supported by the curcumin
result, where reducing ER-retention-associated apoptosis increased the number and
size of myelinated axons.
biological_scale: CELLULAR
mechanism_confidence: ESTABLISHED
cell_types:
- preferred_term: myelinating Schwann cell
term:
id: CL:0000218
label: myelinating Schwann cell
biological_processes:
- preferred_term: apoptotic process
modifier: INCREASED
term:
id: GO:0006915
label: apoptotic process
- preferred_term: myelination in peripheral nervous system
modifier: DECREASED
term:
id: GO:0022011
label: myelination in peripheral nervous system
downstream:
- target: Demyelination of Peripheral Nerve
causal_link_type: DIRECT
evidence:
- reference: PMID:17701891
reference_title: "Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons"
explanation: >-
A rescue result cited as validation of the mechanism it targets, which is an
inference step: reducing apoptosis improves myelination, so apoptosis is
upstream of the myelination failure. Graded INDIRECT for that reason, and
MODEL_ORGANISM because the quoted measurement is in the Trembler-J mouse.
- name: Altered Store-Operated Calcium Handling
description: >-
A third consequence of the mutant protein, on a different axis from proteostasis
and lipid trafficking. PMP22 modulates store-operated calcium channel activity:
heterologous expression increases currents resembling those carried by
store-operated channels, particularly TRPC1. A PMP22 whose amount or sequence is
abnormal therefore changes Schwann-cell calcium handling as well as its own
disposal and its lipid environment.
Marked PROVISIONAL and drawn as an INDIRECT edge. The measurement is in a
heterologous expression system, and it is about PMP22 rather than about a CMT1E
allele specifically, so its weight for this disease is inferential.
biological_scale: MOLECULAR
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
downstream:
- target: Schwann Cell Apoptosis and Failure of Myelination
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31213528
reference_title: "Peripheral myelin protein 22 modulates store-operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology."
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: "heterologous PMP22 expression increases the amplitude of currents similar to those ascribed to store-operated calcium (SOC) channels, particularly those involving transient receptor canonical channel 1 (TrpC1)."
explanation: >-
The electrophysiological measurement. Graded INDIRECT because it establishes that
PMP22 modulates these currents, not that a CMT1E allele's effect on them causes
disease; the authors' own framing is that the role of PMP22 in Schwann cell
physiology is not well understood.
- name: Extracellular Matrix Remodelling With Macrophage-Derived Metalloproteinases
description: >-
The inflammatory arm, and the only route in this entry to a cellular participant
other than the Schwann cell. In Trembler-J nerve the basement membrane is
remodelled - laminin modestly increased, full-length collagen IV and fibronectin
decreased - with MMP-2 and MMP-9 detectable and gelatinolytic activity up. The
paper attributes a significant share of both enzymes to infiltrating macrophages.
This matters because the rest of the pathograph is Schwann-cell-autonomous, so
without this node the entry would imply that nothing else participates in the nerve
pathology.
biological_scale: TISSUE
mechanism_confidence: PROVISIONAL
cell_types:
- preferred_term: infiltrating macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: extracellular matrix disassembly
modifier: INCREASED
term:
id: GO:0022617
label: extracellular matrix disassembly
downstream:
- target: Demyelination of Peripheral Nerve
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:12421361
reference_title: "Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In TrJ nerves, laminin is modestly increased while full-length forms of collagen IV and fibronectin are decreased."
explanation: >-
The measured basement-membrane changes, which is what "remodelling" means here
rather than a general inflammatory description.
- reference: PMID:12421361
reference_title: "Matrix metalloproteinase mediated degradation of basement membrane proteins in Trembler J neuropathy nerves."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "macrophages are a significant source of both MMP-2 and MMP-9."
explanation: >-
Attributes the enzymes to infiltrating macrophages, which is the basis for binding
a macrophage cell type on this node rather than treating the remodelling as
Schwann-cell-autonomous.
- name: Demyelination of Peripheral Nerve
description: >-
Dysmyelination and demyelination of peripheral nerve in a bilateral, symmetric,
length-dependent distribution, with uniformly slowed motor conduction and
secondary axonal loss. The axonal loss is what the clinical impairment tracks.
biological_scale: TISSUE
mechanism_confidence: ESTABLISHED
locations:
- preferred_term: peripheral nervous system
term:
id: UBERON:0000010
label: peripheral nervous system
biological_processes:
- preferred_term: myelination
modifier: DECREASED
term:
id: GO:0042552
label: myelination
downstream:
- target: Distal muscle weakness
causal_link_type: DIRECT
- target: Distal sensory impairment
causal_link_type: DIRECT
- target: Decreased motor nerve conduction velocity
causal_link_type: DIRECT
- target: Areflexia
causal_link_type: DIRECT
- target: Pes cavus
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Hammertoe
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
The same intermediates as pes cavus: chronic denervation imbalance between the
intrinsic foot muscles and the long extrinsic flexors and extensors. The two
deformities are reported together and at the same frequency tier.
- target: Distal amyotrophy
causal_link_type: DIRECT
description: >-
Wasting is the structural counterpart of the weakness node, from denervation of
the same distal muscles rather than from a separate process.
- target: Sensorineural hearing impairment
causal_link_type: UNKNOWN
description: >-
Drawn as UNKNOWN deliberately. Hearing loss is strongly associated with CMT1E
and is the feature that distinguishes it, but none of the sources here shows the
cochlear or auditory-nerve lesion that produces it, so whether it follows from
the same demyelination or from a separate PMP22 role in the auditory system is
not established by this entry's evidence.
evidence:
- reference: PMID:41571707
reference_title: "Charcot-Marie-Tooth disease and related neuropathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits"
explanation: >-
The link from nerve pathology to the clinical picture, stated across CMT as a
class. Graded REVIEW_SYNTHESIS because the source is a review synthesizing work
it did not perform, and because the claim is about CMT generally rather than
about CMT1E specifically.
phenotypes:
- category: Neurologic
name: Distal muscle weakness
description: >-
Distal, symmetric, progressive weakness of the lower and then upper limbs. In
CMT1E the physical severity exceeded that of CMT1A in a head-to-head cohort
comparison.
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A."
explanation: >-
The severity comparison against the commoner dosage disease, in one cohort using
one set of measures.
- category: Neurologic
name: Distal sensory impairment
description: >-
Length-dependent distal sensory loss, part of the sensorimotor picture of
demyelinating CMT.
phenotype_term:
preferred_term: Distal sensory impairment
term:
id: HP:0002936
label: Distal sensory impairment
evidence:
- reference: PMID:41571707
reference_title: "Charcot-Marie-Tooth disease and related neuropathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits"
explanation: >-
The clinical syndrome as described across CMT in a review.
- category: Auditory
name: Sensorineural hearing impairment
description: >-
The feature that distinguishes CMT1E from CMT1A. More than 40 percent of CMT1E
patients in the Korean cohort had hearing loss. It is not universal: the
Portuguese p.Trp28Cys family had none.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "more than 40% of the CMT1E patients showed hearing loss"
explanation: >-
The frequency in the largest reported CMT1E series.
- reference: PMID:34332267
reference_title: "Characterization of a Portuguese family with Charcot-Marie-Tooth disease type 1E due to a novel point mutation in the PMP22 gene."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "Hearing loss does not seem to be associated with this variant, albeit neuropathic pain was reported."
explanation: >-
A REFUTE item against the claim that hearing loss is a constant feature of
CMT1E. An entire family carrying a pathogenic PMP22 point mutation had none. The
two items together are the honest state: hearing loss is frequent and
distinguishing, and it is variant-dependent rather than definitional.
- category: Neurologic
name: Areflexia
description: >-
Absent deep tendon reflexes, an early and near-constant sign in demyelinating CMT.
phenotype_term:
preferred_term: Areflexia
term:
id: HP:0001284
label: Areflexia
evidence:
- reference: PMID:41571707
reference_title: "Charcot-Marie-Tooth disease and related neuropathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "absent deep tendon reflexes and distal sensory deficits"
explanation: >-
Named among the core clinical impairments of CMT in a review.
- category: Musculoskeletal
name: Pes cavus
description: >-
High-arched foot, the classic musculoskeletal consequence of long-standing
imbalance between intrinsic and extrinsic foot muscles in CMT.
phenotype_term:
preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
evidence:
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Patients typically present with muscle weakness, sensory loss, and foot deformities such as pes cavus."
explanation: >-
Re-sourced on review. The previous snippet said only "musculoskeletal deformity"
and the binding to HP:0001761 was the curator's inference; this sentence names pes
cavus. Quoted whole rather than from mid-word, as it was on the first re-sourcing.
Still a review synthesizing the CMT literature rather than a CMT1E observation,
hence REVIEW_SYNTHESIS.
- category: Musculoskeletal
name: Hammertoe
description: >-
Toe deformity accompanying pes cavus in long-standing CMT, and reported alongside it
at comparable frequency. An earlier draft left this node uncited on the claim that no
cached reference named hammertoes; that claim was false, and the sentence below was
in the full text of a reference the entry already cites - see review_notes.
phenotype_term:
preferred_term: Hammertoe
term:
id: HP:0001765
label: Hammertoe
evidence:
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Pes cavus and hammer toes are common, while pes planus is less frequent."
explanation: >-
Names hammertoes directly and puts them at the same frequency tier as pes cavus. A
review of CMT in children rather than a CMT1E series, hence REVIEW_SYNTHESIS.
- category: Neurologic
name: Distal amyotrophy
description: >-
Distal muscle wasting, primarily of the lower then upper extremities, accompanying
the weakness.
phenotype_term:
preferred_term: Distal amyotrophy
term:
id: HP:0003693
label: Distal amyotrophy
evidence:
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "CMT typically manifests as progressively worsening muscle weakness and atrophy, primarily affecting the distal extremities."
explanation: >-
Names the atrophy and its distal distribution, which is what distinguishes
HP:0003693 Distal amyotrophy from a general wasting term.
- category: Respiratory
name: Respiratory insufficiency
description: >-
Respiratory involvement is recognized in neuropathic patients and has now been
characterized in the Trembler-J CMT1E model, where phrenic myelin defects are
accompanied by diaphragm remodelling. Recorded as an uncommon feature rather than a
core one.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: PMID:42105803
reference_title: "Diaphragm hypertrophy and spinal stress response accompany phrenic myelin defects in a murine model of Charcot-Marie-Tooth Disease Type 1E."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: INDIRECT
snippet: "Respiratory problems are known to impact neuropathic patients, yet existing studies have not characterized this pathophysiology in corresponding animal models."
explanation: >-
A mouse study of CMT1E, quoted for the human clinical premise stated in its
opening sentence - hence HUMAN_CLINICAL with quote_role BACKGROUND, which is
exactly the pairing CLAUDE.md documents this combination for. Graded INDIRECT
because the sentence is about neuropathic patients generally, not CMT1E patients,
and its second half says the pathophysiology had not been characterized.
- category: Electrophysiologic
name: Decreased motor nerve conduction velocity
description: >-
Uniformly slowed motor conduction is the electrophysiological signature of
demyelinating CMT1 and the finding that directs genetic testing toward PMP22.
phenotype_term:
preferred_term: Decreased motor nerve conduction velocity
term:
id: HP:0003431
label: Decreased motor nerve conduction velocity
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A."
explanation: >-
The electrophysiological severity comparison. Note the quoted sentence asserts
relative severity rather than naming a conduction velocity, so it supports the
phenotype's presence and grading but does not supply a threshold.
variants:
- name: PMP22 p.Gly150Asp (Trembler)
description: >-
The classic Trembler substitution. In humans it produces the severe end of the
PMP22 point-mutation spectrum: Dejerine-Sottas syndrome with hearing loss and
cognitive impairment, reported in a mother and son.
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:35974257
reference_title: "Expanding the phenotypic spectrum of Dejerine-Sottas syndrome caused by the trembler mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report two cases of DSS in a mother and son with the Trembler mutation, with associated findings of hearing loss and cognitive impairment"
explanation: >-
The severe pole of the allelic series, and the one that carries the phenotype
beyond the peripheral nerve.
- name: PMP22 p.Trp28Cys
description: >-
The mild pole. A Portuguese family with this allele ranged from asymptomatic to
mild distal numbness and gait difficulty, with onset anywhere from the mid-twenties
to the late sixties, and no disability or hearing loss.
variant_type: single nucleotide variant
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:34332267
reference_title: "Characterization of a Portuguese family with Charcot-Marie-Tooth disease type 1E due to a novel point mutation in the PMP22 gene."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "from asymptomatic to mild complaints of distal limb numbness and gait difficulties, with the age of onset of symptoms ranging from mid-twenties to late-sixties"
explanation: >-
Documents the width of expressivity within one family and one allele, which is
the counterweight to the cohort-level severity claim.
animal_models:
- name: Trembler-J mouse
species: Mouse
genotype: Pmp22 Leu16Pro (TrJ), spontaneous
publication: PMID:14627652
description: >-
A spontaneous mouse mutant carrying a PMP22 substitution that also occurs in human
CMT1E families, which is an unusually direct correspondence for a model - the
allele was not engineered to match, it already matched.
modeled_mechanisms:
- target: Aggresome Formation and Proteostatic Burden
relationship: RECAPITULATES
fidelity: HIGH
model_scale: CELLULAR
description: >-
The aggresome, chaperone and lysosome findings, and the autophagy dependence of
clearance, are all measured in this model.
readouts:
- name: Aggresome-like structures in nerve
target: Aggresome Formation and Proteostatic Burden
direction: INCREASED
interpretation: >-
Retained PMP22 forms aggresomes under chaperone and lysosomal surveillance.
evidence:
- reference: PMID:14627652
reference_title: "Emerging role for autophagy in the removal of aggresomes in Schwann cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes"
explanation: >-
The measured aggregate phenotype.
- target: Cholesterol Sequestration in the Golgi
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Schwann cells from homozygous TrJ mice show the Golgi cholesterol retention and
the reciprocal plasma-membrane reduction.
limitations: >-
The cholesterol measurements were made in cells from HOMOZYGOUS TrJ mice, while
human CMT1E is heterozygous. A homozygous mutant Schwann cell has no wild-type
PMP22 competing for the trafficking pathway, so the magnitude of Golgi retention
is not the magnitude a patient's Schwann cell experiences, and the direction of
the effect is better supported than its size.
divergences:
- divergence_type: POPULATION_MISMATCH
materiality: QUALIFYING
description: >-
The genotype measured is homozygous TrJ; the human disease state is a
heterozygote carrying one mutant and one wild-type PMP22 allele. The model
population is therefore not the disease population at the allele level.
readouts:
- name: Golgi and plasma-membrane cholesterol distribution
target: Cholesterol Sequestration in the Golgi
direction: ALTERED
interpretation: >-
Cholesterol accumulates in the Golgi with the mutant protein and falls at the
plasma membrane.
evidence:
- reference: PMID:32511821
reference_title: "Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level"
explanation: >-
The measurement, in Schwann cells from the TrJ mouse.
evidence:
- reference: PMID:15755691
reference_title: "Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms"
explanation: >-
The evidence that this model is the right one for CMT1E specifically: a
point-mutation mouse is transcriptionally distinct from null and overexpressing
mice, so a dosage model cannot stand in for it.
treatments:
- name: Rehabilitation, orthoses and surgical correction
description: >-
No disease-modifying therapy exists for any form of CMT. Management is muscle
strength training, orthotic devices, surgery, symptom relief and anticipatory
monitoring for complications.
treatment_term:
preferred_term: rehabilitation and orthotic management
term:
id: NCIT:C15302
label: Physical Therapy
therapeutic_modality: BEHAVIORAL
evidence:
- reference: PMID:41571707
reference_title: "Charcot-Marie-Tooth disease and related neuropathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications"
explanation: >-
States both the absence of disease-modifying therapy and the content of
supportive management, from a review.
- name: Ascorbic acid
description: >-
Recorded as a NEGATIVE result rather than as an available treatment. Ascorbic acid
corrected the phenotype in the CMT1A transgenic mouse, which is a gene-dosage
model, and failed in humans across three one-year trials. It is listed here because
the failure is mechanistically informative for CMT1E: a therapy aimed at the dosage
mechanism has no reason to help a protein-misfolding disease, and the expression
profiling makes that prediction independently.
treatment_term:
preferred_term: ascorbic acid
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ascorbic acid
term:
id: CHEBI:29073
label: L-ascorbic acid
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:21393063
reference_title: "Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "in three 1-year trials, ascorbic acid had no benefit in human beings"
explanation: >-
A REFUTE item against ascorbic acid as a treatment. The quoted sentence is the
trial report's framing of the prior literature rather than its own result, hence
BACKGROUND. Note also that these trials were in CMT1A, not CMT1E, so this is
evidence against a therapy being carried across to this disease rather than a
trial in it.
- name: Curcumin
description: >-
The mechanism-matched preclinical lead, and the reason it belongs in this entry
rather than in a general CMT one: it targets the ER-retention and
aggregation-induced apoptosis that six of this entry's nodes are about, which is
the arm of PMP22 biology that CMT1A does not share.
Oral curcumin partially mitigates the Trembler-J phenotype in a dose-dependent
manner, decreasing apoptotic Schwann cells and increasing the number and size of
myelinated axons. That is a mouse result with no human trial behind it, and the
entry says so rather than implying an available therapy.
treatment_term:
preferred_term: curcumin
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: curcumin
term:
id: CHEBI:3962
label: curcumin
therapeutic_modality: SMALL_MOLECULE
evidence:
- reference: PMID:17701891
reference_title: "Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner."
explanation: >-
The in vivo result, with the authors' own qualifier "partially". Model organism
only - there is no human trial of curcumin in CMT1E, and this record should not be
read as an available treatment.
- reference: PMID:17701891
reference_title: "Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: a potential therapy for inherited neuropathy."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons"
explanation: >-
The mechanistic readout that makes this a mechanism-matched lead rather than a
symptomatic one: the effect is on the apoptosis node this entry models, and the
myelination improvement follows it.
- name: Genetic counselling
description: >-
Autosomal dominant with a 50 percent recurrence risk, but frequent de novo
mutations mean an apparently sporadic case is common and does not argue against the
diagnosis. Variant identity is a major determinant of severity, so the counselling
conversation is allele-specific rather than disease-specific.
treatment_term:
preferred_term: genetic counselling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "High frequencies of de novo mutations were observed"
explanation: >-
The de novo rate is what makes a negative family history uninformative here.
diagnosis:
- name: Nerve conduction studies
description: >-
Uniformly slowed motor conduction places a patient in the demyelinating CMT1 group
and is what directs testing toward PMP22 in the first place. It does not
distinguish CMT1E from CMT1A; it establishes which gene to look at.
diagnosis_term:
preferred_term: nerve conduction velocity study
term:
id: NCIT:C88502
label: Nerve Conduction Velocity Test
evidence:
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "Demyelinating neuropathies are characterized by severe nerve conduction velocity (NCV) slowing, typically below 38 m/s in upper limb motor nerves."
explanation: >-
The conduction threshold that assigns a patient to the demyelinating group. This
replaces a snippet about axonal loss and clinical impairments that named no
conduction finding at all - it bore on nothing the node claims, which makes it
NO_EVIDENCE for this claim rather than SUPPORT.
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "NCV slowing is uniform and diffuse in CMT due to widespread myelin and Schwann cell dysfunction."
explanation: >-
The word the node leans on: uniform. Uniform diffuse slowing is what separates an
inherited demyelinating neuropathy from an acquired one, where slowing is patchy.
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mean median motor nerve conduction velocity (MNCV) was measured to be 11.5 ± 13.0 m/s in CMT1E patients."
explanation: >-
The measured value in a CMT1E cohort specifically, well inside the demyelinating
range the review defines. The only conduction figure in this entry that is about
CMT1E rather than about CMT.
- name: Audiologic assessment
description: >-
Hearing loss is the feature that separates CMT1E from CMT1A, so hearing status is
assessed rather than assumed. The Korean CMT1E series diagnosed it in 40.6 percent
of patients, which is the yield that justifies testing every patient rather than
only those who report a hearing complaint. No cached source names which audiometric
test was used, so the binding is the general NCIT:C38036 Audiometric Test rather
than the NCIT:C85857 Evoked Response Audiometry offered on review - see review_notes.
diagnosis_term:
preferred_term: audiometric assessment
term:
id: NCIT:C38036
label: Audiometric Test
evidence:
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "hearing loss was diagnosed in 40.6% of the patients (13 of 32)"
explanation: >-
Reports the yield of hearing assessment in a CMT1E cohort rather than recommending
a test, so the recommendation follows by one inference step - a 40.6 percent yield
is the argument for assessing everyone. Graded INDIRECT for that step.
- name: Exclude the PMP22 duplication before sequencing
description: >-
The testing ORDER is the practical consequence of this entry's whole argument.
CMT1A is the common PMP22 disease and is a copy-number change, so it is found by
dosage analysis, not by sequencing; CMT1E is a coding change and is found by
sequencing, not by dosage analysis. A laboratory that sequences first will call a
CMT1A patient negative, and one that stops at MLPA will call a CMT1E patient
negative. The reported combined strategy is dosage analysis of PMP22 with sequencing
of the common CMT1 genes.
This is also why CMT1E cohorts are assembled from duplication-negative families: the
Korean series that supplies most of this entry's clinical data screened 850 families
that had already tested negative for the 17p12 duplication.
diagnosis_term:
preferred_term: PMP22 dosage analysis with sequencing of the common CMT1 genes
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:32506583
reference_title: "Diagnostic yield of targeted sequential and massive panel approaches for inherited neuropathies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the diagnostic yield of the combined strategy of Multiplex-ligation-dependent-probe-amplification (MLPA) of PMP22/GJB1/MPZ and GJB1/MPZ/PMP22 Sanger sequencing was 63."
explanation: >-
Documents the two-step strategy - dosage analysis alongside sequencing of the same
genes - and its yield in an unselected CMT cohort. The percentage is truncated in
the cached abstract at the sentence boundary; the point quoted here is the
strategy, not the figure.
- reference: PMID:35886002
reference_title: "Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP"
explanation: >-
The allele class that sequencing finds, as distinct from the duplication that
dosage analysis finds. Together with the row above this is the argument for the
testing order.
prevalence:
- population: Children, reported range across studies
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_5_PER_10000
rate_per_100000: 45.85
rate_low: 9.7
rate_high: 82.0
notes: >-
This is the prevalence of CHARCOT-MARIE-TOOTH DISEASE AS A WHOLE in children, not of
CMT1E. It is recorded here because no CMT1E-specific prevalence exists and because
the figure is needed to make the entry's own rarity statement meaningful: CMT1E is
caused by point mutations comprising less than 5 percent of CMT1, and CMT1 is about
two thirds of CMT. The wide range reflects differences between the source studies
rather than a measured spread in one population.
evidence:
- reference: PMID:42563944
reference_title: "Charcot-Marie-Tooth disease in children."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: "an estimated prevalence ranging from 9.7 to 82 cases per 100,000 individuals"
explanation: >-
The reported range for CMT overall in children, from a review synthesizing
published estimates rather than measuring one. Graded REVIEW_SYNTHESIS for that
reason, and the population field says explicitly that this is CMT and not CMT1E.
discussions:
- discussion_id: cmt1e_hearing_loss_lesion_site
kind: KNOWLEDGE_GAP
prompt: >-
Where in the auditory system does CMT1E hearing loss arise, and is it the same
demyelinating lesion as the peripheral neuropathy?
attaches_to:
- pathophysiology#Demyelination of Peripheral Nerve
- phenotypes#Sensorineural hearing impairment
rationale: >-
Hearing loss is the feature that distinguishes CMT1E from CMT1A, occurs in more
than 40 percent of a large cohort, and has no mechanism in this entry. The causal
edge to it is drawn UNKNOWN for that reason.
Two readings are live and they are not equivalent. If the lesion is demyelination
of the cochlear nerve, the hearing loss is auditory neuropathy and would show
preserved otoacoustic emissions with absent or grossly abnormal auditory brainstem
responses - and it belongs on the same causal chain as the limb neuropathy. If
PMP22 has a separate role in the cochlea, it is a sensory lesion arising in
parallel, and severity need not track neuropathy severity.
The variant dependence is what makes this more than a labelling question. An entire
family with p.Trp28Cys had no hearing loss, while p.Gly150Asp produced deafness
with cognitive impairment. A mechanism that explained why the auditory system is
spared by some alleles and not others would be a genuine advance, and the
audiological phenotyping needed to distinguish the two readings is routine.
proposed_experiments:
- experiment_id: cmt1e_auditory_neuropathy_phenotyping
name: Otoacoustic emission and auditory brainstem response phenotyping in CMT1E
description: >-
Otoacoustic emissions with auditory brainstem responses in genotyped CMT1E
patients across the allelic series, with peripheral nerve conduction measured in
the same sitting.
readouts:
- name: Otoacoustic emissions with concurrent auditory brainstem response
target: phenotypes#Sensorineural hearing impairment
direction: ALTERED
interpretation: >-
Preserved emissions with abnormal brainstem responses indicates auditory
neuropathy and places the lesion on the demyelination chain; loss of emissions
indicates a cochlear sensory lesion arising separately.
would_support:
- pathophysiology#Demyelination of Peripheral Nerve
supporting_outcome:
- >-
Preserved otoacoustic emissions with absent or desynchronized auditory brainstem
responses, and severity correlating with peripheral conduction slowing.
refuting_outcome:
- >-
Absent otoacoustic emissions indicating outer hair cell loss, with hearing
severity uncorrelated with peripheral nerve conduction.
notes: >-
Deep-research provenance. This entry was curated from an OpenScientist deep-research
report, `research/Charcot-Marie-Tooth_Disease_Type_1E-deep-research-openscientist.md`,
committed alongside it. The report supplied the causal chain and the reference set;
every snippet used here was re-fetched into `references_cache/` and verified against
the cached record rather than taken from the report.
Two corrections were made to the report's ontology suggestions and are recorded here
because the report is committed and a reader will see them.
First, the report gives "myelinating Schwann cell (CL:0002573)". CL:0002573 is
`Schwann cell`; `myelinating Schwann cell` is CL:0000218. The two are used correctly
here - CL:0000218 on the nodes where the source specifies myelinating cells, CL:0002573
on the cholesterol node, where the source says "Schwann cells from homozygous Trembler
J mice" without specifying. This is the failure mode CLAUDE.md describes for gene
bindings, landing on a cell type: the CURIE resolves, the label is a real label, and
the pairing is wrong.
Second, the report's own Term Validation section reports ten terms "named as a
different term". Those are benign - the report had put a table column value such as
"Symptom" or "Clinical sign" where the validator expected a term name, so the CURIEs
are right and the names are category labels. That is worth distinguishing from the
CL:0002573 case above, which the validator could not catch because the report never
stated a name for it.
Reference screening. This PR commits more reference caches than the entry cites,
because the committed deep-research report's own citation validation fetched every
PMID it names. Of those not cited here: PMID:25522693 (a Chinese Han CMT1 cohort with
no point mutations found) and PMID:37170966 (the Italian CMT registry) are
epidemiological and were superseded for the prevalence record by PMID:42563944, which
gives a paediatric range rather than a registry composition; PMID:26662471 is the
Cochrane review of ascorbic acid in CMT1A and is redundant with the trial already
cited as REFUTE; PMID:30685714, PMID:11002284 and PMID:9004143 are PMP22 background;
PMID:19588347 is a foot-drop rehabilitation review and PMID:38784904 a telecoaching
study, neither specific to CMT1E; PMID:40270660 (oesophageal dysmotility) and
PMID:23847051, PMID:25014022, PMID:22528185, PMID:31993930 were screened and not used
because nothing in their cached text bears on a claim this entry makes.
No GO term for "compact myelin" exists in cache/go/terms.csv; searched "compact
myelin" and "Schwann cell development", both returning no rows. GO:0022011
myelination in peripheral nervous system and GO:0042552 myelination are bound instead.
The GeneReviews baseline is PMID:20301532 Charcot-Marie-Tooth Hereditary Neuropathy
Overview, tagged in `references:`. Note that the chapter-level "Charcot-Marie-Tooth
Neuropathy Type 1" chapter, PMID:20301384, is a RETIRED chapter per
cache/bookshelf/genereviews.csv and is deliberately not cited.
review_notes: >-
Lump/split. CMT1E is curated as its own Disease entry rather than as a subtype row on
a PMP22 or CMT1 parent. The argument is mechanistic and it is the point of the entry:
CMT1A and HNPP are gene-dosage diseases of a normal protein, CMT1E is a
protein-misfolding disease, and PMID:15755691 shows the three mouse genotypes have
distinct expression profiles rather than graded ones. The therapeutic consequence
follows: the ascorbic acid failure is what a dosage-derived therapy does in a disease
that is not about dosage. Folding CMT1E into a dosage parent would lose exactly the
claim that makes it worth curating.
Two evidence items are graded REFUTE on purpose, and neither refutes the entry.
PMID:34332267 refutes the claim that hearing loss is constant in CMT1E; PMID:21393063
refutes ascorbic acid as a treatment. Both are recorded as REFUTE rather than omitted
because a reader should be able to see the counter-evidence without leaving the entry.
Two nodes were re-sourced on review and one uncited node was cited, and both changes
came from the same mistake. Pes cavus originally quoted a sentence saying only
"musculoskeletal deformity"; hammertoe was left uncited with a note claiming no cached
reference named hammertoes. Neither claim survived a search of the full text of
PMID:42563944, which the entry already cited: it names pes cavus in its abstract and
says "Pes cavus and hammer toes are common" in its clinical section. I had searched the
abstract and written the negative claim as though I had searched the reference. That is
the exact failure CLAUDE.md's rule about negative-existence claims describes, and it is
the second instance of it in this entry after the GO term note, so it is recorded here
rather than quietly fixed.
Two CURIEs offered on review were checked rather than pasted, and one was declined.
NCIT:C88502 Nerve Conduction Velocity Test and NCIT:C15709 Genetic Testing both
resolve as labelled and are in the treatmentactionterm enum cache, and both are bound.
NCIT:C85857 Evoked Response Audiometry also resolves as labelled, and is still the
wrong binding here: no cached source says which audiometric test was used, and evoked
response audiometry is one particular modality. The audiologic entry binds NCIT:C38036
Audiometric Test instead, which is the generality the source supports.
The prevalence rate_per_100000 was the bottom of the reported range rather than a
point estimate. It is now the midpoint of 9.7-82.0, with both bounds kept; the band is
unchanged and the population scope note still says this is CMT as a whole in children,
not CMT1E.
The edge from Demyelination of Peripheral Nerve to Sensorineural hearing impairment
carries causal_link_type UNKNOWN, and the accompanying discussion says why. This is a
deliberate refusal to draw a mechanism the evidence does not supply, for the most
clinically distinctive feature of the disease.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
Deep-research provenance. This entry was curated from an OpenScientist deep-research report, `research/Charcot-Marie-Tooth_Disease_Type_1E-deep-research-openscientist.md`, committed alongside it. The report supplied the causal chain and the reference set; every snippet used here was re-fetched into `references_cache/` and verified against the cached record rather than taken from the report. Two corrections were made to the report's ontology suggestions and are recorded here because the report is committed and a reader will see them. First, the report gives "myelinating Schwann cell (CL:0002573)". CL:0002573 is `Schwann cell`; `myelinating Schwann cell` is CL:0000218. The two are used correctly here - CL:0000218 on the nodes where the source specifies myelinating cells, CL:0002573 on the cholesterol node, where the source says "Schwann cells from homozygous Trembler J mice" without specifying. This is the failure mode CLAUDE.md describes for gene bindings, landing on a cell type: the CURIE resolves, the label is a real label, and the pairing is wrong. Second, the report's own Term Validation section reports ten terms "named as a different term". Those are benign - the report had put a table column value such as "Symptom" or "Clinical sign" where the validator expected a term name, so the CURIEs are right and the names are category labels. That is worth distinguishing from the CL:0002573 case above, which the validator could not catch because the report never stated a name for it. Reference screening. This PR commits more reference caches than the entry cites, because the committed deep-research report's own citation validation fetched every PMID it names. Of those not cited here: PMID:25522693 (a Chinese Han CMT1 cohort with no point mutations found) and PMID:37170966 (the Italian CMT registry) are epidemiological and were superseded for the prevalence record by PMID:42563944, which gives a paediatric range rather than a registry composition; PMID:26662471 is the Cochrane review of ascorbic acid in CMT1A and is redundant with the trial already cited as REFUTE; PMID:30685714, PMID:11002284 and PMID:9004143 are PMP22 background; PMID:19588347 is a foot-drop rehabilitation review and PMID:38784904 a telecoaching study, neither specific to CMT1E; PMID:40270660 (oesophageal dysmotility) and PMID:23847051, PMID:25014022, PMID:22528185, PMID:31993930 were screened and not used because nothing in their cached text bears on a claim this entry makes. No GO term for "compact myelin" exists in cache/go/terms.csv; searched "compact myelin" and "Schwann cell development", both returning no rows. GO:0022011 myelination in peripheral nervous system and GO:0042552 myelination are bound instead. The GeneReviews baseline is PMID:20301532 Charcot-Marie-Tooth Hereditary Neuropathy Overview, tagged in `references:`. Note that the chapter-level "Charcot-Marie-Tooth Neuropathy Type 1" chapter, PMID:20301384, is a RETIRED chapter per cache/bookshelf/genereviews.csv and is deliberately not cited.
Create: Charcot-Marie-Tooth Disease Type 1E (MONDO:0007311) · 2026-09-22T13:32:21Z · View source
De novo curation of CMT1E (MONDO:0007311), claimed in #12503. entry_type decision: DISEASE, not a has_subtypes row on a PMP22 or CMT1 parent. The argument is mechanistic: CMT1A (duplication) and HNPP (deletion) are gene-dosage diseases of a normal protein, CMT1E is a protein-misfolding disease of an abnormal one, and PMID:15755691 shows the three mouse genotypes have distinct expression profiles rather than graded ones. The therapeutic consequence follows - PMID:21393063 records ascorbic acid working in the CMT1A dosage model and failing in humans. Folding CMT1E into a dosage parent would lose the claim that makes it worth curating. Pathograph: seven nodes. Transmembrane-domain missense to ER/Golgi retention, then two parallel arms - aggresome formation with autophagy-dependent clearance, and cholesterol sequestration in the Golgi with reciprocal plasma-membrane depletion - converging on Schwann cell apoptosis and failure of myelination, then demyelination and the clinical phenotype. The edge from demyelination to sensorineural hearing impairment carries causal_link_type UNKNOWN deliberately: hearing loss is the feature that distinguishes CMT1E and none of the cited sources shows the auditory lesion that produces it. A knowledge gap records the otoacoustic-emission phenotyping that would distinguish auditory neuropathy from a cochlear sensory lesion. Two REFUTE evidence items: PMID:34332267 against hearing loss being constant (a whole family with none), PMID:21393063 against ascorbic acid as a treatment. Deep research reconciliation. Curated from the committed OpenScientist report. Two corrections to its ontology suggestions are recorded in notes: it gives 'myelinating Schwann cell (CL:0002573)' where CL:0002573 is Schwann cell and CL:0000218 is myelinating Schwann cell. Every snippet the report supplied was re-fetched into references_cache and verified against the cached record rather than taken from the report; one (the cholesterol quote) needed the full sentence restored. Reference titles: several reference_title values were initially written from the report's descriptive text rather than copied from the cache frontmatter, and were caught by the title check. All are now copied verbatim from the references_cache title field. Validation: just validate, just validate-terms, just count-verified-snippets (24/24), check-duplicate-keys, check-entity-refs, check-causal-targets. Review round 1 (PR #12509). Four IMPORTANT items taken plus most suggestions. diagnosis: added, and the testing-ORDER point is the one that mattered - it is the practical consequence of this entry's whole not-gene-dosage thesis. Sequencing first calls a CMT1A patient negative; stopping at dosage analysis calls a CMT1E patient negative. Curcumin added to treatments, graded MODEL_ORGANISM with the authors' own "partially" preserved, and the description states there is no human trial. Two mechanism branches added: altered store-operated calcium handling (PMID:31213528) and extracellular matrix remodelling with macrophage-derived MMP-2/-9 (PMID:12421361). Both PROVISIONAL with INDIRECT edges. The MMP branch is the only route in this entry to a cell type other than the Schwann cell. prevalence: added for CMT as a whole in children, with the population field and the notes both stating explicitly that it is not CMT1E-specific. Reference screening recorded in notes for every cached PMID not cited. Three of the five HP CURIEs the reviewer supplied resolve to different concepts: HP:0009830 offered as foot drop is Peripheral neuropathy, HP:0003701 offered as distal amyotrophy is Proximal muscle weakness, HP:0001268 offered as cognitive impairment is Mental deterioration. HP:0001765 Hammertoe and HP:0002093 Respiratory insufficiency are correct and are used. Distal amyotrophy is curated as HP:0003693. Foot drop and cognitive impairment were not added: the correct term for foot drop would be HP:0009027 Foot dorsiflexor weakness and no cached source names it, and Mental deterioration asserts decline from a baseline that no source reports. Hammertoe is curated WITHOUT an evidence block, deliberately: the term is right but no cached sentence names hammertoes, and the node description says so. Pes cavus re-sourced to a sentence that names it, replacing the "musculoskeletal deformity" snippet the previous review_notes had self-flagged.
Target Disease: Charcot-Marie-Tooth Disease Type 1E MONDO ID: MONDO:0007311 | OMIM: #118300 | Gene: PMP22 (HGNC:9118, 17p12) Category: Rare inherited demyelinating peripheral neuropathy
Charcot-Marie-Tooth disease type 1E (CMT1E) is a rare, autosomal dominant demyelinating hereditary motor and sensory neuropathy caused by coding point mutations and small insertions/deletions (indels) in the PMP22 gene on chromosome 17p12. It is molecularly distinct from its two more common allelic disorders that arise from copy-number changes at the same locus: CMT1A (1.4-Mb PMP22 duplication) and hereditary neuropathy with liability to pressure palsies / HNPP (PMP22 deletion). Clinically, CMT1E is frequently more severe than CMT1A and is distinguished by a high frequency of sensorineural hearing loss (>40% of patients in a large Korean cohort), with a phenotypic spectrum that extends into the severe, early-onset Dejerine-Sottas syndrome (DSS) range. Point mutations in PMP22 account for less than 5% of all CMT1 cases, making CMT1E a genuinely rare subtype within an already uncommon disease group (overall CMT prevalence ~1 in 2,500).
Mechanistically, CMT1E is a protein-misfolding / toxic gain-of-function (and dominant-negative) disorder. Most pathogenic substitutions fall within the conserved transmembrane domains of the tetraspan membrane protein PMP22. Mutant PMP22 misfolds, fails to traffic to the plasma membrane, and is retained in the endoplasmic reticulum (ER) and Golgi apparatus, where it forms aggresome-like structures surrounded by molecular chaperones and lysosomes. These aggregates are cleared by autophagy, and their accumulation drives Schwann-cell proteostatic stress, apoptosis, and mis-trafficking of cholesterol (retained with mutant PMP22 in the Golgi, reducing plasma-membrane cholesterol needed for myelin). The downstream consequence is dysmyelination/demyelination of peripheral nerves with secondary length-dependent axonal loss — producing the classic distal, symmetric, progressive sensorimotor phenotype.
There is no approved disease-modifying therapy for CMT1E (or any CMT). Management is entirely supportive — rehabilitation, orthotics, corrective surgery, symptom control, and genetic counseling. Because CMT1E is a point-mutation/proteostasis disease, therapies developed for the gene-dosage disorder CMT1A (e.g., ascorbic acid, PMP22 silencers) are not directly applicable; instead, proteostasis-directed strategies — exemplified preclinically by curcumin, which partially rescues the Trembler-J mouse — are the mechanism-matched experimental leads. The faithful natural mouse models Trembler (Tr) and Trembler-J (TrJ) carry Pmp22 point mutations (TrJ carries the human CMT1E Leu16Pro substitution) and recapitulate the dysmyelinating pathology, providing a strong platform for mechanistic and therapeutic study.
CMT1E is caused by coding point mutations or small indels in PMP22, in contrast to CMT1A (whole-gene duplication) and HNPP (whole-gene deletion). In a Korean cohort of 850 CMT families that were negative for the 17p12 duplication, whole-exome and targeted sequencing identified 14 pathogenic/likely pathogenic PMP22 point mutations across 21 families. Most mutations localized to the conserved transmembrane domains of the protein. Critically, >40% of CMT1E patients showed hearing loss, and both the physical and electrophysiological severity of CMT1E exceeded that of CMT1A, more closely resembling MPZ-related CMT1B (PMID: 35886002). As the authors state: "point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP" and "more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A."
The rarity of this mechanism is quantified: "Point mutations in the Peripheral Myelin Protein 22 (PMP22) gene comprise less than 5% of the Charcot-Marie-Tooth (CMT) type 1 cases" (PMID: 34332267).
Synonyms / alternative names: CMT1E; Charcot-Marie-Tooth neuropathy type 1E; CMT1 with deafness; PMP22-related CMT1 (point mutation type); demyelinating CMT1E. The severe end of the PMP22 point-mutation spectrum overlaps clinically with Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy. Information is derived from aggregated disease-level resources (OMIM, Orphanet) combined with clinical cohort and family studies rather than EHR-derived individual data.
The core pathophysiology is a proteostatic / trafficking defect. In Trembler-J (TrJ, Leu16Pro PMP22) mouse nerves, PMP22 has an extended half-life and forms aggresome-like structures surrounded by molecular chaperones and lysosomes; aggresome clearance is enhanced by autophagy activation and blocked by autophagy inhibition (PMID: 14627652): "PMP22 has an extended half-life and forms aggresome-like structures that are surrounded by molecular chaperones and lysosomes" via "a mechanism that is enhanced when autophagy is activated and is primarily prevented when autophagy is inhibited."
The trafficking lesion is specific to the transmembrane domains: "disease-related missense mutations within transmembrane domains of PMP22 disturb intracellular protein trafficking leading to accumulation of the mutant protein in the endoplasmic reticulum/Golgi compartment" (PMID: 10625337).
A key downstream consequence is disrupted lipid handling: in TrJ Schwann cells, cholesterol is retained with TrJ-PMP22 in the Golgi, with a corresponding reduction in plasma-membrane cholesterol, and cholesterol supplementation improved myelination in PMP22-deficient DRG explants (PMID: 32511821): "cholesterol was retained with TrJ-PMP22 in the Golgi, alongside a corresponding reduction in its plasma membrane level." Because cholesterol is an essential structural lipid of compact myelin, its sequestration provides a direct biochemical link between the misfolded protein and the failure of myelination.
Overall CMT population prevalence is ~1 in 2,500 (PMID: 27584852; PMID: 38784904): "Charcot-Marie-Tooth disease (CMT) is one of the commonest inherited neuromuscular diseases with a population prevalence of 1 in 2500." Within CMT, demyelinating forms dominate. In the Italian National CMT Registry (n=1,012 registered; 711 genetically diagnosed), "Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%)" (PMID: 37170966). The same registry ranked CMT1E among the most disabling subtypes: "CMT4A was the most disabling type, followed by CMT4C and CMT1E."
CMT1E's rarity is reinforced by cohort data: point mutations comprise <5% of CMT1 (PMID: 34332267), and in some populations (e.g., a Chinese Han cohort of 77 CMT1 families) no point mutations were detected among duplication/deletion-negative probands (PMID: 25522693).
| Disorder | PMP22 lesion | Frequency in CMT1 | Relative severity |
|---|---|---|---|
| CMT1A | 1.4-Mb duplication (gene dosage ↑) | ~45% (most common) | Classic, typically milder |
| CMT1E | Point mutation / small indel | <5% | More severe; often with deafness |
| HNPP | Deletion (gene dosage ↓) | — | Episodic pressure palsies |
The Trembler-J mouse is a natural model carrying a genuine human CMT1E mutation: "Trembler J (TrJ) mice carry the same Leu16Pro amino acid substitution in the PMP22 protein that is present in families diagnosed with CMT1E" (PMID: 42105803). TrJ mice display demyelination, aggresome formation, extracellular-matrix remodeling with MMP-2/-9-expressing macrophage infiltration (PMID: 12421361), and respiratory/phrenic-nerve myelin defects with axonal atrophy (p<0.0001) plus diaphragm remodeling (PMID: 42105803).
Comparative profiling shows that point mutations act through a distinct mechanism from gene-dosage changes: across Pmp22-null, Pmp22-overexpressing, and Trembler mice, "the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms" (PMID: 15755691). This is a central caveat for therapy translation (see Finding 7).
In humans, the classic Trembler (Gly150Asp) substitution produces severe disease: "We report two cases of DSS [Dejerine-Sottas syndrome] in a mother and son with the Trembler mutation, with associated findings of hearing loss and cognitive impairment" (PMID: 35974257), underscoring that PMP22 point mutations can drive the severe end of the demyelinating spectrum.
"Disease-modifying therapies are not yet available for any form of CMT. Management includes rehabilitative approaches such as muscle strength training and orthotic devices, surgical interventions, symptom relief and anticipatory monitoring of associated complications" (PMID: 41571707).
The mechanism-matched preclinical lead is curcumin, which targets the ER-retention/aggregation-induced apoptosis specific to mutant PMP22: "oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons" (PMID: 17701891). Emerging strategies under investigation for the broader CMT field include PMP22 silencers (for CMT1A), HDAC6 inhibitors, and unfolded-protein-response modulation (PMID: 40014417).
"All forms of CMT result in length-dependent, progressive axonal loss that correlates with clinical impairments such as distal upper and lower limb weakness, musculoskeletal deformity, absent deep tendon reflexes and distal sensory deficits" (PMID: 41571707). Characteristic features include pes cavus, hammertoes, foot drop, distal muscle atrophy, and reduced quality of life across physical, emotional, and social domains (physical being most disabling).
Diagnosis requires "a detailed family history, comprehensive clinical evaluation, nerve conduction studies, and relevant genetic testing" (PMID: 42563944). Demyelinating CMT1 shows uniformly slowed motor nerve conduction velocity (typically <38 m/s). CMT1E is confirmed by identifying a PMP22 point mutation/indel after the PMP22 duplication has been excluded — usually via MLPA (to exclude duplication/deletion) followed by Sanger sequencing or NGS gene panels / WES (PMID: 35886002; PMID: 32506583). Pediatric CMT prevalence estimates range from 9.7 to 82 per 100,000 (PMID: 42563944). CMT can also involve smooth muscle, causing diaphragmatic and gastrointestinal (esophageal) dysmotility (PMID: 40270660).
CMT1E follows autosomal dominant inheritance. In the Korean cohort, "High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots" (PMID: 35886002). Most mutations lie in conserved transmembrane domains and produce a bimodal early-onset-severe / late-onset-mild phenotype.
Expressivity is highly variable, even within a single family: a Portuguese family carrying p.Trp28Cys ranged "from asymptomatic to mild complaints of distal limb numbness and gait difficulties, with the age of onset of symptoms ranging from mid-twenties to late-sixties" and without disability or hearing loss (PMID: 34332267) — in stark contrast to the severe DSS-with-deafness produced by the Trembler mutation (PMID: 35974257). This demonstrates that the specific variant, and its position within the protein, is a major determinant of severity.
Importantly, dosage-model therapies do not translate to point-mutation disease: ascorbic acid, which benefited CMT1A transgenic mice, "in three 1-year trials... had no benefit in human beings" (PMID: 21393063), and high-quality evidence confirms no meaningful benefit in CMT1A (PMID: 26662471). This negative result cautions strongly against extrapolating CMT1A-directed therapies to CMT1E.
The primary affected cell is the myelinating Schwann cell (CL:0002573); the structural target is compact PNS myelin (GO:0043209), with mutant PMP22 pathology localized to the endoplasmic reticulum (GO:0005783) and Golgi (GO:0005794) and cleared via lysosomes/autophagosomes (PMID: 14627652; PMID: 10625337; PMID: 32511821). Affected anatomy is the peripheral nervous system (UBERON:0000044) — including the sciatic (UBERON:0001322) and phrenic (UBERON:0002385) nerves — in a bilateral, symmetric, length-dependent distribution, with secondary axonal loss, musculoskeletal deformity, auditory (sensorineural hearing loss) involvement, and uncommon respiratory/GI smooth-muscle involvement (PMID: 41571707; PMID: 42105803; PMID: 40270660). PMP22 additionally modulates store-operated calcium channel activity, implicating altered Schwann-cell Ca²⁺ handling in the mechanism (PMID: 31213528).
PMP22 point mutation (TM domain)
│ leads to
▼
Misfolded PMP22 protein
│ retained in
▼
ER / Golgi ──────────────┐
│ aggregates │ sequesters
▼ ▼
Aggresomes Cholesterol trapped in Golgi
│ cleared by │ ↓ plasma-membrane cholesterol
▼ autophagy ▼
Proteostatic stress ──► Schwann-cell apoptosis ◄── impaired myelin lipids
│ (+ Ca²⁺ dysregulation, MMP/ECM remodeling)
▼
Dysmyelination / demyelination of peripheral nerves
│ leads to
▼
Slowed conduction + secondary axonal loss
│ manifests as
▼
Distal progressive sensorimotor neuropathy ± deafness
Upstream vs downstream: The mutation and protein misfolding/ER-Golgi retention are the upstream initiating events; aggresome formation, cholesterol sequestration, Ca²⁺ dysregulation, and ECM remodeling are intermediate Schwann-cell-autonomous processes; demyelination, secondary axonal loss, and the clinical phenotype are downstream. The mechanism is best classified as a toxic gain-of-function / dominant-negative proteostasis disease — fundamentally different from the gene-dosage mechanism of CMT1A and HNPP, which is why CMT1A-directed therapies (ascorbic acid, PMP22-lowering) are not expected to help CMT1E.
Cell types (CL): myelinating Schwann cell (CL:0002573); infiltrating macrophage (CL:0000235). Biological processes (GO): myelination (GO:0042552); ensheathment of neurons / compact myelin (GO:0043209); ER-associated protein catabolic process / ERAD; autophagy (GO:0006914); protein folding (GO:0006457); cholesterol transport (GO:0030301); apoptotic process (GO:0006915). Cellular components (GO): ER (GO:0005783); Golgi apparatus (GO:0005794); lysosome (GO:0005764); aggresome (GO:0016235).
CMT1E is an autosomal dominant demyelinating hereditary motor and sensory neuropathy caused by PMP22 coding point mutations. Identifiers: MONDO:0007311; OMIM #118300; gene PMP22 (HGNC:9118); chromosome 17p12. Orphanet groups it under CMT1/PMP22-related neuropathy. Synonyms: Charcot-Marie-Tooth neuropathy type 1E; CMT1 with deafness; PMP22 point-mutation CMT1. Information derives from aggregated disease-level resources plus clinical cohort/family studies, not EHR data.
Primary cause: heterozygous germline (frequently de novo) point mutation or small indel in PMP22, usually in a transmembrane domain (PMID: 35886002). Genetic risk factors: the specific pathogenic PMP22 variant is causal and largely deterministic; the exact variant is the main modifier of severity (variable expressivity — PMID: 34332267). Environmental risk/protective factors and gene-environment interactions: none established; this is a monogenic Mendelian disorder. Neurotoxic drugs (e.g., vincristine) are a general precaution in CMT but not specifically characterized for CMT1E. No protective alleles identified.
| Phenotype | Type | HPO term | Onset / severity / frequency |
|---|---|---|---|
| Distal muscle weakness/atrophy | Clinical sign | HP:0003693 / HP:0003701 | Childhood–adult; progressive; near-universal |
| Distal sensory loss | Symptom/sign | HP:0002936 | Progressive |
| Pes cavus | Physical manifestation | HP:0001761 | Common |
| Hammertoes / foot deformity | Physical manifestation | HP:0001765 | Common |
| Areflexia / hyporeflexia | Clinical sign | HP:0001315 | Common |
| Foot drop / steppage gait | Clinical sign | HP:0009830 | Common |
| Sensorineural hearing loss | Sign / lab (audiometry) | HP:0000407 | >40% of CMT1E (PMID: 35886002) — distinguishing |
| Slowed motor NCV (<38 m/s) | Lab / electrophysiology | HP:0003431 | Universal in demyelinating CMT1 |
| Respiratory / diaphragmatic involvement | Sign | HP:0002093 | Uncommon (PMID: 42105803, model) |
| Esophageal / GI dysmotility | Symptom | HP:0002015 | Rare (PMID: 40270660) |
| Cognitive impairment (severe/DSS end) | Sign | HP:0001268 | Rare, severe variants (PMID: 35974257) |
Onset: ranges from congenital/infantile (severe, DSS-like) to late-adult (mild), reflecting bimodal expressivity. Progression: slowly progressive, chronic. QoL: reduced across physical, emotional, and social domains, with the physical domain most disabling (PMID: 41571707).
Causal gene: PMP22 (OMIM 601097; HGNC:9118), encoding a 22-kDa tetraspan integral membrane protein of compact PNS myelin (PMID: 11002284). Variant types: missense (predominant, transmembrane domains), plus small indels; classified pathogenic/likely pathogenic per ACMG/AMP. Representative variants: hotspots c.68C>G and c.215C>T (PMID: 35886002); p.Trp28Cys (mild, Portuguese family — PMID: 34332267); Leu16Pro (TrJ / CMT1E); Gly150Asp (Trembler / DSS — PMID: 35974257). Allele frequency: pathogenic variants are private/rare (absent or extremely rare in gnomAD). Origin: germline; frequent de novo. Functional consequence: toxic gain-of-function / dominant-negative via misfolding, not haploinsufficiency. Modifier genes/epigenetics: none established; the causal variant itself is the principal severity determinant. Chromosomal abnormalities:* none (point-mutation disease; distinct from the CNVs underlying CMT1A/HNPP).
No environmental, lifestyle, or infectious contributors are established. CMT1E is monogenic and Mendelian. General neurotoxin avoidance (e.g., vincristine) applies to CMT broadly.
See the Mechanistic Model section above for the ordered causal chain, branch points, and ontology terms. Key steps: transmembrane-domain misfolding → ER/Golgi retention → aggresome formation cleared by autophagy → cholesterol sequestration and Ca²⁺ dysregulation → Schwann-cell apoptosis → dysmyelination → secondary axonal loss → clinical neuropathy with deafness.
Primary: peripheral nerves (UBERON:0000044), especially motor/sensory nerves of distal limbs; sciatic (UBERON:0001322) and phrenic (UBERON:0002385) nerves in models. Body systems: peripheral nervous system; secondary musculoskeletal (foot deformity), auditory system (sensorineural hearing loss), and occasionally respiratory/GI smooth muscle. Cell: myelinating Schwann cell (CL:0002573). Subcellular: ER (GO:0005783), Golgi (GO:0005794), lysosome, aggresome. Laterality: bilateral, symmetric, length-dependent.
Onset: bimodal — early-onset severe (infantile/childhood, DSS-like) vs late-onset mild (adult, up to late-sixties). Course: chronic, slowly progressive, lifelong; not episodic or relapsing-remitting (contrast HNPP). Critical periods: developmental myelination is when PMP22 dysfunction is most consequential; early Schwann-cell proteostasis may be a therapeutic window (PMID: 14627652, PMID: 17701891). No spontaneous remission.
Inheritance: autosomal dominant; frequent de novo mutations (PMID: 35886002). Penetrance: high but variable expressivity even intrafamilially (PMID: 34332267). Prevalence: CMT overall ~1/2,500 (PMID: 27584852); CMT1E <5% of CMT1 (PMID: 34332267); pediatric CMT 9.7–82/100,000 (PMID: 42563944). Anticipation / mosaicism / founder effects: not established for CMT1E specifically; de novo occurrence is common. Sex ratio: no strong sex bias reported. Consanguinity: not relevant (dominant).
Electrophysiology: nerve conduction studies showing uniform motor NCV slowing (<38 m/s) — hallmark of demyelinating CMT1. Genetic testing algorithm: exclude PMP22 duplication/deletion first (MLPA/CMA), then Sanger or NGS panel / WES to detect the point mutation (PMID: 32506583, PMID: 35886002). Audiometry for hearing loss. Nerve biopsy (rarely needed) shows demyelination and onion-bulb formation. Differential diagnosis: CMT1A (duplication), CMT1B (MPZ), CMTX1 (GJB1), CIDP (acquired), Dejerine-Sottas syndrome. Screening: cascade genetic testing of at-risk relatives; prenatal/preimplantation testing available given a known familial variant.
Survival: normal or near-normal life expectancy in typical CMT1E; not directly life-limiting, though severe early-onset (DSS) forms carry higher morbidity, and rare respiratory involvement can affect prognosis (PMID: 42105803). Morbidity: significant, chronic disability from progressive weakness, deformity, and sensory loss; CMT1E ranks among the most disabling CMT subtypes (PMID: 37170966). Prognostic factors: specific variant / domain location, age of onset, presence of hearing loss. No validated molecular prognostic biomarkers.
No disease-modifying therapy (PMID: 41571707, PMID: 40014417). Supportive/rehabilitative (NCIT-type interventions): physical therapy / strength training (NCIT: Physical Therapy), orthoses/AFOs (NCIT: Orthotic Device), occupational therapy, corrective foot surgery, pain management, hearing aids. Strength training showed benefit for timed walking in CMT (PMID: 19588347). Not indicated: ascorbic acid (no benefit in CMT1A; dosage-model therapy — PMID: 21393063, PMID: 26662471). Experimental / mechanism-matched: curcumin (proteostasis/anti-apoptotic; preclinical rescue of TrJ — PMID: 17701891); autophagy enhancers; HDAC6 inhibitors; UPR modulators (PMID: 40014417). PMP22 silencers target CMT1A dosage and are not appropriate for point-mutation CMT1E unless allele-specific.
No primary prevention (monogenic). Genetic counseling is central: autosomal dominant inheritance with 50% transmission risk, plus de novo recurrence counseling. Reproductive options: prenatal diagnosis and preimplantation genetic testing when the familial variant is known. Tertiary prevention: rehabilitation, orthotics, foot care, fall prevention, and anticipatory monitoring for respiratory/auditory complications.
Pmp22 is highly conserved; mouse (NCBI Taxon:10090) orthologue Pmp22 underlies the spontaneous Trembler (Tr) and Trembler-J (TrJ) mutants — naturally occurring dysmyelinating neuropathies that are genuine models of human PMP22 point-mutation disease (PMID: 42105803, PMID: 30685714). No zoonotic potential. Evolutionary conservation of PMP22 function in myelination makes rodent models informative but imperfect (species differences in lesions — PMID: 30685714).
Natural point-mutation mice: Trembler-J (Leu16Pro, the human CMT1E allele) and Trembler (Gly150Asp) (PMID: 42105803, PMID: 15755691). Engineered models: Pmp22-null and Pmp22-overexpressing lines model HNPP and CMT1A respectively, and comparative studies show distinct expression profiles / mechanisms by mutation type (PMID: 15755691). Recapitulation: TrJ faithfully reproduces dysmyelination, aggresome formation, apoptosis, ECM remodeling, and phrenic-nerve/diaphragm pathology. Limitations: rodent lesions differ in some respects from human nerve pathology (PMID: 30685714). In vitro: DRG/Schwann-cell co-cultures and patient-derived iPSC-Schwann cells are relevant for trafficking/proteostasis assays. Resources: MGI, IMSR.
| PMID | Title (abbreviated) | Evidence type | Role |
|---|---|---|---|
| 35886002 | PMP22 mutations in CMT1E patients | Human cohort (Korea) | Defines CMT1E genetics, deafness >40%, severity vs CMT1A, de novo hotspots |
| 34332267 | Portuguese family, novel PMP22 point mutation | Human family | Rarity (<5% of CMT1); variable expressivity (p.Trp28Cys) |
| 14627652 | Autophagy removes aggresomes in Schwann cells | Model (TrJ) | Aggresome formation; autophagic clearance |
| 10625337 | PMP22 and demyelinating neuropathies | In vitro/review | ER/Golgi retention of TM-domain mutants |
| 32511821 | Subcellular diversion of cholesterol by PMP22 | Model/in vitro | Cholesterol trapped in Golgi; myelination rescue |
| 42105803 | Diaphragm/phrenic defects in CMT1E mouse | Model (TrJ) | TrJ = human Leu16Pro; respiratory involvement |
| 15755691 | Distinct mechanisms by PMP22 dosage vs point mutation | Model | Point mutation ≠ dosage mechanism |
| 35974257 | DSS from Trembler mutation | Human | Severe end: DSS + deafness + cognitive |
| 17701891 | Oral curcumin mitigates TrJ phenotype | Model | Mechanism-matched preclinical therapy |
| 41571707 | CMT and related neuropathies | Review | No DMT; supportive care; clinical phenotype |
| 40014417 | CMT management 2025 | Review | Emerging therapies (silencers, HDAC6i, UPR) |
| 42563944 | CMT in children | Review | Diagnostic workup; pediatric prevalence |
| 37170966 | Italian National CMT Registry | Registry | Demyelinating 65.3%; CMT1E among most disabling |
| 27584852 | Recent advances in genetic neuropathies | Review | CMT prevalence 1/2,500 |
| 32506583 | Diagnostic yield of sequencing strategies | Human | MLPA→Sanger/NGS diagnostic algorithm |
| 25522693 | PMP22 neuropathies in Chinese Han | Human cohort | No point mutations detected — rarity |
| 21393063 / 26662471 | Ascorbic acid trials | RCT | Negative: dosage-model therapy fails |
| 31213528 | PMP22 and store-operated Ca²⁺ | In vitro | Ca²⁺-handling contribution |
| 12421361 | MMP-mediated ECM degradation in TrJ | Model | Macrophage/MMP ECM remodeling |
| 11002284 | Membrane topology of PMP22 | In vitro | Tetraspan protein structure |
| 30685714 | Rodent PMP22 models | Review | Model relevance and limitations |
Consistency of the evidence: Findings converge across independent human cohorts (Korea, Portugal, Italy, China, Brazil), natural mouse models (Trembler/TrJ), and in vitro trafficking studies. The proteostasis/misfolding mechanism is supported by ≥4 independent model/in vitro lines. The one important negative result — ascorbic acid failing in CMT1A RCTs — reinforces (rather than challenges) the conclusion that CMT1E, a distinct proteostasis disorder, requires distinct, mechanism-matched therapy.
Report compiled from an autonomous multi-iteration literature investigation (32 papers reviewed; 8 confirmed findings). Evidence types span human clinical/cohort studies, natural and engineered mouse models, and in vitro systems, as annotated throughout.
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 25 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 25 |
| On topic | 16 |
| Off topic | 2 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:40270660 (7 mentions) - Oesophageal Dysmotility in a Patient with Charcot-Marie-Tooth Disease: Report and Literature Review.PMID:19588347 (3 mentions) - Rehabilitation interventions for foot drop in neuromuscular disease.Weighed against this report's own most characteristic terms: pmp22, cmt1e, mutation, loss, model, cmt, hearing, point-mutation, disease, cmt1a, type, trj, cmt1, severe, demyelinating, domain, nerve, mechanism, aggresome, variant.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 30 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 10 |
| Terms named correctly | 0 |
| Terms named as a different term | 10 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0002936 (1 mention) - the report calls it "Symptom/sign"; HP calls it Distal sensory impairmentHP:0001761 (1 mention) - the report calls it "Physical manifestation"; HP calls it Pes cavusHP:0001765 (1 mention) - the report calls it "Physical manifestation"; HP calls it HammertoeHP:0001315 (1 mention) - the report calls it "Clinical sign"; HP calls it Diminished deep tendon reflexHP:0009830 (1 mention) - the report calls it "Clinical sign"; HP calls it Peripheral neuropathyHP:0000407 (1 mention) - the report calls it "Sign / lab (audiometry)"; HP calls it Sensorineural hearing impairmentHP:0003431 (1 mention) - the report calls it "Lab / electrophysiology"; HP calls it Decreased motor nerve conduction velocityHP:0002093 (1 mention) - the report calls it "Sign"; HP calls it Respiratory insufficiencyHP:0002015 (1 mention) - the report calls it "Symptom"; HP calls it DysphagiaHP:0001268 (1 mention) - the report calls it "Sign"; HP calls it Mental deteriorationTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Taxon.