Charcot-Marie-Tooth Disease Type 4C

Mendelian MONDO:0011113 Pathograph 29 Show in embeddings browser Charcot-Marie-Tooth Disease Type 4

Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive demyelinating peripheral neuropathy caused by biallelic variants in SH3TC2, and is the most common of the recessive demyelinating (CMT4) forms. Its molecular lesion is unusual among the myelin neuropathies: SH3TC2 is not a myelin structural protein but a Rab11 effector that holds the Schwann cell's recycling endosome in working order. Disease-causing variants — truncating and missense alike — lose the SH3TC2-Rab11 interaction, so the protein is mistargeted away from the recycling endosome, membrane and receptor recycling fails, and ErbB2 internalization downstream of axonal neuregulin-1 is disturbed. The Schwann cell therefore never reads axonal calibre correctly, and myelinates poorly. Two features distinguish CMT4C clinically. Spinal deformity is early and prominent, to the point that scoliosis can be the presenting and occasionally the only sign; and cranial nerve involvement, especially hearing loss, is common, which is rare in the other CMT4 subtypes. The nodes of Ranvier are structurally disorganized in patient nerve biopsies as well as in the mouse, and correcting that architecture is one of the read-outs by which Schwann-cell-targeted gene replacement has been shown to work in the Sh3tc2-/- mouse.

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1
Inheritance
11
Pathophys.
14
Phenotypes
3
Gaps
29
Pathograph
1
Genes
7
Medical Actions
3
Differentials
1
Trials
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Models
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References
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Deep Research
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Inheritance

1
Autosomal Recessive HP:0000007
Two SH3TC2 pathogenic alleles are required. Homozygosity was seen in 44% of families in the largest published series, consanguinity in 18%; the rest were compound heterozygotes.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301514 SUPPORT DIRECT Other
"SH3TC2-HMSN is inherited in an autosomal recessive manner."
GeneReviews states the mode of inheritance for SH3TC2-related neuropathy.
PMID:14574644 SUPPORT DIRECT Human Clinical
"In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state."
The gene-discovery cohort found two mutant alleles in every affected individual, which is what autosomal recessive inheritance requires.
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Discussions and Knowledge Gaps

3
Why is spinal deformity so much more prominent in CMT4C than in the other demyelinating neuropathies, and does it arise from paraspinal denervation alone?
KNOWLEDGE GAP cmt4c_scoliosis_mechanism
Attached to
pathophysiology#Early-Onset Spinal Deformity
Scoliosis is the feature that most distinguishes CMT4C, present in 73-81% of patients and severe enough to require surgery in a third, and it can be the only clinical sign. The route from a length-dependent neuropathy to axial deformity is assumed to be weakness of trunk musculature during growth, but no study has measured paraspinal involvement in CMT4C, and the assumption does not explain why this subtype is affected so much more than others whose limb neuropathy is comparable or worse. The edge in this entry is therefore curated as a mechanism claim without direct supporting measurement.
Is the hearing loss in CMT4C due to demyelination of the eighth nerve, to cochlear pathology, or to both?
KNOWLEDGE GAP cmt4c_cranial_nerve_substrate
Attached to
pathophysiology#Cranial Nerve Involvement
Hearing loss affects over a third of patients and cranial nerve involvement nearly half, but no temporal bone or cochlear pathology from a CMT4C patient has been reported, and the published series record the deficit clinically without localizing it. Since SH3TC2 expression in peripheral nerve is restricted to Schwann cells, a myelin lesion of the eighth nerve is the natural hypothesis, but it has not been demonstrated.
Do the constitutive Sh3tc2 null mice model the missense alleles that make up a fifth of human CMT4C, in which a full-length protein is made but cannot bind Rab11?
HUMAN MODEL MISMATCH cmt4c_missense_mouse_gap
Attached to
animal_models#Mouse
Both published mouse lines are nulls. Roughly 20% of human alleles are missense, and the cell-based work shows their defect is loss of Rab11 binding and consequent mistargeting rather than absence of protein — a mislocalized protein could in principle have effects a null does not. The clinical evidence is that missense and truncating alleles give the same disease, and the largest cohort found no severity difference between the one-truncating and zero-truncating groups, so the null is a reasonable proxy. But the proposition has been tested only in transfected cells, never in an animal carrying a knock-in missense allele, and gene-replacement results obtained in nulls are being read as evidence for a therapy that would be given to missense carriers too.
Proposed experiments
Knock-in mouse carrying a CMT4C missense allele
cmt4c_missense_knockin_mouse
Generate a mouse carrying a Rab11-binding-deficient Sh3tc2 missense allele equivalent to a human CMT4C variant, and compare its nerve phenotype and its response to SH3TC2 gene replacement with the null.
Would support
pathophysiology#Loss of the SH3TC2-Rab11 Interaction
Would refute
pathophysiology#Loss of the SH3TC2-Rab11 Interaction
Supporting outcome
  • A missense knock-in reproduces the null's hypomyelination and nodal disorganization and responds comparably to gene replacement, confirming that loss of Rab11 binding is the whole of the missense mechanism.
Refuting outcome
  • The missense knock-in shows a phenotype the null does not, or fails to respond to gene replacement, indicating the mislocalized protein does something beyond losing its Rab11 function.
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Pathophysiology

11
Biallelic SH3TC2 Loss of Function
Two pathogenic SH3TC2 alleles remove functional SH3TC2 from myelinating Schwann cells. The allelic spectrum is dominated by truncating variants — in a 103-patient series, nonsense and frameshift alleles together accounted for 69% of alleles, with p.Arg954* alone accounting for 45.6% — but missense variants produce the same clinical picture, which is what first pointed to a shared downstream defect rather than to simple dosage.
Genetic context SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of the SH3TC2-Rab11 Interaction Every disease-causing SH3TC2 construct tested loses the ability to bind Rab11, so this is the immediate molecular consequence of the genotype.
Cranial Nerve Involvement Cranial nerve deficits are attributed to the same genotype but are not routed through the limb-nerve chain, because whether the lesion is in cranial nerve myelin or in the cochlea has never been established. The edge is typed as having unknown intermediates rather than left absent, so the node is reachable from the genotype without asserting a mechanism the literature does not support.
Show evidence (2 references)
PMID:14574644 SUPPORT DIRECT Human Clinical
"We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution."
Establishes that both truncating and missense SH3TC2 alleles cause the disease, the observation that motivates a shared downstream mechanism.
PMID:40745932 SUPPORT DIRECT Human Clinical
"Frameshift variants accounted for 10% of the series, contributing to a total of 69% truncated protein."
Quantifies the predominance of truncating alleles in the largest published CMT4C cohort.
Loss of the SH3TC2-Rab11 Interaction
Wild-type SH3TC2 is a Rab11 effector: it binds preferentially to GTP-loaded Rab11 and is thereby held on the perinuclear recycling endosome. Disease-causing variants cannot associate with Rab11, and are mistargeted away from that compartment. The authors of the localization study proposed this mistargeting as the fundamental molecular defect of CMT4C — the step where truncating and missense alleles converge.
SH3TC2 binding to GTP-loaded Rab11 GO:0031267 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased SH3TC2 binding to GTP-loaded Rab11, annotated with small GTPase binding (GO:0031267). GO:0031267 is a molecular function from the Gene Ontology. ↓ DECREASED
recycling endosome GO:0055037 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves recycling endosome (GO:0055037). GO:0055037 is a cellular component from the Gene Ontology.
Downstream
Impaired Schwann Cell Endosomal Recycling Losing the Rab11 effector removes SH3TC2 from the compartment that returns internalized membrane and receptors to the cell surface.
Show evidence (3 references)
PMID:20028792 SUPPORT DIRECT In Vitro
"We show that wild-type SH3TC2 targets to the intracellular recycling endosome by associating with the small GTPase, Rab11, which is known to regulate the recycling of internalized membrane and receptors back to the plasma membrane."
Establishes the normal SH3TC2-Rab11 interaction whose loss this node describes.
PMID:20028792 SUPPORT DIRECT In Vitro
"Of clinical pathological relevance, all SH3TC2 constructs harbouring disease-causing mutations are shown to be unable to associate with Rab11 with consequent loss of recycling endosome localization."
Every disease-causing construct tested loses Rab11 binding and recycling endosome localization, which is the claim of this node.
PMID:20826437 SUPPORT DIRECT In Vitro
"Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro."
Independent replication of the loss of Rab11 binding, and the reciprocal experiment showing that blocking Rab11 alone impairs myelination.
Impaired Schwann Cell Endosomal Recycling
SH3TC2 expression in peripheral nerve is restricted to Schwann cells, where it sits on the plasma membrane and the perinuclear endocytic recycling compartment. With SH3TC2 mistargeted, receptor recycling is measurably altered: wild-type but not mutant SH3TC2 influences transferrin receptor dynamics.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
endocytic recycling GO:0032456 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endocytic recycling (GO:0032456). GO:0032456 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling ErbB2 is one of the receptors whose movement between the surface and the recycling compartment SH3TC2 controls.
Hypomyelination and Segmental Demyelination Recycling failure impairs myelination through the ErbB2 arm and, in the knockout mouse, through broader changes in myelination and cell-adhesion transcripts that are not individually modelled here.
Show evidence (2 references)
PMID:20826437 SUPPORT DIRECT In Vitro
"SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment."
Establishes both the cell type and the subcellular compartment this node is about.
PMID:20028792 SUPPORT DIRECT In Vitro
"Moreover, we show that wild-type SH3TC2, but not mutant SH3TC2, influences transferrin receptor dynamics, consistent with a functional role on the endocytic recycling pathway."
A functional read-out showing that mutant SH3TC2 fails to support receptor recycling, not merely that it is mislocalized.
Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling
Axonal neuregulin-1 acting on Schwann cell ErbB receptors is the signal by which a Schwann cell measures the axon it must myelinate. Sh3tc2 interacts with ErbB2 and regulates its internalization from the plasma membrane after Nrg1 stimulation; both mouse Sh3tc2 loss and the missense variants found in patients disturb that internalization. The authors frame the consequence as a failure of axonal size sensing.
myelinating Schwann cell CL:0000218 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myelinating Schwann cell (CL:0000218). CL:0000218 is a cell type from the Cell Ontology.
ERBB2 signaling pathway GO:0038128 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated ERBB2 signaling pathway (GO:0038128). GO:0038128 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Animal models
Sh3tc2 exon 1 knockout mouse Mouse recapitulates The same line was used to show that Sh3tc2 loss perturbs the Nrg1/ErbB pathway and ErbB2 internalization.
Downstream
Hypomyelination and Segmental Demyelination Misread axonal neuregulin signal produces myelin sheaths that are too thin for the axons they surround.
Show evidence (2 references)
PMID:23553667 SUPPORT DIRECT Model Organism
"This early phenotype is associated with changes in the canonical Nrg1/ErbB pathway involved in control of myelination."
Links Sh3tc2 loss in the mouse to the Nrg1/ErbB pathway that controls myelination.
PMID:23553667 SUPPORT DIRECT In Vitro
"Interestingly, both the loss of Sh3tc2 function in mice and the pathological mutations present in CMT4C patients affect ErbB2 internalization, potentially altering its downstream intracellular signaling pathways."
Extends the trafficking defect from the mouse null to the specific missense alleles carried by patients, which is what makes this node relevant to human CMT4C rather than only to the model.
Hypomyelination and Segmental Demyelination
The Schwann cell fails to build and maintain a normal sheath. Nerve biopsy in patients shows demyelination with onion bulb formation; the Sh3tc2 knockout mouse shows hypomyelination from an early stage.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
myelination GO:0042552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myelination (GO:0042552). GO:0042552 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Sh3tc2 exon 1 knockout mouse Mouse recapitulates The knockout develops progressive hypomyelinating neuropathy with reduced motor and sensory conduction velocity, matching the human demyelinating phenotype.
Sh3tc2 exon 1 knockout mouse Mouse rescues Schwann-cell-targeted SH3TC2 replacement improved myelin thickness, g-ratios and the proportion of demyelinated fibres, and increased motor conduction velocities — a causal test of the myelination arm of the mechanism.
Downstream
Nodal and Paranodal Disorganization The node of Ranvier is built by the myelinating Schwann cell, so a disordered sheath is accompanied by a disordered node.
Nerve Conduction Slowing and Conduction Block Loss of myelin slows saltatory conduction and, where demyelination is focal, blocks it.
Progressive Axonal Loss Chronic demyelination is followed by axonal loss, which in this disease is detectable as a fall in motor amplitudes only after middle age.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Nerve biopsy was performed in 6 patients and showed demyelination, including onion bulb formations, in all cases."
Direct histological demonstration of demyelination in CMT4C patients.
PMID:19805030 SUPPORT DIRECT Model Organism
"The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination."
Establishes hypomyelination as the tissue consequence of Sh3tc2 loss in the mouse.
Nodal and Paranodal Disorganization
Abnormal organization of the node of Ranvier was found in the Sh3tc2 knockout mouse and then confirmed in CMT4C patient nerve biopsies. It is the structural read-out that Schwann-cell-targeted gene replacement normalizes in the mouse, which is why it is modelled as its own node rather than folded into demyelination.
node of Ranvier GO:0033268 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves node of Ranvier (GO:0033268). GO:0033268 is a cellular component from the Gene Ontology.
Animal models
Sh3tc2 exon 1 knockout mouse Mouse recapitulates Abnormal node of Ranvier organization was found first in this model and then confirmed in CMT4C patient nerve biopsies, so the model led the human observation rather than following it.
Sh3tc2 exon 1 knockout mouse Mouse rescues Both the lentiviral and the AAV9 vector normalized nodal molecular architecture, including after delayed treatment.
Downstream
Nerve Conduction Slowing and Conduction Block Conduction depends on the molecular organization of the node, so nodal disorganization contributes to the slowing independently of sheath thickness.
Show evidence (1 reference)
PMID:19805030 SUPPORT DIRECT Human Clinical
"a phenotype that we confirmed in CMT4C patient nerve biopsies"
Nodal disorganization was confirmed in nerve biopsies from CMT4C patients. Only the patient clause of the source sentence is quoted here; the mouse clause is quoted separately on the animal-model readout, so each item carries a single evidence_source.
Nerve Conduction Slowing and Conduction Block
Motor conduction velocities fall into the demyelinating range in essentially every patient, and half also show a motor conduction block or temporal dispersion — a pattern more often associated with acquired inflammatory neuropathy, and one reason CMT4C is sometimes mistaken for CIDP.
Downstream
Progressive Demyelinating Sensorimotor Neuropathy Slowed and blocked conduction in motor and sensory fibres is what produces the clinical deficit.
Demyelinating Peripheral Neuropathy Conduction velocity in the demyelinating range is the finding that defines the phenotype; it was present in every patient of the 103-patient cohort.
Show evidence (3 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases."
Demyelinating-range conduction in all 103 patients.
PMID:40745932 SUPPORT DIRECT Human Clinical
"Half the patients (50%) had at least one motor conduction block or temporal dispersion"
Quantifies conduction block and temporal dispersion in the largest cohort.
PMID:22462672 SUPPORT DIRECT Human Clinical
"The hallmark of the electrophysiological study was the presence of probable conduction block and temporal dispersion."
Independent series reporting the same electrophysiological signature.
Progressive Axonal Loss
CMT4C is an almost pure demyelinating neuropathy, but motor amplitudes fall with age: median nerve CMAP amplitude is significantly lower after age 50 than in younger patients. This is the axonal component that accumulates secondarily, and it tracks the loss of ambulation seen in older patients.
Downstream
Progressive Demyelinating Sensorimotor Neuropathy Axonal loss adds a component of fixed deficit to the demyelinating neuropathy and drives the late loss of walking.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Interestingly, we observed a significant reduction of median nerve CMAP amplitude after age 50 years in comparison with younger patients, indicative of progressive axonal loss with age"
The authors' own interpretation of the amplitude decline as progressive axonal loss.
Progressive Demyelinating Sensorimotor Neuropathy
The clinical syndrome: a length-dependent sensorimotor demyelinating polyneuropathy, usually beginning before age 10 but with adult onset in a quarter of patients, producing distal weakness, sensory loss, foot deformity and, in a significant proportion after age 50, loss of independent walking.
Downstream
Early-Onset Spinal Deformity Weakness of the trunk musculature during growth is the accepted route from the neuropathy to the scoliosis, although it has not been demonstrated directly in CMT4C.
Distal Limb Weakness Distal motor involvement of the length-dependent neuropathy.
Distal Sensory Loss Distal sensory involvement of the length-dependent neuropathy.
Impaired Pain Sensation Distal pin-prick loss is part of the same length-dependent sensory involvement as the vibration loss.
Sensory Ataxia Loss of distal proprioceptive input from the sensory neuropathy impairs balance and gait.
Proximal Limb Weakness Unusually for CMT, proximal weakness is present in a large minority.
Pes Cavus and Foot Deformity Foot deformity follows from imbalanced weakness of intrinsic and extrinsic foot muscles during growth.
Walking Difficulty and Loss of Ambulation The functional endpoint of the combined distal weakness, sensory loss and foot deformity.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"This study shows CMT4C is a severe childhood- and adult-onset demyelinating peripheral neuropathy often associated with scoliosis, hearing loss, and ambulation loss in a significant proportion of patients after age 50 years."
The authors' summary of the clinical syndrome this node represents.
Early-Onset Spinal Deformity
Early, severe scoliosis or kyphoscoliosis is the feature that most sets CMT4C apart from the other CMT4 subtypes. It can be the presenting sign, and in two patients of a 103-patient cohort it was the only clinical abnormality, with the neuropathy detectable on nerve conduction study alone. The mechanical consequence — a restrictive respiratory deficit — is what drives the ventilatory morbidity in this disease.
Downstream
Scoliosis The clinical spinal deformity.
Scoliosis-Related Respiratory Insufficiency Chest wall deformity restricts ventilation.
Show evidence (2 references)
PMID:14574644 SUPPORT DIRECT Human Clinical
"Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology."
Establishes early-onset scoliosis as a defining feature of the entity.
PMID:40745932 SUPPORT DIRECT Human Clinical
"Two patients (2%) presented with scoliosis and no neurological symptoms."
Shows spinal deformity can be the sole clinical manifestation, which is why this is modelled as its own node rather than as a downstream detail.
Cranial Nerve Involvement
Roughly half of patients have cranial nerve involvement, most often the eighth nerve with hearing loss, and also the seventh, ninth, tenth and twelfth. This is uncommon in the other CMT4 subtypes and is a practical diagnostic pointer. Whether the lesion is in the cranial nerve myelin itself or in the cochlea has not been settled, so the edge from the genotype to this node is left as an unknown-intermediate one rather than routed through the limb-nerve chain.
Downstream
Hearing Impairment Eighth nerve involvement.
Cranial Nerve Palsy Seventh, ninth, tenth and twelfth nerve involvement.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Cranial nerve involvement was observed in 48% of patients, including hearing loss in 37% of cases"
Quantifies cranial nerve involvement in the largest cohort.
PMID:22462672 SUPPORT DIRECT Human Clinical
"Cranial nerve involvement affecting either the VIIIth, VIIth, XIIth or a combination of the IXth and Xth nerves was noted in 10 patients."
Identifies which cranial nerves are affected.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Charcot-Marie-Tooth Disease Type 4C Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Ear 1
Hearing Impairment FREQUENT HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"hearing loss in 37% of cases"
37% falls in the FREQUENT band (30-79%).
Genitourinary 1
Genitourinary Involvement OCCASIONAL Neurogenic bladder HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder and erectile dysfunction, annotated with Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Genitourinary involvement was observed in 6% of cases, including atonic bladder with urinary leakage and erectile dysfunction."
6% falls in the OCCASIONAL band (5-29%).
PMID:40745932 SUPPORT DIRECT Human Clinical
"The pathophysiology underlying CMT-related genitourinary disorders is unclear."
The cohort authors' own statement that the mechanism is unknown, which is why the phenotype is not wired to a pathophysiology node.
Limbs 1
Pes Cavus and Foot Deformity VERY_FREQUENT HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Foot deformity (pes cavus, pes planus or pes valgus), annotated with Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"foot deformities, including pes cavus and flat foot, in 83%"
83% falls in the VERY_FREQUENT band (80-99%).
PMID:20301514 SUPPORT DIRECT Other
"foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence"
Records that the deformity is not exclusively pes cavus, which is why preferred_term is broader than the bound HP term.
Musculoskeletal 3
Distal Limb Weakness VERY_FREQUENT Distal muscle weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal limb weakness, annotated with Distal muscle weakness (HP:0002460). HP:0002460 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Clinical features when last examined included distal limb weakness in 93% of cases"
93% falls in the VERY_FREQUENT band (80-99%).
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650), qualified as childhood onset. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Onset: CHILDHOOD
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"scoliosis in 73%, and proximal limb weakness in 40%"
73% falls in the FREQUENT band (30-79%).
PMID:36947133 SUPPORT DIRECT Human Clinical
"There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants."
An independent cohort reports 81%, which would band VERY_FREQUENT. The lower 73% figure from the larger and more recent series is used for the band; both are curated so the discrepancy is visible rather than averaged.
Proximal Limb Weakness FREQUENT Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"proximal limb weakness in 40%"
40% falls in the FREQUENT band (30-79%).
PMID:22462672 SUPPORT DIRECT Human Clinical
"Remarkably, 50% of the patients had proximal limb involvement at the time of examination."
An independent series reporting proximal involvement in half of patients.
Nervous System 7
Demyelinating Peripheral Neuropathy OBLIGATE HP:0007108 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Demyelinating peripheral neuropathy (HP:0007108), qualified as course progressive. HP:0007108 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Nerve conduction studies showed sensorimotor abnormalities within the demyelinating range in all cases."
Demyelinating-range conduction in 103 of 103 patients supports OBLIGATE.
Distal Sensory Loss VERY_FREQUENT Impaired vibratory sensation HP:0002495 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired distal vibratory sensation, annotated with Impaired vibratory sensation (HP:0002495). HP:0002495 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"distal limb vibration sensory loss in 86%"
86% falls in the VERY_FREQUENT band (80-99%).
Impaired Pain Sensation FREQUENT HP:0007328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired distal pin-prick sensation, annotated with Impaired pain sensation (HP:0007328). HP:0007328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"distal limb impaired pin sensitivity in 77%"
77% falls in the FREQUENT band (30-79%).
Cranial Nerve Palsy FREQUENT Abnormal cranial nerve physiology HP:0031910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cranial nerve involvement, annotated with Abnormal cranial nerve physiology (HP:0031910). HP:0031910 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"cranial nerve involvement (48%), hearing loss (37%)"
48% falls in the FREQUENT band (30-79%). The band is for cranial nerve involvement as a whole, of which hearing loss is curated separately.
PMID:20301514 SUPPORT DIRECT Other
"Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems."
Enumerates which cranial nerve deficits occur.
Walking Difficulty and Loss of Ambulation VERY_FREQUENT Gait disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Walking difficulty progressing to loss of ambulation, annotated with Gait disturbance (HP:0001288), qualified as course progressive. HP:0001288 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:36947133 SUPPORT DIRECT Human Clinical
"There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants."
94% falls in the VERY_FREQUENT band (80-99%).
PMID:40745932 SUPPORT DIRECT Human Clinical
"Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound."
Gives the age dependence behind the progressive clinical course, which the 94% figure alone does not convey.
Sensory Ataxia HP:0010871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory ataxia (HP:0010871). HP:0010871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30001926 SUPPORT DIRECT Human Clinical
"Most patients had debut in the first decade with foot deformities, distal limb paresis, sensory ataxia and scoliosis."
Names sensory ataxia among the presenting features without quantifying it, which is why no frequency band is set.
Cerebellar Signs and Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar signs with cerebellar atrophy, annotated with Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31346473 SUPPORT DIRECT Human Clinical
"On examination she had generalized muscle atrophy, leg flaccidity, pes cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging demonstrated atrophy in the frontoparietal regions and cerebellar hemispheres."
The single case on which this phenotype rests, described in full so the strength of the claim is visible.
PMID:31346473 SUPPORT DIRECT Human Clinical
"Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype."
The authors' own statement that this was previously undescribed, which is the reason no frequency is assigned.
Respiratory 1
🧬

Genetic Associations

1
SH3TC2 (Biallelic Pathogenic Variants)
Gene: SH3TC2 hgnc:29427 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SH3TC2 (hgnc:29427). hgnc:29427 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:40745932 SUPPORT DIRECT Human Clinical
"the pathogenic variant c.2860C>T, p.(Arg954*) being the most frequently identified, that is, 45.6% of the alleles and 67% of families"
Quantifies the recurrent p.Arg954* allele in the largest cohort.
PMID:20301514 SUPPORT DIRECT Other
"Because the carrier frequency for SH3TC2-HMSN in certain populations (e.g., individuals of Spanish Roma heritage) is relatively high and the onset of SH3TC2-HMSN may be late, some individuals who undergo carrier testing may be identified as being homozygous."
Records the population carrier-frequency point and its practical consequence for carrier testing.
💊

Medical Actions

7
Multidisciplinary Symptomatic Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
No disease-modifying therapy exists. GeneReviews describes management as symptomatic and delivered by a team spanning neurology, physiatry, orthopaedic surgery, therapy services, audiology, speech and language, and respiratory medicine.
Show evidence (1 reference)
PMID:20301514 SUPPORT DIRECT Other
"Treatment is symptomatic. Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, audiologists/otolaryngologists, speech and language therapists, and pulmonologists."
The management standard for this disorder.
Scoliosis Surgery
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Platform: Surgery
Surgical correction of spinal deformity. In the Inherited Neuropathy Consortium cohort 36% of participants had undergone scoliosis surgery, which makes this the most frequently performed intervention in CMT4C.
Mechanism Target:
Early-Onset Spinal Deformity — Surgery corrects the deformity itself; it does not act on the neuropathy that causes it.
Show evidence (1 reference)
PMID:36947133 SUPPORT DIRECT Human Clinical
"There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants."
Documents how often scoliosis surgery is actually performed in this population.
Non-Invasive Ventilation
Action: non-invasive ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is non-invasive ventilation, annotated with Non-Invasive Mechanical Ventilation (NCIT:C171457). NCIT:C171457 is a clinical intervention from the NCI Thesaurus. Ontology label: Non-Invasive Mechanical Ventilation NCIT:C171457
Platform: Device
For scoliosis-related restrictive respiratory failure. Three of 103 patients in the largest cohort were treated this way, and the authors recommend systematic respiratory assessment in patients with scoliosis.
Mechanism Target:
Scoliosis-Related Respiratory Insufficiency — Ventilatory support for the restrictive deficit produced by chest wall deformity.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Three patients (3%) were treated with non-invasive ventilation (NIV) for scoliosis-related respiratory insufficiency."
Documents the use of non-invasive ventilation in CMT4C patients.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal recessive inheritance with a 25% sibling recurrence risk. Carrier testing is complicated in populations with high carrier frequency, where an apparently asymptomatic person tested as a carrier may turn out to be homozygous.
Show evidence (1 reference)
PMID:20301514 SUPPORT DIRECT Other
"If both parents are known to be heterozygous for an SH3TC2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic SH3TC2 pathogenic variants and being affected"
The recurrence risk that genetic counselling communicates.
Schwann-Cell-Targeted SH3TC2 Gene Replacement (preclinical)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Lentiviral and AAV9 vectors carrying human SH3TC2 under a myelin protein zero promoter, delivered intrathecally to Sh3tc2-/- mice. This is preclinical only: no human trial has been reported, and it is curated here because the rescue is the strongest causal test of the entry's mechanism, not because it is available to patients.
Mechanism Target:
Biallelic SH3TC2 Loss of Function — Restores SH3TC2 expression in myelinating Schwann cells, acting at the root of the pathograph.
Show evidence (1 reference)
PMID:30907403 SUPPORT DIRECT Model Organism
"This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C"
Establishes the approach as a proof of principle in the mouse, which is the limit of what is claimed here.
Neurotrophin-3 Surrogate Gene Therapy (preclinical)
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
An alternative to correcting the Schwann cell gene: intramuscular scAAV1.tMCK.NT-3 turns skeletal muscle into a source of circulating neurotrophin-3, an autocrine factor for Schwann cell survival, differentiation and myelination. In Sh3tc2-/- mice it improved rotarod, grip strength and conduction velocity, and improved hypomyelination and neuromuscular junction denervation. Its rationale is explicitly the difficulty of reaching human Schwann cells with an intrathecal vector, so it is a bypass rather than a correction of the SH3TC2 defect. Preclinical only.
Mechanism Target:
Hypomyelination and Segmental Demyelination — Circulating NT-3 acts on the Schwann cell to promote myelination downstream of, and without repairing, the SH3TC2 defect.
Show evidence (2 references)
PMID:39544702 SUPPORT DIRECT Model Organism
"NT-3 gene therapy improved functional and electrophysiological outcomes including rotarod, grip strength and nerve conduction velocity."
Reports the functional benefit of NT-3 gene therapy in the CMT4C mouse.
PMID:39544702 SUPPORT DIRECT Model Organism
"Qualitative and quantitative histopathological studies showed that hypomyelination of peripheral nerves and denervated status of neuromuscular junctions at lumbrical muscles were also improved in the NT-3-treated mice."
Reports the structural benefit on the myelination node this treatment targets.
Avoidance of Neurotoxic Medication and Obesity
Action: preventive interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is preventive intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Platform: Behavioral / lifestyle
GeneReviews lists obesity and neurotoxic drugs as circumstances to avoid in this disorder.
Show evidence (1 reference)
PMID:20301514 SUPPORT DIRECT Other
"Agents/circumstances to avoid: Obesity, which makes walking more difficult; medications that are toxic or potentially toxic to persons with hereditary motor and sensory neuropathy."
The GeneReviews avoidance recommendation.
🔬

Diagnosis

1
Nerve conduction studies with SH3TC2 sequencing
Demyelinating-range motor conduction in a patient with early scoliosis, foot deformity and cranial nerve involvement, confirmed by biallelic SH3TC2 variants. The largest cohort makes the additional point that nerve conduction studies are worth doing in apparently isolated scoliosis, since two of its patients were found that way.
Show evidence (2 references)
PMID:20301514 SUPPORT DIRECT Other
"The diagnosis of SH3TC2-HMSN is established in a proband with suggestive findings and biallelic pathogenic variants in SH3TC2 identified by molecular genetic testing."
States the diagnostic criterion.
PMID:40745932 SUPPORT DIRECT Human Clinical
"These observations suggest EDX studies should be considered in patients with isolated scoliosis to investigate an underlying CMT disease."
The authors' recommendation arising from the two patients whose only sign was scoliosis.
📈

Progression

2
Childhood onset
Sixty percent of patients develop symptoms before age 10, typically with foot deformity, distal weakness, sensory ataxia and scoliosis. A quarter, however, present only after age 20, so childhood onset is the rule rather than a criterion.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Mean age at disease onset was 14 years (0-52), 60% of patients started the disease before age 10 years, and 24% after age 20 years."
Establishes both the childhood-onset majority and the substantial adult-onset minority.
Adult loss of ambulation
Walking deteriorates with age. Nearly half of patients walked independently before age 50 but only 13% did so after 50, and 23% of those over 50 were wheelchair-bound.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Half the patients (48%) walked independently before age 50 years, in contrast with only 13% after age 50 years. After age 50 years, 23% of patients were wheelchair-bound."
Quantifies the age-related decline in ambulation.
📊

Prevalence

1
Norway
Point Prevalence 0.7 per 100,000 1–9 per 1,000,000
A minimum prevalence from national diagnostic registries, so it is a floor rather than an estimate; undiagnosed and late-onset patients are not counted.
Show evidence (1 reference)
PMID:30001926 SUPPORT DIRECT Human Clinical
"A total of 35 patients from 31 families were found with CMT4C, which gives a minimum prevalence of 0.7/100,000 in Norway."
Source of the rate and its status as a minimum.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Type 4C:

Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Overlapping Features CMT4C produces motor conduction block and temporal dispersion in half of patients, which is the electrophysiological signature usually taken to indicate an acquired inflammatory neuropathy. Two patients in the largest cohort were diagnosed with CIDP and given intravenous immunoglobulin before the genetic diagnosis was made; treatment was ineffective in both.
Show evidence (1 reference)
PMID:40745932 SUPPORT DIRECT Human Clinical
"Two patients were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) and were treated with intravenous immunoglobulins (IVIg) before being diagnosed with hereditary neuropathy."
Documents the misdiagnosis actually occurring in this cohort.
Friedreich Ataxia
Overlapping Features Both share polyneuropathy and scoliosis, and the CMT4C patient with cerebellar signs had carried an FRDA diagnosis. The authors distinguish them by the absence in CMT4C of cardiomyopathy, endocrine abnormality and dentate iron accumulation.
Show evidence (1 reference)
PMID:31346473 SUPPORT DIRECT Human Clinical
"Some clinical features of FRDA and CMT4C overlap, with both conditions featuring polyneuropathy and scoliosis."
States the overlap that creates the differential.
Other CMT4 Subtypes
Overlapping Features CMT4A, 4B1, 4B2, 4D, 4F and 4J are also autosomal recessive demyelinating neuropathies and are curated as has_subtypes entries on Charcot-Marie-Tooth Disease Type 4. CMT4C is distinguished by the prominence of early scoliosis and by frequent cranial nerve involvement.
🔬

Clinical Trials

1
NCT01193075 NOT_APPLICABLE RECRUITING
Observational longitudinal natural history study of CMT1B, CMT2A, CMT4A and CMT4C run by the Inherited Neuropathy Consortium. This is the study the CMT4C natural-history data cited throughout this entry come from: PMID:36947133 analyses the INC-RDCRN longitudinal dataset.
Target Phenotypes: Demyelinating peripheral neuropathy HP:0007108 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Demyelinating peripheral neuropathy (HP:0007108). HP:0007108 is a phenotype from the Human Phenotype Ontology. Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT01193075 SUPPORT DIRECT Human Clinical
"This is an observational longitudinal study to determine the natural history and genotype-phenotype correlations of disease causing mutations in Charcot Marie Tooth disease (CMT) type 1B (CMT1B), 2A (CMT2A), 4A (CMT4A), and 4C (CMT4C)."
The registration record naming CMT4C as one of the four subtypes under longitudinal study, which is what makes this trial CMT4C-specific rather than generically about CMT.
🐁

Animal Models

1
Sh3tc2 exon 1 knockout mouse
Constitutive knockout in which exon 1 of Sh3tc2 is replaced by an EGFP cassette. It reproduces the demyelinating neuropathy and, importantly, the nodal disorganization that was subsequently confirmed in patient nerve biopsies. This is a single line, not two: the "Sh3tc2-/-" mouse used in the gene-replacement and neurotrophin-3 trials is the same allele, distributed as JAX stock #033933, so the RECAPITULATES and RESCUES links below all attach to one model.
Species
Mouse
Genotype
Sh3tc2(DeltaEx1/DeltaEx1)
Publication
PMID:19805030
Pathograph links
Hypomyelination and Segmental Demyelination recapitulates fidelity: high The knockout develops progressive hypomyelinating neuropathy with reduced motor and sensory conduction velocity, matching the human demyelinating phenotype.
Limitations: A constitutive null models the truncating alleles that dominate the human allelic spectrum but not the missense alleles, whose defect is loss of Rab11 binding by a protein that is still made.
Readouts
Motor and sensory nerve conduction velocity
Direction: DECREASED
Interpretation: Slowed conduction is the functional signature of the hypomyelination.
Show evidence (1 reference)
PMID:19805030 SUPPORT DIRECT Model Organism
"The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination."
Reports the conduction and myelination measurements.
Show evidence (1 reference)
PMID:19805030 SUPPORT DIRECT Model Organism
"The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy"
The authors' own assessment that the line models CMT4C.
Nodal and Paranodal Disorganization recapitulates fidelity: high Abnormal node of Ranvier organization was found first in this model and then confirmed in CMT4C patient nerve biopsies, so the model led the human observation rather than following it.
Limitations: Ultrastructural nodal analysis in the mouse is far more complete than what the confirmatory patient biopsies could show, so the degree of correspondence is not quantified.
Readouts
Node of Ranvier organization on peripheral nerve ultrastructure
Direction: ALTERED
Interpretation: Disorganized nodal architecture, the structural correlate of this node.
Show evidence (1 reference)
PMID:19805030 SUPPORT DIRECT Model Organism
"detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals revealed abnormal organization of the node of Ranvier"
The ultrastructural nodal measurement made in the mouse. The patient confirmation from the same sentence is quoted on the pathophysiology node instead.
Show evidence (1 reference)
PMID:19805030 SUPPORT DIRECT Model Organism
"a morphological phenotype that can be used as an additional CMT4C diagnostic marker"
The authors treat the nodal phenotype as directly informative for human CMT4C.
Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling recapitulates fidelity: moderate The same line was used to show that Sh3tc2 loss perturbs the Nrg1/ErbB pathway and ErbB2 internalization.
Limitations: The signalling work is mouse and cell-based. The bridge to human disease is that patient missense alleles also impair ErbB2 internalization, which is an in vitro result rather than a measurement in patient nerve.
Readouts
ErbB2 internalization after neuregulin-1 stimulation
Direction: ALTERED
Interpretation: Sh3tc2 loss changes the rate at which ErbB2 leaves the plasma membrane, the trafficking step this node describes.
Show evidence (1 reference)
PMID:23553667 SUPPORT DIRECT Model Organism
"We demonstrated that Sh3tc2 interacts with ErbB2 and plays a role in the regulation of ErbB2 intracellular trafficking from the plasma membrane upon Nrg1 activation."
Reports the trafficking measurement.
Show evidence (1 reference)
PMID:23553667 SUPPORT DIRECT Model Organism
"Altogether, our results indicate that the molecular mechanism for the axonal size sensing is disturbed in Sh3tc2-deficient myelinating Schwann cells, thus providing a novel insight into the pathophysiology of CMT4C neuropathy."
The authors present this model as informative for CMT4C pathophysiology.
Hypomyelination and Segmental Demyelination rescues fidelity: moderate Schwann-cell-targeted SH3TC2 replacement improved myelin thickness, g-ratios and the proportion of demyelinated fibres, and increased motor conduction velocities — a causal test of the myelination arm of the mechanism.
Limitations: Rescue was partial and was measured 4-8 weeks after a single intrathecal injection in young mice. No human trial exists, and the mouse null does not carry the missense alleles that make up a fifth of the human allelic spectrum.
Readouts
Myelin thickness and g-ratio in sciatic nerve and lumbar roots
Direction: RESTORED
Interpretation: Restoring SH3TC2 to Schwann cells improves the myelin measurements, showing the demyelination is a consequence of the Schwann cell defect and is at least partly reversible.
Show evidence (1 reference)
PMID:30907403 SUPPORT DIRECT Model Organism
"On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2-/- mice."
Reports the myelin morphometry after treatment.
Motor nerve conduction velocity
Direction: INCREASED
Interpretation: Faster conduction after treatment, the functional counterpart of the myelin measurements.
Show evidence (1 reference)
PMID:30907403 SUPPORT DIRECT Model Organism
"Moreover, motor nerve conduction velocities were increased in treated Sh3tc2-/- mice."
Reports the conduction measurement after treatment.
Show evidence (1 reference)
PMID:30907403 SUPPORT DIRECT Model Organism
"Sh3tc2-/- mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture."
Establishes that this line models the demyelinating phenotype the rescue acts on.
Nodal and Paranodal Disorganization rescues fidelity: moderate Both the lentiviral and the AAV9 vector normalized nodal molecular architecture, including after delayed treatment.
Limitations: Nodal normalization is a molecular-marker read-out in the mouse; no equivalent measurement has been made in a treated human nerve, and no human trial exists.
Readouts
Nodal molecular architecture
Direction: RESTORED
Interpretation: Nodal organization is restored by returning SH3TC2 to Schwann cells.
Show evidence (1 reference)
PMID:37641403 SUPPORT DIRECT Model Organism
"Moreover, treatment led to normalization of the organization of the nodes of Ranvier, which is typically deficient in CMT4C patients and Sh3tc2-/- mice, along with reduced ratios of demyelinated fibers, increased myelin thickness and reduced g-ratios at both time points of intervention."
Reports nodal normalization after both early and delayed treatment.
Show evidence (1 reference)
PMID:37641403 SUPPORT DIRECT Model Organism
"Taken together, our results provide a proof of concept for an effective and potentially translatable gene replacement therapy for CMT4C treatment."
The authors' assessment of the model's translational relevance for CMT4C.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease Type 4C
creation_date: "2026-09-01T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive
  demyelinating peripheral neuropathy caused by biallelic variants in SH3TC2,
  and is the most common of the recessive demyelinating (CMT4) forms. Its
  molecular lesion is unusual among the myelin neuropathies: SH3TC2 is not a
  myelin structural protein but a Rab11 effector that holds the Schwann cell's
  recycling endosome in working order. Disease-causing variants — truncating and
  missense alike — lose the SH3TC2-Rab11 interaction, so the protein is
  mistargeted away from the recycling endosome, membrane and receptor recycling
  fails, and ErbB2 internalization downstream of axonal neuregulin-1 is
  disturbed. The Schwann cell therefore never reads axonal calibre correctly,
  and myelinates poorly. Two features distinguish CMT4C clinically. Spinal
  deformity is early and prominent, to the point that scoliosis can be the
  presenting and occasionally the only sign; and cranial nerve involvement,
  especially hearing loss, is common, which is rare in the other CMT4 subtypes.
  The nodes of Ranvier are structurally disorganized in patient nerve biopsies
  as well as in the mouse, and correcting that architecture is one of the
  read-outs by which Schwann-cell-targeted gene replacement has been shown to
  work in the Sh3tc2-/- mouse.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease type 4C
  term:
    id: MONDO:0011113
    label: Charcot-Marie-Tooth disease type 4C
synonyms:
- CMT4C
- CMT 4C
- autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4C
- Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4C
- Charcot-Marie-Tooth neuropathy, type 4C
- SH3TC2-related hereditary motor and sensory neuropathy
- SH3TC2 Charcot-Marie-Tooth disease type 4
parents:
- Charcot-Marie-Tooth Disease Type 4
references:
- reference: PMID:20301514
  title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
  tags:
  - GeneReviews
  findings: []
inheritance:
- name: Autosomal Recessive
  description: >-
    Two SH3TC2 pathogenic alleles are required. Homozygosity was seen in 44% of
    families in the largest published series, consanguinity in 18%; the rest were
    compound heterozygotes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: "SH3TC2-HMSN is inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews states the mode of inheritance for SH3TC2-related neuropathy.
  - reference: PMID:14574644
    reference_title: Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      In all families, we identified a mutation on each disease allele, either in
      the homozygous or in the compound heterozygous state.
    explanation: >-
      The gene-discovery cohort found two mutant alleles in every affected
      individual, which is what autosomal recessive inheritance requires.
pathophysiology:
- name: Biallelic SH3TC2 Loss of Function
  biological_scale: MOLECULAR
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Two pathogenic SH3TC2 alleles remove functional SH3TC2 from myelinating
    Schwann cells. The allelic spectrum is dominated by truncating variants — in
    a 103-patient series, nonsense and frameshift alleles together accounted for
    69% of alleles, with p.Arg954* alone accounting for 45.6% — but missense
    variants produce the same clinical picture, which is what first pointed to a
    shared downstream defect rather than to simple dosage.
  genetic_context:
    gene:
      preferred_term: SH3TC2
      term:
        id: hgnc:29427
        label: SH3TC2
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:14574644
    reference_title: Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      We observed eight distinct protein-truncating mutations and three
      nonconservative missense mutations affecting amino acids conserved through
      evolution.
    explanation: >-
      Establishes that both truncating and missense SH3TC2 alleles cause the
      disease, the observation that motivates a shared downstream mechanism.
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Frameshift variants accounted for 10% of the series, contributing to a
      total of 69% truncated protein.
    explanation: >-
      Quantifies the predominance of truncating alleles in the largest published
      CMT4C cohort.
  downstream:
  - target: Loss of the SH3TC2-Rab11 Interaction
    causal_link_type: DIRECT
    description: >-
      Every disease-causing SH3TC2 construct tested loses the ability to bind
      Rab11, so this is the immediate molecular consequence of the genotype.
  - target: Cranial Nerve Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cranial nerve deficits are attributed to the same genotype but are not
      routed through the limb-nerve chain, because whether the lesion is in
      cranial nerve myelin or in the cochlea has never been established. The
      edge is typed as having unknown intermediates rather than left absent, so
      the node is reachable from the genotype without asserting a mechanism the
      literature does not support.
- name: Loss of the SH3TC2-Rab11 Interaction
  biological_scale: MOLECULAR
  description: >-
    Wild-type SH3TC2 is a Rab11 effector: it binds preferentially to GTP-loaded
    Rab11 and is thereby held on the perinuclear recycling endosome.
    Disease-causing variants cannot associate with Rab11, and are mistargeted
    away from that compartment. The authors of the localization study proposed
    this mistargeting as the fundamental molecular defect of CMT4C — the step
    where truncating and missense alleles converge.
  molecular_functions:
  - preferred_term: SH3TC2 binding to GTP-loaded Rab11
    term:
      id: GO:0031267
      label: small GTPase binding
    modifier: DECREASED
  cellular_components:
  - preferred_term: recycling endosome
    term:
      id: GO:0055037
      label: recycling endosome
  evidence:
  - reference: PMID:20028792
    reference_title: Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      We show that wild-type SH3TC2 targets to the intracellular recycling
      endosome by associating with the small GTPase, Rab11, which is known to
      regulate the recycling of internalized membrane and receptors back to the
      plasma membrane.
    explanation: >-
      Establishes the normal SH3TC2-Rab11 interaction whose loss this node
      describes.
  - reference: PMID:20028792
    reference_title: Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Of clinical pathological relevance, all SH3TC2 constructs harbouring
      disease-causing mutations are shown to be unable to associate with Rab11
      with consequent loss of recycling endosome localization.
    explanation: >-
      Every disease-causing construct tested loses Rab11 binding and recycling
      endosome localization, which is the claim of this node.
  - reference: PMID:20826437
    reference_title: "SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2
      mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and
      forced expression of dominant negative Rab11 strongly impairs myelin
      formation in vitro.
    explanation: >-
      Independent replication of the loss of Rab11 binding, and the reciprocal
      experiment showing that blocking Rab11 alone impairs myelination.
  downstream:
  - target: Impaired Schwann Cell Endosomal Recycling
    causal_link_type: DIRECT
    description: >-
      Losing the Rab11 effector removes SH3TC2 from the compartment that returns
      internalized membrane and receptors to the cell surface.
- name: Impaired Schwann Cell Endosomal Recycling
  biological_scale: CELLULAR
  description: >-
    SH3TC2 expression in peripheral nerve is restricted to Schwann cells, where
    it sits on the plasma membrane and the perinuclear endocytic recycling
    compartment. With SH3TC2 mistargeted, receptor recycling is measurably
    altered: wild-type but not mutant SH3TC2 influences transferrin receptor
    dynamics.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: endocytic recycling
    term:
      id: GO:0032456
      label: endocytic recycling
    modifier: DECREASED
  evidence:
  - reference: PMID:20826437
    reference_title: "SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      SH3TC2 expression is restricted to Schwann cells in the peripheral nervous
      system, and the gene product, SH3TC2, localizes to the perinuclear
      recycling compartment.
    explanation: >-
      Establishes both the cell type and the subcellular compartment this node
      is about.
  - reference: PMID:20028792
    reference_title: Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Moreover, we show that wild-type SH3TC2, but not mutant SH3TC2, influences
      transferrin receptor dynamics, consistent with a functional role on the
      endocytic recycling pathway.
    explanation: >-
      A functional read-out showing that mutant SH3TC2 fails to support receptor
      recycling, not merely that it is mislocalized.
  downstream:
  - target: Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling
    causal_link_type: DIRECT
    description: >-
      ErbB2 is one of the receptors whose movement between the surface and the
      recycling compartment SH3TC2 controls.
  - target: Hypomyelination and Segmental Demyelination
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Recycling failure impairs myelination through the ErbB2 arm and, in the
      knockout mouse, through broader changes in myelination and cell-adhesion
      transcripts that are not individually modelled here.
- name: Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling
  biological_scale: CELLULAR
  description: >-
    Axonal neuregulin-1 acting on Schwann cell ErbB receptors is the signal by
    which a Schwann cell measures the axon it must myelinate. Sh3tc2 interacts
    with ErbB2 and regulates its internalization from the plasma membrane after
    Nrg1 stimulation; both mouse Sh3tc2 loss and the missense variants found in
    patients disturb that internalization. The authors frame the consequence as
    a failure of axonal size sensing.
  cell_types:
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: ERBB2 signaling pathway
    term:
      id: GO:0038128
      label: ERBB2 signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:23553667
    reference_title: Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      This early phenotype is associated with changes in the canonical Nrg1/ErbB
      pathway involved in control of myelination.
    explanation: >-
      Links Sh3tc2 loss in the mouse to the Nrg1/ErbB pathway that controls
      myelination.
  - reference: PMID:23553667
    reference_title: Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    snippet: >-
      Interestingly, both the loss of Sh3tc2 function in mice and the
      pathological mutations present in CMT4C patients affect ErbB2
      internalization, potentially altering its downstream intracellular
      signaling pathways.
    explanation: >-
      Extends the trafficking defect from the mouse null to the specific
      missense alleles carried by patients, which is what makes this node
      relevant to human CMT4C rather than only to the model.
  downstream:
  - target: Hypomyelination and Segmental Demyelination
    causal_link_type: DIRECT
    description: >-
      Misread axonal neuregulin signal produces myelin sheaths that are too thin
      for the axons they surround.
- name: Hypomyelination and Segmental Demyelination
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Dysmyelination and Segmental Demyelination of Peripheral Nerve"
  description: >-
    The Schwann cell fails to build and maintain a normal sheath. Nerve biopsy in
    patients shows demyelination with onion bulb formation; the Sh3tc2 knockout
    mouse shows hypomyelination from an early stage.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Nerve biopsy was performed in 6 patients and showed demyelination,
      including onion bulb formations, in all cases.
    explanation: >-
      Direct histological demonstration of demyelination in CMT4C patients.
  - reference: PMID:19805030
    reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive
      peripheral neuropathy manifested by decreased motor and sensory nerve
      conduction velocity and hypomyelination.
    explanation: >-
      Establishes hypomyelination as the tissue consequence of Sh3tc2 loss in
      the mouse.
  downstream:
  - target: Nodal and Paranodal Disorganization
    causal_link_type: DIRECT
    description: >-
      The node of Ranvier is built by the myelinating Schwann cell, so a
      disordered sheath is accompanied by a disordered node.
  - target: Nerve Conduction Slowing and Conduction Block
    causal_link_type: DIRECT
    description: >-
      Loss of myelin slows saltatory conduction and, where demyelination is
      focal, blocks it.
  - target: Progressive Axonal Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic demyelination is followed by axonal loss, which in this disease is
      detectable as a fall in motor amplitudes only after middle age.
- name: Nodal and Paranodal Disorganization
  biological_scale: TISSUE
  description: >-
    Abnormal organization of the node of Ranvier was found in the Sh3tc2
    knockout mouse and then confirmed in CMT4C patient nerve biopsies. It is
    the structural read-out that Schwann-cell-targeted gene replacement
    normalizes in the mouse, which is why it is modelled as its own node rather
    than folded into demyelination.
  cellular_components:
  - preferred_term: node of Ranvier
    term:
      id: GO:0033268
      label: node of Ranvier
  evidence:
  - reference: PMID:19805030
    reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      a phenotype that we confirmed in CMT4C patient nerve biopsies
    explanation: >-
      Nodal disorganization was confirmed in nerve biopsies from CMT4C patients.
      Only the patient clause of the source sentence is quoted here; the mouse
      clause is quoted separately on the animal-model readout, so each item
      carries a single evidence_source.
  downstream:
  - target: Nerve Conduction Slowing and Conduction Block
    causal_link_type: DIRECT
    description: >-
      Conduction depends on the molecular organization of the node, so nodal
      disorganization contributes to the slowing independently of sheath
      thickness.
- name: Nerve Conduction Slowing and Conduction Block
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Nerve Conduction Slowing and Conduction Block"
  description: >-
    Motor conduction velocities fall into the demyelinating range in essentially
    every patient, and half also show a motor conduction block or temporal
    dispersion — a pattern more often associated with acquired inflammatory
    neuropathy, and one reason CMT4C is sometimes mistaken for CIDP.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Nerve conduction studies showed sensorimotor abnormalities within the
      demyelinating range in all cases.
    explanation: >-
      Demyelinating-range conduction in all 103 patients.
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Half the patients (50%) had at least one motor conduction block or
      temporal dispersion
    explanation: >-
      Quantifies conduction block and temporal dispersion in the largest cohort.
  - reference: PMID:22462672
    reference_title: Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The hallmark of the electrophysiological study was the presence of
      probable conduction block and temporal dispersion.
    explanation: >-
      Independent series reporting the same electrophysiological signature.
  downstream:
  - target: Progressive Demyelinating Sensorimotor Neuropathy
    causal_link_type: DIRECT
    description: >-
      Slowed and blocked conduction in motor and sensory fibres is what produces
      the clinical deficit.
  - target: Demyelinating Peripheral Neuropathy
    causal_link_type: DIRECT
    description: >-
      Conduction velocity in the demyelinating range is the finding that defines
      the phenotype; it was present in every patient of the 103-patient cohort.
- name: Progressive Axonal Loss
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Secondary Axonal Loss and Length-Dependent Deficit"
  description: >-
    CMT4C is an almost pure demyelinating neuropathy, but motor amplitudes fall
    with age: median nerve CMAP amplitude is significantly lower after age 50
    than in younger patients. This is the axonal component that accumulates
    secondarily, and it tracks the loss of ambulation seen in older patients.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Interestingly, we observed a significant reduction of median nerve CMAP
      amplitude after age 50 years in comparison with younger patients,
      indicative of progressive axonal loss with age
    explanation: >-
      The authors' own interpretation of the amplitude decline as progressive
      axonal loss.
  downstream:
  - target: Progressive Demyelinating Sensorimotor Neuropathy
    causal_link_type: DIRECT
    description: >-
      Axonal loss adds a component of fixed deficit to the demyelinating
      neuropathy and drives the late loss of walking.
- name: Progressive Demyelinating Sensorimotor Neuropathy
  biological_scale: ORGANISM
  description: >-
    The clinical syndrome: a length-dependent sensorimotor demyelinating
    polyneuropathy, usually beginning before age 10 but with adult onset in a
    quarter of patients, producing distal weakness, sensory loss, foot deformity
    and, in a significant proportion after age 50, loss of independent walking.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This study shows CMT4C is a severe childhood- and adult-onset demyelinating
      peripheral neuropathy often associated with scoliosis, hearing loss, and
      ambulation loss in a significant proportion of patients after age 50 years.
    explanation: >-
      The authors' summary of the clinical syndrome this node represents.
  downstream:
  - target: Early-Onset Spinal Deformity
    causal_link_type: DIRECT
    description: >-
      Weakness of the trunk musculature during growth is the accepted route from
      the neuropathy to the scoliosis, although it has not been demonstrated
      directly in CMT4C.
  - target: Distal Limb Weakness
    causal_link_type: DIRECT
    description: Distal motor involvement of the length-dependent neuropathy.
  - target: Distal Sensory Loss
    causal_link_type: DIRECT
    description: Distal sensory involvement of the length-dependent neuropathy.
  - target: Impaired Pain Sensation
    causal_link_type: DIRECT
    description: >-
      Distal pin-prick loss is part of the same length-dependent sensory
      involvement as the vibration loss.
  - target: Sensory Ataxia
    causal_link_type: DIRECT
    description: >-
      Loss of distal proprioceptive input from the sensory neuropathy impairs
      balance and gait.
  - target: Proximal Limb Weakness
    causal_link_type: DIRECT
    description: >-
      Unusually for CMT, proximal weakness is present in a large minority.
  - target: Pes Cavus and Foot Deformity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Foot deformity follows from imbalanced weakness of intrinsic and extrinsic
      foot muscles during growth.
  - target: Walking Difficulty and Loss of Ambulation
    causal_link_type: DIRECT
    description: >-
      The functional endpoint of the combined distal weakness, sensory loss and
      foot deformity.
- name: Early-Onset Spinal Deformity
  biological_scale: ORGANISM
  description: >-
    Early, severe scoliosis or kyphoscoliosis is the feature that most sets
    CMT4C apart from the other CMT4 subtypes. It can be the presenting sign, and
    in two patients of a 103-patient cohort it was the only clinical
    abnormality, with the neuropathy detectable on nerve conduction study alone.
    The mechanical consequence — a restrictive respiratory deficit — is what
    drives the ventilatory morbidity in this disease.
  evidence:
  - reference: PMID:14574644
    reference_title: Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset
      demyelinating form of hereditary motor and sensory neuropathy associated
      with an early-onset scoliosis and a distinct Schwann cell pathology.
    explanation: >-
      Establishes early-onset scoliosis as a defining feature of the entity.
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two patients (2%) presented with scoliosis and no neurological symptoms.
    explanation: >-
      Shows spinal deformity can be the sole clinical manifestation, which is
      why this is modelled as its own node rather than as a downstream detail.
  downstream:
  - target: Scoliosis
    causal_link_type: DIRECT
    description: The clinical spinal deformity.
  - target: Scoliosis-Related Respiratory Insufficiency
    causal_link_type: DIRECT
    description: >-
      Chest wall deformity restricts ventilation.
- name: Cranial Nerve Involvement
  biological_scale: ORGANISM
  description: >-
    Roughly half of patients have cranial nerve involvement, most often the
    eighth nerve with hearing loss, and also the seventh, ninth, tenth and
    twelfth. This is uncommon in the other CMT4 subtypes and is a practical
    diagnostic pointer. Whether the lesion is in the cranial nerve myelin itself
    or in the cochlea has not been settled, so the edge from the genotype to this
    node is left as an unknown-intermediate one rather than routed through the
    limb-nerve chain.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Cranial nerve involvement was observed in 48% of patients, including
      hearing loss in 37% of cases
    explanation: >-
      Quantifies cranial nerve involvement in the largest cohort.
  - reference: PMID:22462672
    reference_title: Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Cranial nerve involvement affecting either the VIIIth, VIIth, XIIth or a
      combination of the IXth and Xth nerves was noted in 10 patients.
    explanation: >-
      Identifies which cranial nerves are affected.
  downstream:
  - target: Hearing Impairment
    causal_link_type: DIRECT
    description: Eighth nerve involvement.
  - target: Cranial Nerve Palsy
    causal_link_type: DIRECT
    description: Seventh, ninth, tenth and twelfth nerve involvement.
phenotypes:
- category: Neurological
  name: Demyelinating Peripheral Neuropathy
  description: >-
    A length-dependent sensorimotor neuropathy with motor conduction velocities
    in the demyelinating range in every patient studied.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Demyelinating peripheral neuropathy
    term:
      id: HP:0007108
      label: Demyelinating peripheral neuropathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Nerve conduction studies showed sensorimotor abnormalities within the
      demyelinating range in all cases.
    explanation: >-
      Demyelinating-range conduction in 103 of 103 patients supports OBLIGATE.
- category: Neurological
  name: Distal Limb Weakness
  description: Distal motor weakness, the commonest clinical finding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Distal limb weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Clinical features when last examined included distal limb weakness in 93%
      of cases
    explanation: >-
      93% falls in the VERY_FREQUENT band (80-99%).
- category: Neurological
  name: Distal Sensory Loss
  description: >-
    Distal vibration sensory loss in 86% and impaired pin sensitivity in 77% of
    the largest cohort. Banded on the vibration figure, which is the higher and
    the one the abstract reports.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Impaired distal vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      distal limb vibration sensory loss in 86%
    explanation: >-
      86% falls in the VERY_FREQUENT band (80-99%).
- category: Neurological
  name: Impaired Pain Sensation
  description: >-
    Impaired pin-prick sensitivity distally in 77% of the 103-patient cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Impaired distal pin-prick sensation
    term:
      id: HP:0007328
      label: Impaired pain sensation
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      distal limb impaired pin sensitivity in 77%
    explanation: >-
      77% falls in the FREQUENT band (30-79%).
- category: Musculoskeletal
  name: Pes Cavus and Foot Deformity
  description: >-
    Foot deformity, including pes cavus and flat foot, in 83% of patients.
    GeneReviews describes the spectrum as pes cavus, pes planus or pes valgus,
    typically appearing in the first decade or early adolescence.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Foot deformity (pes cavus, pes planus or pes valgus)
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      foot deformities, including pes cavus and flat foot, in 83%
    explanation: >-
      83% falls in the VERY_FREQUENT band (80-99%).
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      foot deformities (pes cavus, pes planus, or pes valgus) that typically
      present in the first decade of life or early adolescence
    explanation: >-
      Records that the deformity is not exclusively pes cavus, which is why
      preferred_term is broader than the bound HP term.
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Early-onset scoliosis or kyphoscoliosis, present in 73% of a 103-patient
    cohort and 81% of the Inherited Neuropathy Consortium series, in which 36%
    had undergone scoliosis surgery.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      scoliosis in 73%, and proximal limb weakness in 40%
    explanation: >-
      73% falls in the FREQUENT band (30-79%).
  - reference: PMID:36947133
    reference_title: "Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There was a high rate of scoliosis (81%), scoliosis surgery (36%), and
      walking difficulty (94%) among study participants.
    explanation: >-
      An independent cohort reports 81%, which would band VERY_FREQUENT. The
      lower 73% figure from the larger and more recent series is used for the
      band; both are curated so the discrepancy is visible rather than averaged.
- category: Musculoskeletal
  name: Scoliosis-Related Respiratory Insufficiency
  description: >-
    Restrictive respiratory failure secondary to chest wall deformity. Three
    patients in the 103-patient cohort required non-invasive ventilation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis-related restrictive respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      scoliosis-related respiratory insufficiency (14%), and genitourinary
      disorders (6%)
    explanation: >-
      14% falls in the OCCASIONAL band (5-29%). The body of the same paper gives
      15 patients (15%) for this feature; the difference does not change the
      band.
- category: Neurological
  name: Proximal Limb Weakness
  description: >-
    Proximal limb weakness in 40% of the largest cohort and about half of two
    smaller series — unusual for a length-dependent neuropathy and a diagnostic
    clue.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      proximal limb weakness in 40%
    explanation: >-
      40% falls in the FREQUENT band (30-79%).
  - reference: PMID:22462672
    reference_title: Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Remarkably, 50% of the patients had proximal limb involvement at the time
      of examination.
    explanation: >-
      An independent series reporting proximal involvement in half of patients.
- category: Neurological
  name: Hearing Impairment
  description: >-
    Sensorineural hearing loss from eighth nerve involvement, in 37% of the
    103-patient cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      hearing loss in 37% of cases
    explanation: >-
      37% falls in the FREQUENT band (30-79%).
- category: Neurological
  name: Cranial Nerve Palsy
  description: >-
    Involvement of the seventh, ninth, tenth and twelfth cranial nerves,
    producing facial weakness, tongue involvement and dysarthria. Trigeminal
    neuralgia and ptosis were also recorded in the largest cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cranial nerve involvement
    term:
      id: HP:0031910
      label: Abnormal cranial nerve physiology
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      cranial nerve involvement (48%), hearing loss (37%)
    explanation: >-
      48% falls in the FREQUENT band (30-79%). The band is for cranial nerve
      involvement as a whole, of which hearing loss is curated separately.
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Other findings can include cranial nerve involvement (most commonly tongue
      involvement, facial weakness/paralysis, hearing impairment, dysarthria)
      and respiratory problems.
    explanation: >-
      Enumerates which cranial nerve deficits occur.
- category: Genitourinary
  name: Genitourinary Involvement
  description: >-
    Atonic bladder with urinary leakage and erectile dysfunction, reported in 6%
    of the largest cohort at a mean age of 55 years, as a late feature. No
    causal edge is drawn to it: the cohort authors state that the mechanism of
    genitourinary disorders in CMT is unclear, and although autonomic
    dysfunction has been suspected, the autonomic nerves are not myelinated.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Neurogenic bladder and erectile dysfunction
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Genitourinary involvement was observed in 6% of cases, including atonic
      bladder with urinary leakage and erectile dysfunction.
    explanation: >-
      6% falls in the OCCASIONAL band (5-29%).
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      The pathophysiology underlying CMT-related genitourinary disorders is
      unclear.
    explanation: >-
      The cohort authors' own statement that the mechanism is unknown, which is
      why the phenotype is not wired to a pathophysiology node.
- category: Musculoskeletal
  name: Walking Difficulty and Loss of Ambulation
  description: >-
    Walking difficulty affected 94% of the Inherited Neuropathy Consortium
    cohort. Ambulation deteriorates with age rather than being lost early: 48%
    of the nationwide cohort walked independently before age 50 against 13%
    after it, and 23% of those over 50 were wheelchair-bound.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Walking difficulty progressing to loss of ambulation
    term:
      id: HP:0001288
      label: Gait disturbance
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36947133
    reference_title: "Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There was a high rate of scoliosis (81%), scoliosis surgery (36%), and
      walking difficulty (94%) among study participants.
    explanation: >-
      94% falls in the VERY_FREQUENT band (80-99%).
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Half the patients (48%) walked independently before age 50 years, in
      contrast with only 13% after age 50 years. After age 50 years, 23% of
      patients were wheelchair-bound.
    explanation: >-
      Gives the age dependence behind the progressive clinical course, which the
      94% figure alone does not convey.
- category: Neurological
  name: Sensory Ataxia
  description: >-
    Sensory ataxia was among the presenting features in the Norwegian national
    cohort. No frequency is assigned: the source names it as one of the common
    first-decade presentations without giving a proportion.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  evidence:
  - reference: PMID:30001926
    reference_title: "Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Most patients had debut in the first decade with foot deformities, distal
      limb paresis, sensory ataxia and scoliosis.
    explanation: >-
      Names sensory ataxia among the presenting features without quantifying it,
      which is why no frequency band is set.
- category: Neurological
  name: Cerebellar Signs and Cerebellar Atrophy
  description: >-
    A single reported patient, homozygous for p.Arg954*, had limb dysmetria,
    dysarthria, gaze-evoked nystagmus, bilateral vestibular areflexia and
    imaging-confirmed cerebellar atrophy, having been misdiagnosed as Friedreich
    ataxia. This is one patient in one five-patient cohort and the authors state
    that cerebellar involvement had not previously been documented in CMT4C; it
    is curated as a described but unquantified extension of the phenotype, not
    as a feature to expect.
  phenotype_term:
    preferred_term: Cerebellar signs with cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:31346473
    reference_title: The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      On examination she had generalized muscle atrophy, leg flaccidity, pes
      cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked
      nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging
      demonstrated atrophy in the frontoparietal regions and cerebellar
      hemispheres.
    explanation: >-
      The single case on which this phenotype rests, described in full so the
      strength of the claim is visible.
  - reference: PMID:31346473
    reference_title: The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Beyond nystagmus reported in some patients, neither ataxia nor cerebellar
      atrophy has been documented as part of the CMT4C phenotype.
    explanation: >-
      The authors' own statement that this was previously undescribed, which is
      the reason no frequency is assigned.
prevalence:
- population: Norway
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.7
  notes: >-
    A minimum prevalence from national diagnostic registries, so it is a floor
    rather than an estimate; undiagnosed and late-onset patients are not counted.
  evidence:
  - reference: PMID:30001926
    reference_title: "Charcot-Marie-Tooth disease type 4C in Norway: Clinical characteristics, mutation spectrum and minimum prevalence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      A total of 35 patients from 31 families were found with CMT4C, which gives
      a minimum prevalence of 0.7/100,000 in Norway.
    explanation: >-
      Source of the rate and its status as a minimum.
progression:
- phase: Childhood onset
  notes: >-
    Sixty percent of patients develop symptoms before age 10, typically with
    foot deformity, distal weakness, sensory ataxia and scoliosis. A quarter,
    however, present only after age 20, so childhood onset is the rule rather
    than a criterion.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Mean age at disease onset was 14 years (0-52), 60% of patients started the
      disease before age 10 years, and 24% after age 20 years.
    explanation: >-
      Establishes both the childhood-onset majority and the substantial
      adult-onset minority.
- phase: Adult loss of ambulation
  notes: >-
    Walking deteriorates with age. Nearly half of patients walked independently
    before age 50 but only 13% did so after 50, and 23% of those over 50 were
    wheelchair-bound.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Half the patients (48%) walked independently before age 50 years, in
      contrast with only 13% after age 50 years. After age 50 years, 23% of
      patients were wheelchair-bound.
    explanation: >-
      Quantifies the age-related decline in ambulation.
clinical_trials:
- name: NCT01193075
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Observational longitudinal natural history study of CMT1B, CMT2A, CMT4A and
    CMT4C run by the Inherited Neuropathy Consortium. This is the study the
    CMT4C natural-history data cited throughout this entry come from:
    PMID:36947133 analyses the INC-RDCRN longitudinal dataset.
  target_phenotypes:
  - preferred_term: Demyelinating peripheral neuropathy
    term:
      id: HP:0007108
      label: Demyelinating peripheral neuropathy
  - preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: clinicaltrials:NCT01193075
    reference_title: "Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Type (CMT1B), 2A (CMT2A), 4A (CMT4A), 4C (CMT4C), and Others"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      This is an observational longitudinal study to determine the natural
      history and genotype-phenotype correlations of disease causing mutations
      in Charcot Marie Tooth disease (CMT) type 1B (CMT1B), 2A (CMT2A), 4A
      (CMT4A), and 4C (CMT4C).
    explanation: >-
      The registration record naming CMT4C as one of the four subtypes under
      longitudinal study, which is what makes this trial CMT4C-specific rather
      than generically about CMT.
genetic:
- name: SH3TC2
  gene_term:
    preferred_term: SH3TC2
    term:
      id: hgnc:29427
      label: SH3TC2
  relationship_type: CAUSATIVE
  association: Biallelic Pathogenic Variants
  notes: >-
    SH3TC2 (originally KIAA1985) is the only gene known to cause CMT4C. The
    p.Arg954* nonsense allele is the dominant recurrent variant across European
    cohorts, and founder effects have been reported in French Canadians and in a
    Swedish cohort in which all five patients were homozygous for it. Carrier
    frequency is relatively high in some populations, notably individuals of
    Spanish Roma heritage.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      the pathogenic variant c.2860C>T, p.(Arg954*) being the most frequently
      identified, that is, 45.6% of the alleles and 67% of families
    explanation: >-
      Quantifies the recurrent p.Arg954* allele in the largest cohort.
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Because the carrier frequency for SH3TC2-HMSN in certain populations
      (e.g., individuals of Spanish Roma heritage) is relatively high and the
      onset of SH3TC2-HMSN may be late, some individuals who undergo carrier
      testing may be identified as being homozygous.
    explanation: >-
      Records the population carrier-frequency point and its practical
      consequence for carrier testing.
  case_fractions:
  - population: All Charcot-Marie-Tooth disease
    case_fraction_low: 0.0
    case_fraction_high: 7.0
    notes: >-
      A range compiled across published series rather than a single measurement,
      and the zero lower bound reflects series in which no CMT4C was found. Not a
      population estimate.
    evidence:
    - reference: PMID:40745932
      reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      snippet: >-
        It is a rare disease, representing 0%-7% of all CMT
      explanation: >-
        Source of the CMT4C share of all CMT across published series.
diagnosis:
- name: Nerve conduction studies with SH3TC2 sequencing
  description: >-
    Demyelinating-range motor conduction in a patient with early scoliosis, foot
    deformity and cranial nerve involvement, confirmed by biallelic SH3TC2
    variants. The largest cohort makes the additional point that nerve
    conduction studies are worth doing in apparently isolated scoliosis, since
    two of its patients were found that way.
  evidence:
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      The diagnosis of SH3TC2-HMSN is established in a proband with suggestive
      findings and biallelic pathogenic variants in SH3TC2 identified by
      molecular genetic testing.
    explanation: >-
      States the diagnostic criterion.
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      These observations suggest EDX studies should be considered in patients
      with isolated scoliosis to investigate an underlying CMT disease.
    explanation: >-
      The authors' recommendation arising from the two patients whose only sign
      was scoliosis.
animal_models:
- name: Sh3tc2 exon 1 knockout mouse
  species: Mouse
  genotype: Sh3tc2(DeltaEx1/DeltaEx1)
  description: >-
    Constitutive knockout in which exon 1 of Sh3tc2 is replaced by an EGFP
    cassette. It reproduces the demyelinating neuropathy and, importantly, the
    nodal disorganization that was subsequently confirmed in patient nerve
    biopsies. This is a single line, not two: the "Sh3tc2-/-" mouse used in the
    gene-replacement and neurotrophin-3 trials is the same allele, distributed
    as JAX stock #033933, so the RECAPITULATES and RESCUES links below all
    attach to one model.
  publication: PMID:19805030
  modeled_mechanisms:
  - target: Hypomyelination and Segmental Demyelination
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The knockout develops progressive hypomyelinating neuropathy with reduced
      motor and sensory conduction velocity, matching the human demyelinating
      phenotype.
    limitations: >-
      A constitutive null models the truncating alleles that dominate the human
      allelic spectrum but not the missense alleles, whose defect is loss of
      Rab11 binding by a protein that is still made.
    readouts:
    - name: Motor and sensory nerve conduction velocity
      target: Hypomyelination and Segmental Demyelination
      direction: DECREASED
      interpretation: >-
        Slowed conduction is the functional signature of the hypomyelination.
      evidence:
      - reference: PMID:19805030
        reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          The Sh3tc2(DeltaEx1/DeltaEx1) knockout animals develop progressive
          peripheral neuropathy manifested by decreased motor and sensory nerve
          conduction velocity and hypomyelination.
        explanation: Reports the conduction and myelination measurements.
    evidence:
    - reference: PMID:19805030
      reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        The generated Sh3tc2 knockout mice thus present a reliable model of
        CMT4C neuropathy
      explanation: >-
        The authors' own assessment that the line models CMT4C.
  - target: Nodal and Paranodal Disorganization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Abnormal node of Ranvier organization was found first in this model and
      then confirmed in CMT4C patient nerve biopsies, so the model led the human
      observation rather than following it.
    limitations: >-
      Ultrastructural nodal analysis in the mouse is far more complete than what
      the confirmatory patient biopsies could show, so the degree of
      correspondence is not quantified.
    readouts:
    - name: Node of Ranvier organization on peripheral nerve ultrastructure
      target: Nodal and Paranodal Disorganization
      direction: ALTERED
      interpretation: >-
        Disorganized nodal architecture, the structural correlate of this node.
      evidence:
      - reference: PMID:19805030
        reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          detailed analyses of the structures composed of compact and noncompact
          myelin in the peripheral nerve of Sh3tc2(DeltaEx1/DeltaEx1) animals
          revealed abnormal organization of the node of Ranvier
        explanation: >-
          The ultrastructural nodal measurement made in the mouse. The patient
          confirmation from the same sentence is quoted on the pathophysiology
          node instead.
    evidence:
    - reference: PMID:19805030
      reference_title: SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        a morphological phenotype that can be used as an additional CMT4C
        diagnostic marker
      explanation: >-
        The authors treat the nodal phenotype as directly informative for human
        CMT4C.
  - target: Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The same line was used to show that Sh3tc2 loss perturbs the Nrg1/ErbB
      pathway and ErbB2 internalization.
    limitations: >-
      The signalling work is mouse and cell-based. The bridge to human disease
      is that patient missense alleles also impair ErbB2 internalization, which
      is an in vitro result rather than a measurement in patient nerve.
    readouts:
    - name: ErbB2 internalization after neuregulin-1 stimulation
      target: Disturbed Neuregulin-1/ErbB2 Trafficking and Signalling
      direction: ALTERED
      interpretation: >-
        Sh3tc2 loss changes the rate at which ErbB2 leaves the plasma membrane,
        the trafficking step this node describes.
      evidence:
      - reference: PMID:23553667
        reference_title: Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          We demonstrated that Sh3tc2 interacts with ErbB2 and plays a role in
          the regulation of ErbB2 intracellular trafficking from the plasma
          membrane upon Nrg1 activation.
        explanation: Reports the trafficking measurement.
    evidence:
    - reference: PMID:23553667
      reference_title: Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Altogether, our results indicate that the molecular mechanism for the
        axonal size sensing is disturbed in Sh3tc2-deficient myelinating Schwann
        cells, thus providing a novel insight into the pathophysiology of CMT4C
        neuropathy.
      explanation: >-
        The authors present this model as informative for CMT4C pathophysiology.
  - target: Hypomyelination and Segmental Demyelination
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Schwann-cell-targeted SH3TC2 replacement improved myelin thickness,
      g-ratios and the proportion of demyelinated fibres, and increased motor
      conduction velocities — a causal test of the myelination arm of the
      mechanism.
    limitations: >-
      Rescue was partial and was measured 4-8 weeks after a single intrathecal
      injection in young mice. No human trial exists, and the mouse null does not
      carry the missense alleles that make up a fifth of the human allelic
      spectrum.
    readouts:
    - name: Myelin thickness and g-ratio in sciatic nerve and lumbar roots
      target: Hypomyelination and Segmental Demyelination
      direction: RESTORED
      interpretation: >-
        Restoring SH3TC2 to Schwann cells improves the myelin measurements,
        showing the demyelination is a consequence of the Schwann cell defect
        and is at least partly reversible.
      evidence:
      - reference: PMID:30907403
        reference_title: Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          On a structural level, morphological analysis revealed significant
          improvement in g-ratios, myelin thickness, and ratios of demyelinated
          fibres in lumbar roots and sciatic nerves of treated Sh3tc2-/- mice.
        explanation: Reports the myelin morphometry after treatment.
    - name: Motor nerve conduction velocity
      target: Hypomyelination and Segmental Demyelination
      direction: INCREASED
      interpretation: >-
        Faster conduction after treatment, the functional counterpart of the
        myelin measurements.
      evidence:
      - reference: PMID:30907403
        reference_title: Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          Moreover, motor nerve conduction velocities were increased in treated
          Sh3tc2-/- mice.
        explanation: Reports the conduction measurement after treatment.
    evidence:
    - reference: PMID:30907403
      reference_title: Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Sh3tc2-/- mice represent a well characterized disease model developing
        early onset progressive peripheral neuropathy with hypo- and
        demyelination, slowing of nerve conduction velocities and disturbed
        nodal architecture.
      explanation: >-
        Establishes that this line models the demyelinating phenotype the rescue
        acts on.
  - target: Nodal and Paranodal Disorganization
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Both the lentiviral and the AAV9 vector normalized nodal molecular
      architecture, including after delayed treatment.
    limitations: >-
      Nodal normalization is a molecular-marker read-out in the mouse; no
      equivalent measurement has been made in a treated human nerve, and no
      human trial exists.
    readouts:
    - name: Nodal molecular architecture
      target: Nodal and Paranodal Disorganization
      direction: RESTORED
      interpretation: >-
        Nodal organization is restored by returning SH3TC2 to Schwann cells.
      evidence:
      - reference: PMID:37641403
        reference_title: AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        directness: DIRECT
        snippet: >-
          Moreover, treatment led to normalization of the organization of the
          nodes of Ranvier, which is typically deficient in CMT4C patients and
          Sh3tc2-/- mice, along with reduced ratios of demyelinated fibers,
          increased myelin thickness and reduced g-ratios at both time points of
          intervention.
        explanation: >-
          Reports nodal normalization after both early and delayed treatment.
    evidence:
    - reference: PMID:37641403
      reference_title: AAV9-mediated SH3TC2 gene replacement therapy targeted to Schwann cells for the treatment of CMT4C.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      snippet: >-
        Taken together, our results provide a proof of concept for an effective
        and potentially translatable gene replacement therapy for CMT4C
        treatment.
      explanation: >-
        The authors' assessment of the model's translational relevance for CMT4C.
treatments:
- name: Multidisciplinary Symptomatic Management
  description: >-
    No disease-modifying therapy exists. GeneReviews describes management as
    symptomatic and delivered by a team spanning neurology, physiatry,
    orthopaedic surgery, therapy services, audiology, speech and language, and
    respiratory medicine.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Treatment is symptomatic. Affected individuals are often managed by a
      multidisciplinary team that includes neurologists, physiatrists,
      orthopedic surgeons, physical and occupational therapists,
      audiologists/otolaryngologists, speech and language therapists, and
      pulmonologists.
    explanation: >-
      The management standard for this disorder.
- name: Scoliosis Surgery
  description: >-
    Surgical correction of spinal deformity. In the Inherited Neuropathy
    Consortium cohort 36% of participants had undergone scoliosis surgery, which
    makes this the most frequently performed intervention in CMT4C.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_mechanisms:
  - target: Early-Onset Spinal Deformity
    description: >-
      Surgery corrects the deformity itself; it does not act on the neuropathy
      that causes it.
  evidence:
  - reference: PMID:36947133
    reference_title: "Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      There was a high rate of scoliosis (81%), scoliosis surgery (36%), and
      walking difficulty (94%) among study participants.
    explanation: >-
      Documents how often scoliosis surgery is actually performed in this
      population.
- name: Non-Invasive Ventilation
  description: >-
    For scoliosis-related restrictive respiratory failure. Three of 103 patients
    in the largest cohort were treated this way, and the authors recommend
    systematic respiratory assessment in patients with scoliosis.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: non-invasive ventilation
    term:
      id: NCIT:C171457
      label: Non-Invasive Mechanical Ventilation
  target_mechanisms:
  - target: Scoliosis-Related Respiratory Insufficiency
    description: >-
      Ventilatory support for the restrictive deficit produced by chest wall
      deformity.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Three patients (3%) were treated with non-invasive ventilation (NIV) for
      scoliosis-related respiratory insufficiency.
    explanation: >-
      Documents the use of non-invasive ventilation in CMT4C patients.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance with a 25% sibling recurrence risk. Carrier
    testing is complicated in populations with high carrier frequency, where an
    apparently asymptomatic person tested as a carrier may turn out to be
    homozygous.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      If both parents are known to be heterozygous for an SH3TC2 pathogenic
      variant, each sib of an affected individual has at conception a 25% chance
      of inheriting biallelic SH3TC2 pathogenic variants and being affected
    explanation: >-
      The recurrence risk that genetic counselling communicates.
- name: Schwann-Cell-Targeted SH3TC2 Gene Replacement (preclinical)
  description: >-
    Lentiviral and AAV9 vectors carrying human SH3TC2 under a myelin protein
    zero promoter, delivered intrathecally to Sh3tc2-/- mice. This is preclinical
    only: no human trial has been reported, and it is curated here because the
    rescue is the strongest causal test of the entry's mechanism, not because it
    is available to patients.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Biallelic SH3TC2 Loss of Function
    description: >-
      Restores SH3TC2 expression in myelinating Schwann cells, acting at the
      root of the pathograph.
  evidence:
  - reference: PMID:30907403
    reference_title: Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      This study provides a proof of principle for viral gene replacement
      therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease
      type 4C
    explanation: >-
      Establishes the approach as a proof of principle in the mouse, which is
      the limit of what is claimed here.
- name: Neurotrophin-3 Surrogate Gene Therapy (preclinical)
  description: >-
    An alternative to correcting the Schwann cell gene: intramuscular
    scAAV1.tMCK.NT-3 turns skeletal muscle into a source of circulating
    neurotrophin-3, an autocrine factor for Schwann cell survival, differentiation
    and myelination. In Sh3tc2-/- mice it improved rotarod, grip strength and
    conduction velocity, and improved hypomyelination and neuromuscular junction
    denervation. Its rationale is explicitly the difficulty of reaching human
    Schwann cells with an intrathecal vector, so it is a bypass rather than a
    correction of the SH3TC2 defect. Preclinical only.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Hypomyelination and Segmental Demyelination
    description: >-
      Circulating NT-3 acts on the Schwann cell to promote myelination
      downstream of, and without repairing, the SH3TC2 defect.
  evidence:
  - reference: PMID:39544702
    reference_title: AAV1.tMCK.NT-3 gene therapy improves phenotype in Sh3tc2(-/-) mouse model of Charcot-Marie-Tooth Type 4C.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      NT-3 gene therapy improved functional and electrophysiological outcomes
      including rotarod, grip strength and nerve conduction velocity.
    explanation: >-
      Reports the functional benefit of NT-3 gene therapy in the CMT4C mouse.
  - reference: PMID:39544702
    reference_title: AAV1.tMCK.NT-3 gene therapy improves phenotype in Sh3tc2(-/-) mouse model of Charcot-Marie-Tooth Type 4C.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    snippet: >-
      Qualitative and quantitative histopathological studies showed that
      hypomyelination of peripheral nerves and denervated status of
      neuromuscular junctions at lumbrical muscles were also improved in the
      NT-3-treated mice.
    explanation: >-
      Reports the structural benefit on the myelination node this treatment
      targets.
- name: Avoidance of Neurotoxic Medication and Obesity
  description: >-
    GeneReviews lists obesity and neurotoxic drugs as circumstances to avoid in
    this disorder.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: preventive intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  evidence:
  - reference: PMID:20301514
    reference_title: SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: DIRECT
    snippet: >-
      Agents/circumstances to avoid: Obesity, which makes walking more
      difficult; medications that are toxic or potentially toxic to persons with
      hereditary motor and sensory neuropathy.
    explanation: >-
      The GeneReviews avoidance recommendation.
differential_diagnoses:
- name: Chronic Inflammatory Demyelinating Polyradiculoneuropathy
  description: >-
    CMT4C produces motor conduction block and temporal dispersion in half of
    patients, which is the electrophysiological signature usually taken to
    indicate an acquired inflammatory neuropathy. Two patients in the largest
    cohort were diagnosed with CIDP and given intravenous immunoglobulin before
    the genetic diagnosis was made; treatment was ineffective in both.
  evidence:
  - reference: PMID:40745932
    reference_title: "Nationwide Phenotypic and Genotypic Characterisation of 103 Patients With SH3TC2 Gene-Related Demyelinating Peripheral Neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Two patients were diagnosed with chronic inflammatory demyelinating
      polyneuropathy (CIDP) and were treated with intravenous immunoglobulins
      (IVIg) before being diagnosed with hereditary neuropathy.
    explanation: >-
      Documents the misdiagnosis actually occurring in this cohort.
- name: Friedreich Ataxia
  description: >-
    Both share polyneuropathy and scoliosis, and the CMT4C patient with
    cerebellar signs had carried an FRDA diagnosis. The authors distinguish them
    by the absence in CMT4C of cardiomyopathy, endocrine abnormality and dentate
    iron accumulation.
  evidence:
  - reference: PMID:31346473
    reference_title: The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    snippet: >-
      Some clinical features of FRDA and CMT4C overlap, with both conditions
      featuring polyneuropathy and scoliosis.
    explanation: >-
      States the overlap that creates the differential.
- name: Other CMT4 Subtypes
  description: >-
    CMT4A, 4B1, 4B2, 4D, 4F and 4J are also autosomal recessive demyelinating
    neuropathies and are curated as has_subtypes entries on Charcot-Marie-Tooth
    Disease Type 4. CMT4C is distinguished by the prominence of early scoliosis
    and by frequent cranial nerve involvement.
discussions:
- discussion_id: cmt4c_scoliosis_mechanism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Early-Onset Spinal Deformity
  prompt: >-
    Why is spinal deformity so much more prominent in CMT4C than in the other
    demyelinating neuropathies, and does it arise from paraspinal denervation
    alone?
  rationale: >-
    Scoliosis is the feature that most distinguishes CMT4C, present in 73-81% of
    patients and severe enough to require surgery in a third, and it can be the
    only clinical sign. The route from a length-dependent neuropathy to axial
    deformity is assumed to be weakness of trunk musculature during growth, but
    no study has measured paraspinal involvement in CMT4C, and the assumption
    does not explain why this subtype is affected so much more than others whose
    limb neuropathy is comparable or worse. The edge in this entry is therefore
    curated as a mechanism claim without direct supporting measurement.
- discussion_id: cmt4c_cranial_nerve_substrate
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Cranial Nerve Involvement
  prompt: >-
    Is the hearing loss in CMT4C due to demyelination of the eighth nerve, to
    cochlear pathology, or to both?
  rationale: >-
    Hearing loss affects over a third of patients and cranial nerve involvement
    nearly half, but no temporal bone or cochlear pathology from a CMT4C patient
    has been reported, and the published series record the deficit clinically
    without localizing it. Since SH3TC2 expression in peripheral nerve is
    restricted to Schwann cells, a myelin lesion of the eighth nerve is the
    natural hypothesis, but it has not been demonstrated.
- discussion_id: cmt4c_missense_mouse_gap
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - animal_models#Mouse
  prompt: >-
    Do the constitutive Sh3tc2 null mice model the missense alleles that make up
    a fifth of human CMT4C, in which a full-length protein is made but cannot
    bind Rab11?
  rationale: >-
    Both published mouse lines are nulls. Roughly 20% of human alleles are
    missense, and the cell-based work shows their defect is loss of Rab11 binding
    and consequent mistargeting rather than absence of protein — a mislocalized
    protein could in principle have effects a null does not. The clinical
    evidence is that missense and truncating alleles give the same disease, and
    the largest cohort found no severity difference between the one-truncating
    and zero-truncating groups, so the null is a reasonable proxy. But the
    proposition has been tested only in transfected cells, never in an animal
    carrying a knock-in missense allele, and gene-replacement results obtained in
    nulls are being read as evidence for a therapy that would be given to
    missense carriers too.
  proposed_experiments:
  - experiment_id: cmt4c_missense_knockin_mouse
    name: Knock-in mouse carrying a CMT4C missense allele
    description: >-
      Generate a mouse carrying a Rab11-binding-deficient Sh3tc2 missense allele
      equivalent to a human CMT4C variant, and compare its nerve phenotype and
      its response to SH3TC2 gene replacement with the null.
    would_support:
    - pathophysiology#Loss of the SH3TC2-Rab11 Interaction
    supporting_outcome:
    - >-
      A missense knock-in reproduces the null's hypomyelination and nodal
      disorganization and responds comparably to gene replacement, confirming
      that loss of Rab11 binding is the whole of the missense mechanism.
    would_refute:
    - pathophysiology#Loss of the SH3TC2-Rab11 Interaction
    refuting_outcome:
    - >-
      The missense knock-in shows a phenotype the null does not, or fails to
      respond to gene replacement, indicating the mislocalized protein does
      something beyond losing its Rab11 function.
notes: >-
  Entry type. This is curated as a standalone Disease rather than as a
  has_subtypes entry on Charcot-Marie-Tooth Disease Type 4, which already carries
  a CMT4C subtype block naming SH3TC2. The reason is that the umbrella binds the
  gene and the subtype label but curates no CMT4C-specific mechanism beyond a
  single node, while CMT4C has a distinct molecular pathway (Rab11 effector loss
  and recycling-endosome mistargeting), its own natural history cohorts, its own
  minimum prevalence, one mouse model (the two published Sh3tc2 lines are the
  same allele) and preclinical gene therapies. This follows the standalone CMT4
  subtype entries already curated for Charcot-Marie-Tooth Disease Types 4B3, 4D
  and 4K. The umbrella was not modified.

  Named entity confusion. SH3TC2 has one substantial off-target literature: it is
  reported as an oncogene in colorectal cancer (PMID:35954399, not cited here),
  and pan-cancer expression studies are the main non-neuropathy hits on the gene
  symbol. Every reference cited in this entry was checked to be about SH3TC2
  neuropathy specifically. Two further care points: PMID:40745932 is a nationwide
  SH3TC2 neuropathy cohort, not a general CMT cohort, so its percentages are
  CMT4C percentages; and PMID:31346473 is a five-patient single-centre cohort in
  which the cerebellar findings rest on one patient, which the phenotype entry
  states rather than implying a frequency.

  Frequency banding. All phenotype bands come from PMID:40745932 (n=103) unless
  stated. Where a second cohort disagrees — scoliosis at 73% versus 81% — both
  numbers are curated and the band follows the larger, more recent series, with
  the disagreement recorded in the phenotype description rather than averaged
  away. Sensory ataxia and the cerebellar phenotype carry no frequency at all
  because their sources give none.

  Prevalence. The only published figure is the Norwegian minimum prevalence of
  0.7/100,000, which is a floor derived from diagnostic registries. The Orphanet
  epidemiology class for this disorder has not yet been consulted, and this
  entry should gain it as a second prevalence record.

  Cerebellar findings and PDF extraction. PMID:31346473 is a PDF-derived cache
  whose body text carries extraction artifacts, including a mangled "CMTC4A" for
  CMT4C in the concluding sentence and several missing spaces around the gene
  symbol. The two snippets quoted here were taken from the clean abstract block
  and checked character by character; the damaged conclusion sentence is
  deliberately not quoted.

  Gene therapy caveat. Two Schwann-cell-targeted SH3TC2 replacement studies and
  one neurotrophin-3 surrogate study are curated, all preclinical. The NT-3
  authors argue directly that intrathecal Schwann-cell transduction may not
  translate from mouse to human because of the anatomy of the human sciatic
  nerve, and recommend non-human primate testing first. That caveat is stated in
  the NT-3 treatment description rather than left implicit, so the two
  approaches are not read as equally close to the clinic.

  Trials. One is curated, NCT01193075, because its registration record names
  CMT4C explicitly and it is the study behind PMID:36947133, the natural-history
  source used throughout this entry. NCT05902351, the Global Registry for
  Inherited Neuropathies natural history study, is deliberately not curated: its
  record is about Charcot-Marie-Tooth disease generally and does not mention
  CMT4C or SH3TC2 anywhere, so curating it would be relevance by adjacency --
  the same failure the named-entity note above guards against. Its status and
  phase would also have to be asserted from outside the cached record. There is
  no interventional trial in CMT4C; the gene therapies are preclinical.

  Not curated. No histopathology block: the only quantified pathology statement
  is the six-biopsy demyelination and onion-bulb finding, which is curated on the
  demyelination node where it does mechanistic work. No biochemical block: blood
  neurofilament light is reported as a treatment-response biomarker in the mouse
  gene-therapy study, not as a validated human CMT4C biomarker, so it is recorded
  in the model readout description rather than promoted to a biomarker claim. No
  datasets block: no CMT4C-specific accession was identified.
📚

References & Deep Research

References

1
PMID:20301514
SH3TC2-Related Hereditary Motor and Sensory Neuropathy.
No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (1)

Create: Charcot-Marie-Tooth Disease Type 4C (MONDO:0011113, SH3TC2) · 2026-09-01T17:24:55Z · View source

New standalone Disease entry for CMT4C, the most common recessive demyelinating CMT. Curated from primary literature (gene discovery PMID:14574644; SH3TC2-Rab11 recycling-endosome mechanism PMID:20028792 and PMID:20826437; NRG1/ErbB2 trafficking PMID:23553667; Sh3tc2 knockout mouse PMID:19805030; natural history PMID:36947133 and PMID:40745932; Norwegian minimum prevalence PMID:30001926; cerebellar phenotype PMID:31346473; gene-replacement and NT-3 preclinical therapy PMID:30907403, PMID:37641403, PMID:39544702) with a falcon deep-research report used as a lead source only. preflight-dr PASS (SH3TC2 51 mentions, next gene PMID-level noise). Entry-type decision recorded in notes: standalone rather than a has_subtypes entry on Charcot-Marie-Tooth Disease Type 4, following the merged Charcot-Marie-Tooth Disease Type 4K precedent; the umbrella was not modified and the open entry_type SUBTYPE policy question from PR #9696 is explicitly not treated as settled. All phenotype frequency bands derived from the 103-patient cohort; the scoliosis disagreement between cohorts (73 vs 81 percent) is curated rather than averaged. The two published mouse lines were found to be one line (JAX 033933) and merged into a single animal_models entry carrying both RECAPITULATES and RESCUES links. Validation: linkml-validate clean, 70/70 snippets verified, term validation clean, entity refs and duplicate keys clean.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 39 citations 2026-09-01T10:21:30.910801

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Charcot-Marie-Tooth disease type 4C (CMT4C, SH3TC2-related autosomal recessive demyelinating neuropathy)
  • MONDO ID: MONDO:0011113 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Charcot-Marie-Tooth disease type 4C (CMT4C, SH3TC2-related autosomal recessive demyelinating neuropathy) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

10. Diagnostics

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

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

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

11. Outcome/Prognosis

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

12. Treatment

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

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

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

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

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

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

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

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

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

    Search first: VBO (Vertebrate Breed Ontology)

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

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Charcot–Marie–Tooth disease type 4C (CMT4C): disease-characteristics research report

Scope and evidence standard

CMT4C is a rare Mendelian neuropathy, so most quantitative evidence comes from small cohorts, one international natural-history study, and animal or cell models rather than randomized trials. The strongest current clinical dataset is the 2023 Inherited Neuropathy Consortium study of 56 molecularly confirmed patients; the newest therapeutic evidence is preclinical AAV work published in 2023–2024. Database statements below are aggregated disease-level assertions; cohort statistics are patient-level observations aggregated by investigators. No individual EHR data were accessed.

Evidence/source and date Evidence type Sample/model Key quantitative finding Exact short abstract quote where actually available DOI/URL and PMID if known
Rehbein et al., Brain (Mar 2023) (rehbein2023neuropathydueto pages 1-2, rehbein2023neuropathydueto pages 9-10, rehbein2023neuropathydueto pages 2-3) Human cohort, longitudinal natural history 56 individuals from 52 families with biallelic SH3TC2 variants; 28 with longitudinal follow-up 59% female; median age 27 years (range 2–67); mean CMTES 13; scoliosis 81%; scoliosis surgery 36%; walking difficulty 94%; orthotic aids 59%; wheelchair dependence 21%; CMTES SRM 0.81 and CMTES-R 0.71 over 3 years “56 individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified”; “There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants.” DOI: 10.1093/brain/awad095; URL: https://doi.org/10.1093/brain/awad095; PMID: not retrieved
Ozes et al., Brain Communications (Nov 2024) (ozes2024aav1.tmck.nt3genetherapy pages 1-3) Mouse interventional study Sh3tc2−/− mouse; intramuscular scAAV1.tMCK.NT-3 at 4 weeks; assessed 6 months later Dose 1×10^11 vg; improved rotarod, grip strength, nerve conduction velocity; improved hypomyelination and NMJ denervation; increased myelinated axons in 3–6 µm range “NT-3 gene therapy improved functional and electrophysiological outcomes including rotarod, grip strength and nerve conduction velocity.” DOI: 10.1093/braincomms/fcae394; URL: https://doi.org/10.1093/braincomms/fcae394; PMID: not retrieved
Schiza et al., Brain (Mar 2019) (schiza2019genereplacementtherapy pages 1-2, schiza2019genereplacementtherapy pages 1-1) Mouse gene-replacement study plus human disease background Sh3tc2−/− mouse; lentiviral human SH3TC2 cDNA under Mpz promoter, intrathecal injection at 3 weeks 8 weeks post-injection: improved motor performance, increased motor NCV, improved g-ratios/myelin thickness, fewer demyelinated fibers, improved nodal architecture, reduced blood neurofilament light No abstract quote available in retrieved context DOI: 10.1093/brain/awz064; URL: https://doi.org/10.1093/brain/awz064; PMID: not retrieved
Piscosquito et al., J Peripher Nerv Syst (Sep 2016) (piscosquito2016screeningforsh3tc2 pages 3-4, piscosquito2016screeningforsh3tc2 pages 4-6) Human cohort, genotype-phenotype study 12 patients with SH3TC2 mutations from 43 screened recessive demyelinating CMT cases Foot deformities/walking difficulties 11/12; scoliosis 11/12 (92%), surgery 4/12; cranial nerve involvement 9/12; hearing loss 7/12; mean onset 7 years; mean duration 33 years; recurrent alleles p.R954 8/24 and p.R1109 6/24 No abstract quote available in retrieved context DOI: 10.1111/jns.12175; URL: https://doi.org/10.1111/jns.12175; PMID: not retrieved
Jerath et al., Muscle & Nerve (May 2018) (jerath2018charcot–marie–toothdiseasetype pages 1-3, jerath2018charcot–marie–toothdiseasetype pages 8-10) Human case series 5 CMT4C patients with biallelic/private SH3TC2 variants All 5 had scoliosis and demyelinating nerve conduction studies; childhood onset; cranial nerve deficits included oculomotor, facial, auditory, and hypoglossal involvement; 3 novel variants reported No abstract quote available in retrieved context DOI: 10.1002/mus.25981; URL: https://doi.org/10.1002/mus.25981; PMID: not retrieved
Open Targets Genetics/Platform (accessed via context) (OpenTargets Search: Charcot-Marie-Tooth disease type 4C-SH3TC2) Database / aggregated disease-target evidence MONDO_0011113 ↔ SH3TC2 Disease-target association score 0.8002627934413797; evidence count 5; linked literature includes PMID 14574644, 34193129, 19805030, 20301514 No abstract quote applicable URL: https://platform.opentargets.org; MONDO: MONDO_0011113; PMID: literature links include 14574644, 34193129, 19805030, 20301514
Duan et al., Frontiers in Neurology (Feb 2021) (piscosquito2016screeningforsh3tc2 pages 3-4, schiza2019genereplacementtherapy pages 1-2) Human cohort 465 unrelated Chinese CMT patients, 650 controls; 7 families with SH3TC2 variants 12 SH3TC2 variants identified (8 novel); CMT4C frequency 4.24% among demyelinating/intermediate CMT without PMP22 duplication; R954* present at low frequency in Chinese cohort “The CMT4C frequency was calculated to be 4.24% in demyelinating or intermediate CMT patients without PMP22 duplication.” DOI: 10.3389/fneur.2021.598168; URL: https://doi.org/10.3389/fneur.2021.598168; PMID: not retrieved
Cipriani et al., Int J Mol Sci (Dec 2018) (from retrieved paper context) Mouse mechanistic/proteomic study SH3TC2-deficient mouse NMJs in gastrocnemius; sciatic nerve proteomics Increased post-synaptic fragmentation/dispersal; increased AChR gamma subunit expression; altered extracellular matrix proteins; no change in axonal width or axonal inputs “Together these observations suggest that CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.” DOI: 10.3390/ijms19124072; URL: https://doi.org/10.3390/ijms19124072; PMID: not retrieved
Arnaud et al., PNAS (Oct 2009) (from retrieved paper context) Mouse mechanistic study Sh3tc2 mutant mouse peripheral nerve Demonstrated requirement for proper myelination and node of Ranvier integrity; model recapitulated neuropathy phenotypes No abstract quote available in retrieved context DOI: 10.1073/pnas.0905523106; URL: https://doi.org/10.1073/pnas.0905523106; PMID: not retrieved
Stendel et al., Brain (Aug 2010) (from retrieved paper context) In vitro + mouse mechanistic study Schwann-cell/endosomal recycling studies; Sh3tc2-deficient mouse Linked SH3TC2 to Rab11-positive recycling endosomes and peripheral nerve myelination; established Schwann-cell-specific expression No abstract quote available in retrieved context DOI: 10.1093/brain/awq168; URL: https://doi.org/10.1093/brain/awq168; PMID: not retrieved
Gouttenoire et al., Glia (Jul 2013) (from retrieved paper context) Mouse mechanistic study Sh3tc2-deficient mouse Schwann cells Showed altered neuregulin-1/ErbB signaling in deficiency state, supporting disturbed axon-Schwann signaling in hypomyelination No abstract quote available in retrieved context DOI: 10.1002/glia.22493; URL: https://doi.org/10.1002/glia.22493; PMID: not retrieved
Vijay et al., BBA Mol Basis Dis (Jul 2016) (from retrieved paper context) In vitro / expression-localization study Schwann-cell expression and trafficking analyses Established exclusive Schwann-cell expression and linked SH3TC2/Rab11 to integrin-α6 trafficking and myelin maintenance No abstract quote available in retrieved context DOI: 10.1016/j.bbadis.2016.04.003; URL: https://doi.org/10.1016/j.bbadis.2016.04.003; PMID: not retrieved

Table: This table summarizes the highest-yield evidence for SH3TC2-related Charcot-Marie-Tooth disease type 4C across human cohorts, mouse models, mechanistic studies, and database resources. It highlights quantitative findings, exact abstract quotations when actually available in retrieved context, and traceable source links for rapid knowledge-base curation.

1. Disease information

Definition

Charcot–Marie–Tooth disease type 4C is an autosomal-recessive, usually childhood-onset sensorimotor demyelinating polyneuropathy caused by biallelic pathogenic variants in SH3TC2. It is distinguished clinically by early or disproportionate scoliosis, distal weakness and wasting, foot deformity, sensory impairment, areflexia, very slow nerve conduction, and variably cranial-nerve involvement. Phenotypic severity ranges from relatively mild adult ambulatory disease to childhood-onset disability requiring spinal surgery, orthoses, or a wheelchair. The 2023 cohort aptly states: “CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable.” (rehbein2023neuropathydueto pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0011113.
  • OMIM phenotype: 601596, Charcot-Marie-Tooth disease, type 4C; SH3TC2 gene: OMIM 608206. These should be verified against the live OMIM record before automated ingestion because OMIM content is versioned.
  • Orphanet: commonly represented as ORPHA:99955; verify against the current Orphanet nomenclature release.
  • ICD-10-CM: no subtype-specific code; generally G60.0, hereditary motor and sensory neuropathy.
  • ICD-11: classify under hereditary motor and sensory neuropathy/Charcot–Marie–Tooth disease; a stable CMT4C-specific leaf code was not established in the retrieved evidence.
  • MeSH: Charcot-Marie-Tooth Disease; no separately validated CMT4C MeSH descriptor was retrieved.
  • Synonyms: CMT4C; SH3TC2-related neuropathy; SH3TC2-related autosomal-recessive demyelinating neuropathy; autosomal-recessive Charcot–Marie–Tooth disease type 4C; hereditary motor and sensory neuropathy type 4C; formerly KIAA1985-related neuropathy.

Open Targets maps MONDO_0011113 specifically to SH3TC2/ENSG00000169247, with five evidence records and an association score of 0.8003; linked literature includes PMIDs 14574644, 19805030, 20301514, and 34193129. This is an aggregated disease–target resource, not a prevalence estimate. (OpenTargets Search: Charcot-Marie-Tooth disease type 4C-SH3TC2)

2. Etiology, risk, and protective factors

Primary cause

The necessary initiating lesion is usually biallelic germline loss of SH3TC2 function, either homozygous or compound heterozygous. Pathogenic classes include nonsense, frameshift, canonical splice-site, and functionally damaging missense variants. Premature truncation generally abolishes functional protein; missense alleles may mislocalize SH3TC2 or disrupt protein interactions/endosomal architecture. Examples include recurrent p.Arg954Ter (R954*), p.Arg1109Ter (R1109*), p.Tyr680Cys, p.Asn881Ser, and splice variants. (schiza2019genereplacementtherapy pages 2-2, jerath2018charcot–marie–toothdiseasetype pages 8-10, piscosquito2016screeningforsh3tc2 pages 3-4)

Genetic risk and modifiers

  • A child of two heterozygous carriers has a 25% recurrence risk, 50% carrier probability, and 25% probability of inheriting neither familial allele per pregnancy.
  • Consanguinity, endogamy, and founder alleles increase the probability of biallelic inheritance. R1109* is a recognized Roma/Gypsy founder allele; R954* is recurrent in European populations and also occurs in Asia. In an Italian series, R954* accounted for 8/24 and R1109* for 6/24 disease alleles. (piscosquito2016screeningforsh3tc2 pages 3-4, piscosquito2016screeningforsh3tc2 pages 4-6)
  • Protein-truncating versus non-truncating genotype did not significantly separate mean clinical examination scores in the 2023 cohort. However, ulnar CMAP, radial SNAP, and scoliosis prevalence differed, suggesting—but not proving—a milder phenotype when at least one non-truncating allele remains. (rehbein2023neuropathydueto pages 1-2)
  • Marked intrafamilial variability implies additional genetic, epigenetic, stochastic, or environmental modifiers, but no reproducible human modifier gene is clinically validated. (jerath2018charcot–marie–toothdiseasetype pages 1-3, jerath2018charcot–marie–toothdiseasetype pages 8-10)

Environmental, lifestyle, infectious, and protective factors

No toxin, infection, diet, smoking pattern, occupation, radiation exposure, or lifestyle is known to cause CMT4C. No validated protective allele or environmental factor prevents penetrance after biallelic pathogenic variants. General measures—safe aerobic activity, preservation of joint range, fall prevention, weight management, and avoidance of neurotoxic exposure—may reduce secondary disability but are tertiary management, not disease prevention. Gene–environment interaction is plausible for functional reserve and acquired neuropathic insults, but CMT4C-specific quantitative evidence is lacking.

3. Phenotypes

The best contemporary estimates are from 56 patients (median age 27, range 2–67; 59% female). Mean CMT Examination Score was 13, indicating moderate severity; 94% had walking difficulty, 59% used orthotic aids, and 21% were wheelchair-dependent. Scoliosis affected 81%, 36% had spinal surgery, and hearing loss affected 36%. (rehbein2023neuropathydueto pages 1-2, rehbein2023neuropathydueto pages 2-3)

Phenotype Characteristics/frequency Suggested HPO term
Distal lower-limb weakness and wasting Usually childhood onset; progressive; often precedes hand involvement; major determinant of gait impairment Distal muscle weakness HP:0002460; muscular atrophy HP:0003202
Walking difficulty/delayed walking 94% in the 2023 cohort; orthoses 59%, wheelchair 21%; chronic progression Abnormal gait HP:0001288; delayed walking HP:0002060
Sensory loss, sensory ataxia, impaired proprioception Length-dependent; sensory nerves may be more affected than motor nerves; four of 12 Italian patients lost independent ambulation mainly because of sensory ataxia Peripheral sensory neuropathy HP:0007067; sensory ataxia HP:0002066
Areflexia/hyporeflexia Common, progressive peripheral neuropathy sign Areflexia HP:0001284
Pes cavus/other foot deformity 11/12 had foot deformity or walking difficulty in one series; develops through childhood/adolescence and may require surgery Pes cavus HP:0001761; foot deformity HP:0001760
Scoliosis/kyphoscoliosis Hallmark but not obligatory; 81% in the largest cohort, 92% in a 12-patient Italian series; often begins in the first two decades; surgery 36% in the 2023 cohort Scoliosis HP:0002650; kyphoscoliosis HP:0002751
Demyelinating neuropathy Motor conduction velocity commonly <38 m/s; historical mean approximately 22.6 m/s; secondary axonal loss increases with duration Demyelinating peripheral neuropathy HP:0007108
Hearing impairment 36% in the largest cohort; 7/12 in an Italian series Sensorineural hearing impairment HP:0000407
Cranial neuropathy 9/12 in one series; reported oculomotor, facial, auditory and hypoglossal deficits, slow pupils and tongue fasciculation Cranial nerve abnormality HP:0001291; facial weakness HP:0007209
Vestibular dysfunction/imbalance Variable; may compound proprioceptive loss and cause severe imbalance Bilateral vestibular areflexia HP:0012105
Rare cerebellar-appearing phenotype Nystagmus, dysarthria/dysmetria and cerebellar atrophy are exceptional; consider alternative or dual diagnoses Cerebellar atrophy HP:0001272; nystagmus HP:0000639

In the 12-patient Italian series, mean onset was seven years, all began before 15, 11/12 had scoliosis, 9/12 cranial involvement, 7/12 hearing loss, and four lost independent walking. Sural biopsy showed myelinated-fiber loss, thin myelin, onion bulbs and de-/remyelination. (piscosquito2016screeningforsh3tc2 pages 3-4, piscosquito2016screeningforsh3tc2 pages 4-6)

Quality of life: no CMT4C-specific EQ-5D or SF-36 population norm was retrieved. Nevertheless, walking difficulty, orthotic dependence, wheelchair use, sensory ataxia, hearing impairment, and repeated orthopedic surgery indicate substantial effects on mobility, education/work, self-care, participation and fatigue. CMTES/CMTNS and CMTPedS are clinician-rated disease measures, not full health-related-QOL instruments. (rehbein2023neuropathydueto pages 2-3, rehbein2023neuropathydueto pages 1-2)

4. Genetic and molecular information

Gene and protein

  • Gene: SH3TC2, SH3 domain and tetratricopeptide repeats 2; chromosome 5q32; Ensembl ENSG00000169247.
  • Protein: approximately 1,288 amino acids, containing SH3 and tetratricopeptide-repeat domains; functions as a Rab11-associated trafficking protein in myelinating Schwann cells. (schiza2019genereplacementtherapy pages 2-2)
  • Suggested annotations: HGNC:29427 should be checked against the current HGNC release; UniProt and transcript accession should be locked to the laboratory’s reporting transcript before variant ingestion.

Variant interpretation

Pathogenic/likely pathogenic variants should satisfy ACMG/AMP criteria in the context of a recessive phenotype, including rarity in population databases, trans configuration, predicted loss of function where applicable, segregation, and phenotype specificity. A single heterozygous pathogenic variant is insufficient for molecular confirmation; search for a second SNV/indel, exon-level deletion/duplication, deep-intronic variant, or other structural lesion. Germline origin is expected; somatic SH3TC2 mutation is not the disease mechanism.

The 2023 cohort contained 34 unique variants, 14 previously unpublished, illustrating extensive allelic heterogeneity. In a Chinese study, 12 variants in seven families included eight novel variants; seven were considered likely pathogenic and one, p.Ser221Pro, remained a VUS. The CMT4C frequency was 4.24% among demyelinating/intermediate CMT cases lacking PMP22 duplication. (rehbein2023neuropathydueto pages 1-2, piscosquito2016screeningforsh3tc2 pages 3-4)

Population allele frequencies must be retrieved per exact HGVS allele and ancestry from the current gnomAD release; no universal frequency applies. Disease-causing alleles are individually rare, although founder variants can be locally enriched. No consistent epigenetic signature or disease-causing aneuploidy, translocation, or inversion is established. Exonic or larger SH3TC2 copy-number loss remains technically possible and should be assessed when sequencing finds only one allele.

5. Environmental information

CMT4C is not infectious, transmissible, occupational, nutritional, or toxic in origin. Environmental factors primarily influence complications: inactivity and contracture can worsen mobility; poorly fitted footwear can promote pressure injury in an insensate foot; neurotoxic chemotherapy or other acquired neuropathy may reduce residual nerve function. Evidence for CMT4C-specific smoking, alcohol, diet, pollution, microbiome, or infectious interactions is absent.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic pathogenic SH3TC2 variants lead to absent, reduced, mislocalized, or dysfunctional SH3TC2 in myelinating Schwann cells.
  2. SH3TC2 dysfunction leads to impaired Rab11-positive recycling-endosome trafficking and altered delivery/recycling of Schwann-cell surface cargo; integrin-α6 trafficking is implicated, and some receptor-level details remain inferred from cell and mouse studies. (schiza2019genereplacementtherapy pages 2-2, jerath2018charcot–marie–toothdiseasetype pages 8-10)
  3. Abnormal membrane trafficking leads to dysregulated axon–Schwann-cell signaling, including altered neuregulin-1/ERBB2 signaling and impaired sensing of axonal caliber. (schiza2019genereplacementtherapy pages 2-2)
  4. Defective signaling and membrane organization lead to inadequate myelin maintenance/hypomyelination, segmental de-/remyelination, and disrupted node-of-Ranvier architecture. (schiza2019genereplacementtherapy pages 1-2, rehbein2023neuropathydueto pages 9-10)
  5. Chronic demyelination leads to markedly slowed conduction and conduction failure; over time it also results in secondary axonal degeneration and reduced CMAP/SNAP amplitudes. (schiza2019genereplacementtherapy pages 1-2, piscosquito2016screeningforsh3tc2 pages 4-6)
  6. Motor and sensory axon dysfunction leads to distal weakness, wasting, areflexia, sensory loss, proprioceptive ataxia and gait impairment.
  7. Chronic neuromuscular imbalance during growth leads to pes cavus, contractures and scoliosis; the precise link from peripheral neuropathy to severe spinal deformity is clinically strong but mechanistically incompletely resolved.
  8. Branch: involvement of auditory, vestibular or other cranial nerves results in hearing loss, imbalance and occasional facial/ocular/bulbar signs.
  9. Branch demonstrated in mice: altered extracellular-matrix/NMJ organization leads to postsynaptic fragmentation and denervation-like NMJ abnormalities, potentially adding to weakness; its quantitative contribution in humans remains unproven.

Cellular and molecular detail

SH3TC2 is concentrated at the plasma membrane and perinuclear recycling compartment and associates with Rab11. Missense alleles can impair recycling-endosome condensation or protein interactions even when targeting appears preserved. SH3TC2 deficiency perturbs NRG1/ERBB signaling, providing a mechanistic connection between axonal caliber cues and Schwann-cell myelin thickness. (schiza2019genereplacementtherapy pages 1-1, schiza2019genereplacementtherapy pages 2-2, jerath2018charcot–marie–toothdiseasetype pages 8-10)

Nerve pathology includes hypomyelination, thinly myelinated fibers, segmental de-/remyelination, myelinated-fiber loss, onion bulbs, excessive basement membrane and unusual Schwann-cell cytoplasmic extensions. Sh3tc2-null nerves exhibit disrupted nodes/paranodes. (schiza2019genereplacementtherapy pages 1-2, piscosquito2016screeningforsh3tc2 pages 4-6)

Suggested ontology annotations:

  • Processes: endosomal recycling (GO:0032456); receptor recycling (GO:0001881); peripheral nervous system myelination (GO:0022011); axon ensheathment (GO:0008366); regulation of myelination; node-of-Ranvier organization; Schwann-cell differentiation; neuromuscular-junction organization.
  • Cell types: myelinating Schwann cell (CL:0002573, verify release), peripheral sensory neuron, spinal motor neuron, skeletal-muscle fiber.
  • Compartments: recycling endosome (GO:0055037); endosome; trans-Golgi network; plasma membrane; myelin sheath (GO:0043209); node of Ranvier (GO:0033268); neuromuscular junction.

No validated CMT4C-specific human metabolomic, lipidomic, methylomic, single-cell, spatial-transcriptomic, or multi-omic diagnostic signature was retrieved. Sciatic-nerve proteomics in knockout mice identified altered extracellular-matrix proteins associated with NMJ integrity, but this is exploratory model evidence.

7. Anatomical structures affected

The primary system is the peripheral nervous system, especially long motor and sensory nerves of the distal limbs. Myelinating Schwann cells are the initiating cellular compartment; axons are secondarily injured. Roots and cranial nerves may also be involved. Skeletal muscle undergoes neurogenic denervation and atrophy, while feet and spine develop secondary orthopedic deformity. Laterality is generally bilateral and length-dependent, although severity can be asymmetric.

Suggested anatomical terms include peripheral nerve (UBERON:0001021), sciatic nerve (UBERON:0001322), spinal nerve root, sural nerve, skeletal muscle (UBERON:0001134), foot (UBERON:0002387), and vertebral column (UBERON:0001130). Subcellular loci are Rab11-positive recycling endosomes, Schwann-cell plasma membrane, compact/noncompact myelin, and nodal/paranodal regions.

8. Temporal development

Onset is usually insidious in the first decade, sometimes first recognized through delayed walking, foot deformity, gait difficulty, or scoliosis. Later onset occurs and absence of scoliosis or cranial involvement does not exclude SH3TC2 disease. Progression is chronic, lifelong, and generally slow but variable. (schiza2019genereplacementtherapy pages 1-2, piscosquito2016screeningforsh3tc2 pages 3-4)

In the prospective cohort, significant worsening in CMTES and CMTES-R became detectable from three years and continued through six years; three-year standardized response means were 0.81 and 0.71, respectively. These data support multi-year trials or more sensitive biomarkers. (rehbein2023neuropathydueto pages 1-2, rehbein2023neuropathydueto pages 9-10)

Practical stages are not formally standardized: (1) childhood gait/spinal onset; (2) progressive distal weakness, sensory loss and deformity; (3) orthotic or surgical dependence; and (4) advanced ambulatory limitation or wheelchair use. There is no spontaneous remission. Childhood growth is likely a critical window for preventing fixed scoliosis and contracture, while preclinical gene-replacement results suggest early treatment may preserve myelin and axons; neither proposition has yet been tested in a human CMT4C intervention trial.

9. Inheritance and population

Inheritance is autosomal recessive with variable expressivity. Penetrance for convincingly pathogenic biallelic genotypes appears high, but age dependence and mild adult presentations prevent a defensible universal percentage. Anticipation is not expected; repeat expansion is not the mechanism. Germline mosaicism is theoretically possible but not a recognized common contributor.

No reliable population-wide incidence or prevalence estimate for CMT4C was found. It represents approximately 18% of autosomal-recessive CMT in some clinical series and nearly half of molecularly defined CMT4 in selected cohorts, but referral, ethnicity and consanguinity strongly bias these figures. Overall CMT prevalence—often quoted near 1:2,500—must not be assigned to CMT4C. (schiza2019genereplacementtherapy pages 1-2, jerath2018charcot–marie–toothdiseasetype pages 1-3)

Regional enrichment occurs around the Mediterranean and in founder populations. In the Chinese cohort, CMT4C comprised 4.24% of demyelinating/intermediate CMT after excluding PMP22 duplication. The 2023 international cohort’s 59% female proportion is compatible with no sex-linked risk; there is no established biological sex bias. (rehbein2023neuropathydueto pages 1-2, piscosquito2016screeningforsh3tc2 pages 3-4)

Carrier frequency is ancestry- and allele-specific and should be calculated from current gnomAD data rather than inferred from patient cohorts.

10. Diagnostics

Clinical and physiological diagnosis

Suspect CMT4C in childhood or adult patients with a chronic length-dependent sensorimotor neuropathy, especially when scoliosis is early/severe, inheritance appears recessive, or hearing/cranial involvement accompanies foot deformity. Examination should document strength, wasting, reflexes, sensation, balance, feet and spine; CMTES/CMTNS or CMTPedS facilitates longitudinal measurement.

Nerve-conduction studies usually demonstrate a diffuse demyelinating or occasionally intermediate sensorimotor neuropathy, commonly with upper-limb motor conduction velocity below 38 m/s and secondary amplitude loss. One review of CMT4C data reported mean MNCV around 22.6 m/s. EMG can demonstrate chronic neurogenic change. (schiza2019genereplacementtherapy pages 1-2, piscosquito2016screeningforsh3tc2 pages 3-4)

Standing spinal radiographs quantify scoliosis; foot radiography is used for surgical planning. Audiology is indicated if symptoms or cranial involvement are present. Pulmonary function or sleep evaluation is symptom-driven or appropriate with severe scoliosis/bulbar signs, although CMT4C-specific surveillance intervals are not evidence-based. MRI is not diagnostic but can investigate atypical central signs or alternative diagnoses. Nerve ultrasound was reported as supportive in a 2024 case, but it is not molecular confirmation.

Nerve biopsy is usually unnecessary after genetic confirmation. If performed in an unresolved case, it may show marked fiber loss, thin myelin, onion bulbs, de-/remyelination, basement-membrane proliferation and Schwann-cell extensions. (piscosquito2016screeningforsh3tc2 pages 4-6, schiza2019genereplacementtherapy pages 1-2)

Genetic workflow

  1. Exclude the common PMP22 duplication where phenotype and ancestry justify it.
  2. Use a comprehensive inherited-neuropathy panel including SH3TC2, with SNV/indel and exon-level CNV detection.
  3. Use exome or genome sequencing for atypical or panel-negative disease; genome sequencing offers better structural and noncoding coverage.
  4. Confirm candidate variants by an orthogonal method where required, phase the two alleles in relatives, apply ACMG/AMP criteria, and test segregation.
  5. If only one SH3TC2 pathogenic allele is found, pursue CNV, coverage-gap, deep-intronic/structural, and alternative-gene analysis rather than diagnosing recessive CMT4C.

The 2023 cohort accepted diagnoses established by single-gene testing, panels or exome sequencing. A prior Italian workflow combined exclusion of PMP22 duplication/GJB1/MPZ with 54–94-gene NGS panels and Sanger confirmation. (rehbein2023neuropathydueto pages 2-3, piscosquito2016screeningforsh3tc2 pages 3-4)

CMA, karyotyping, FISH, mitochondrial testing and repeat-expansion testing are not first-line tests for isolated classic CMT4C, but may be appropriate for a syndromic or unresolved phenotype. RNA sequencing may resolve splice variants in research or specialized diagnostics; no routine proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic exists.

Differential diagnosis

Important alternatives include PMP22-related CMT1A, MPZ/GJB1 demyelinating CMT, other recessive CMT4 genes, hereditary sensory neuropathy, Friedreich ataxia, hereditary spastic paraplegia, distal spinal muscular atrophy, and acquired CIDP. Early uniform slowing, long-standing deformity, recessive pedigree and biallelic SH3TC2 variants favor CMT4C; subacute progression, conduction block, proximal weakness, elevated CSF protein and treatment response favor CIDP. Rare cerebellar-appearing CMT4C can mimic Friedreich ataxia; absent cardiomyopathy/endocrine abnormalities and lack of dentate iron accumulation were distinguishing findings in one small cohort.

11. Outcome and prognosis

CMT4C is generally not considered a primary life-shortening disorder, but robust survival and disease-specific mortality rates do not exist. Most morbidity is chronic motor/sensory disability and orthopedic disease. Many patients remain ambulant into middle age, while a minority lose independent ambulation earlier, particularly with severe sensory ataxia, deformity or axonal loss. In the largest cohort, 21% used wheelchairs and 36% had scoliosis surgery. (piscosquito2016screeningforsh3tc2 pages 4-6, rehbein2023neuropathydueto pages 2-3)

Potential complications include falls, fractures, pressure lesions, fixed foot/ankle contracture, severe scoliosis, chronic pain, hearing impairment, and reduced independence. Recovery of established axonal loss is limited; rehabilitation and surgery can improve function or alignment but do not correct SH3TC2 deficiency. Candidate prognostic factors include baseline axonal amplitudes, age/duration, scoliosis, ambulatory status, and possibly truncating genotype, but none is a validated individual prognostic calculator. Blood neurofilament light responded to therapy in mice, not yet as a validated human CMT4C prognostic biomarker. (schiza2019genereplacementtherapy pages 1-1)

12. Treatment and current applications

Current standard care

There is no approved disease-modifying pharmacotherapy specifically for CMT4C. Real-world care is multidisciplinary and individualized:

  • Physical therapy: low-to-moderate intensity aerobic and strengthening exercise, balance work, stretching, preservation of ankle range, fall prevention and fatigue-aware pacing.
  • Occupational therapy: hand function, energy conservation, adaptive equipment, school/work accommodations.
  • Orthoses: ankle-foot orthoses, insoles, supportive footwear, walking aids and wheelchairs as needed; 59% used orthotic aids in the 2023 cohort. (rehbein2023neuropathydueto pages 2-3)
  • Orthopedic treatment: serial monitoring during growth; tendon/soft-tissue or bony foot reconstruction for painful rigid deformity; scoliosis bracing or spinal fusion according to curve progression, skeletal maturity, function and respiratory considerations. CMT4C-specific surgical comparative trials are absent.
  • Symptom management: neuropathic/nociceptive pain treatment, podiatry and skin protection, audiology/hearing aids, and respiratory assessment when clinically indicated.
  • Medication review: minimize avoidable peripheral-neurotoxic agents when alternatives exist; decisions about essential chemotherapy require individualized risk–benefit assessment.

Suggested NCIt intervention concepts include Physical Therapy (C15300), Occupational Therapy, Orthotic Device, Hearing Aid, Spinal Fusion, Scoliosis Surgery, Genetic Counseling, and Gene Therapy; codes other than the explicitly given physical-therapy code should be validated against the current NCIt release.

Experimental and recent therapeutic developments

Schwann-cell SH3TC2 replacement: intrathecal lentiviral expression of human SH3TC2 under an Mpz promoter in three-week-old Sh3tc2-null mice improved motor behavior, motor conduction velocity, myelin thickness/g-ratio, demyelinated-fiber burden and nodal architecture, and reduced blood neurofilament light. This is proof-of-concept mouse evidence, not a human treatment. (schiza2019genereplacementtherapy pages 1-1)

A 2023 AAV9 Schwann-cell-targeted SH3TC2 replacement study further advanced vector delivery (Georgiou et al., Molecular Therapy, November 2023, DOI 10.1016/j.ymthe.2023.08.020); it remains preclinical.

NT-3 gene therapy: in 2024, 4-week-old Sh3tc2-null mice received intramuscular scAAV1.tMCK.NT-3 (1×10¹¹ vg). At six months, treatment improved rotarod, grip strength, conduction velocity, hypomyelination and NMJ denervation and increased 3–6-µm myelinated axons. The abstract states: “NT-3 gene therapy improved functional and electrophysiological outcomes including rotarod, grip strength and nerve conduction velocity.” This is a trophic, genotype-nonspecific strategy and does not replace SH3TC2. (ozes2024aav1.tmck.nt3genetherapy pages 1-3)

No CMT4C-specific human response rate, adverse-event profile, pharmacogenomic guideline, CRISPR therapy, ASO, cell therapy, or approved targeted drug is available.

Trials and readiness

NCT01193075, Natural History Evaluation of CMT types including CMT4C, is a recruiting observational study led by the University of Iowa with planned enrollment up to 5,000; the 2023 CMT4C analysis drew from this network. NCT05902351 is a broader recruiting observational natural-history study planned for up to 10,000 participants. Neither is a CMT4C therapeutic trial. The 2023 longitudinal data support CMTES/CMTES-R as multi-year outcomes, but also show the need for more responsive biomarkers. (rehbein2023neuropathydueto pages 9-10, rehbein2023neuropathydueto pages 2-3)

13. Prevention

Primary lifestyle prevention is not possible because the cause is inherited. Primary genetic prevention options, after counseling, include carrier testing of partners/relatives, preimplantation genetic testing for monogenic disease, prenatal diagnosis by chorionic-villus sampling or amniocentesis, and donor gametes. Decisions must remain nondirective.

Secondary prevention consists of cascade testing in relatives and early assessment of genetically affected children—not general-population or newborn screening. Early identification permits surveillance of gait, feet, spine and hearing before fixed complications. Tertiary prevention includes stretching, orthoses, fall and pressure-injury prevention, scoliosis monitoring, hearing support and timely orthopedic intervention. Vaccines and anti-infective prophylaxis have no CMT4C-specific role.

14. Other species and natural disease

No well-established naturally occurring SH3TC2-equivalent CMT4C syndrome in companion animals or wildlife was identified in the retrieved literature. There is no zoonotic or cross-species transmission. Orthologues are conserved across vertebrates, supporting experimental modeling, but orthologue IDs should be pulled directly from NCBI Gene/Alliance releases during database ingestion. Relevant taxa include Homo sapiens (NCBI Taxon 9606) and Mus musculus (10090).

15. Model organisms

Mouse models

The principal model is the Sh3tc2−/− mouse, including exon-1 knockout and spontaneous loss-of-function lines. It recapitulates early progressive peripheral neuropathy, slowed conduction, hypomyelination/demyelination and nodal abnormalities, establishing Schwann-cell SH3TC2 as necessary for myelin maintenance and node integrity. (schiza2019genereplacementtherapy pages 1-2, rehbein2023neuropathydueto pages 9-10)

A detailed NMJ study found postsynaptic fragmentation/dispersal, increased fetal acetylcholine-receptor γ-subunit expression and altered sciatic-nerve extracellular-matrix proteins without altered axonal width or input number. Its conclusion was that “CMT4C pathology includes a compromised NMJ even in the absence of changes to the innervating axon.”

Applications include mechanism discovery, vector biodistribution, myelin/nodal outcome testing, electrophysiology, neurofilament biomarker development and therapeutic proof-of-concept. Limitations include species-specific nerve length and biomechanics, compressed disease timescale, incomplete capture of human scoliosis/cranial phenotypes, and uncertain translation of intrathecal or intramuscular vector dose and immunity.

Cellular models

Transfected cells and Schwann-cell systems have been used to study plasma-membrane/recycling-endosome localization, Rab11 association and mutant behavior. Human iPSC-derived Schwann cells are conceptually attractive for patient-specific trafficking and therapeutic studies, but no mature CMT4C organoid or validated high-throughput human cellular platform was established in the retrieved evidence.

Key interpretation and knowledge gaps

Authoritative clinical opinion is converging on three points. First, scoliosis is a powerful clue but not a requirement; absence of scoliosis, cranial disease or early onset must not preclude SH3TC2 testing. Second, broad sequencing with rigorous biallelic interpretation is superior to phenotype-only diagnosis because both private variants and dual diagnoses occur. Third, CMT4C is biologically attractive for gene replacement because it is recessive and Schwann-cell restricted, but delivery to the extensive human peripheral nervous system, durability, dose, immunity and treatment timing remain major translational barriers. (rehbein2023neuropathydueto pages 1-2, jerath2018charcot–marie–toothdiseasetype pages 1-3, jerath2018charcot–marie–toothdiseasetype pages 8-10)

Priority gaps are population prevalence/incidence, ancestry-specific carrier frequencies, validated modifiers, patient-reported QOL, respiratory natural history, pediatric progression biomarkers, human biofluid biomarkers, and interventional safety/efficacy data. Claims concerning epigenomics, metabolomics, protective factors, natural animal disease, or treatment response should therefore be represented as not established, not as negative biological findings.

Selected source links and publication dates

  1. Rehbein et al. “Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history.” Brain. March 2023. DOI 10.1093/brain/awad095. (rehbein2023neuropathydueto pages 1-2)
  2. Ozes et al. “AAV1.tMCK.NT-3 gene therapy improves phenotype in Sh3tc2−/− mouse model of CMT4C.” Brain Communications. November 2024. DOI 10.1093/braincomms/fcae394. (ozes2024aav1.tmck.nt3genetherapy pages 1-3)
  3. Schiza et al. “Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy.” Brain. March 2019. DOI 10.1093/brain/awz064. (schiza2019genereplacementtherapy pages 1-1)
  4. Jerath et al. “Charcot–Marie–Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges.” Muscle & Nerve. May 2018. DOI 10.1002/mus.25981. (jerath2018charcot–marie–toothdiseasetype pages 1-3)
  5. Piscosquito et al. “Screening for SH3TC2 gene mutations in demyelinating recessive CMT.” Journal of the Peripheral Nervous System. September 2016. DOI 10.1111/jns.12175. (piscosquito2016screeningforsh3tc2 pages 3-4)
  6. Open Targets disease–target record; literature-linked PMIDs include 14574644, 19805030, 20301514 and 34193129. Open Targets Platform. (OpenTargets Search: Charcot-Marie-Tooth disease type 4C-SH3TC2)

Curation caution: PMID values are supplied only where recovered from the authoritative linked database. DOI links are provided for the remaining primary studies rather than inferring unverified PMID numbers.

References

  1. (rehbein2023neuropathydueto pages 1-2): Tyler Rehbein, Tong Tong Wu, Simona Treidler, Davide Pareyson, Richard Lewis, Sabrina W Yum, Brett A McCray, Sindhu Ramchandren, Joshua Burns, Jun Li, Richard S Finkel, Steven S Scherer, Stephan Zuchner, Michael E Shy, Mary M Reilly, and David N Herrmann. Neuropathy due to bi-allelic sh3tc2 variants: genotype-phenotype correlation and natural history. Brain : a journal of neurology, 146:3826-3835, Mar 2023. URL: https://doi.org/10.1093/brain/awad095, doi:10.1093/brain/awad095. This article has 28 citations.

  2. (rehbein2023neuropathydueto pages 9-10): Tyler Rehbein, Tong Tong Wu, Simona Treidler, Davide Pareyson, Richard Lewis, Sabrina W Yum, Brett A McCray, Sindhu Ramchandren, Joshua Burns, Jun Li, Richard S Finkel, Steven S Scherer, Stephan Zuchner, Michael E Shy, Mary M Reilly, and David N Herrmann. Neuropathy due to bi-allelic sh3tc2 variants: genotype-phenotype correlation and natural history. Brain : a journal of neurology, 146:3826-3835, Mar 2023. URL: https://doi.org/10.1093/brain/awad095, doi:10.1093/brain/awad095. This article has 28 citations.

  3. (rehbein2023neuropathydueto pages 2-3): Tyler Rehbein, Tong Tong Wu, Simona Treidler, Davide Pareyson, Richard Lewis, Sabrina W Yum, Brett A McCray, Sindhu Ramchandren, Joshua Burns, Jun Li, Richard S Finkel, Steven S Scherer, Stephan Zuchner, Michael E Shy, Mary M Reilly, and David N Herrmann. Neuropathy due to bi-allelic sh3tc2 variants: genotype-phenotype correlation and natural history. Brain : a journal of neurology, 146:3826-3835, Mar 2023. URL: https://doi.org/10.1093/brain/awad095, doi:10.1093/brain/awad095. This article has 28 citations.

  4. (ozes2024aav1.tmck.nt3genetherapy pages 1-3): Burcak Ozes, Lingying Tong, Kyle Moss, Morgan Myers, Lilye Morrison, Zayed Attia, and Zarife Sahenk. Aav1.tmck.nt-3 gene therapy improves phenotype in sh3tc2−/− mouse model of charcot–marie–tooth type 4c. Brain Communications, Nov 2024. URL: https://doi.org/10.1093/braincomms/fcae394, doi:10.1093/braincomms/fcae394. This article has 6 citations and is from a peer-reviewed journal.

  5. (schiza2019genereplacementtherapy pages 1-2): Natasa Schiza, Elena Georgiou, Alexia Kagiava, Jean-Jacques Médard, Jan Richter, Christina Tryfonos, Irene Sargiannidou, Amanda J Heslegrave, Alexander M Rossor, Henrik Zetterberg, Mary M Reilly, Christina Christodoulou, Roman Chrast, and Kleopas A Kleopa. Gene replacement therapy in a model of charcot-marie-tooth 4c neuropathy. Brain, 142(5):1227-1241, Mar 2019. URL: https://doi.org/10.1093/brain/awz064, doi:10.1093/brain/awz064. This article has 60 citations and is from a highest quality peer-reviewed journal.

  6. (schiza2019genereplacementtherapy pages 1-1): Natasa Schiza, Elena Georgiou, Alexia Kagiava, Jean-Jacques Médard, Jan Richter, Christina Tryfonos, Irene Sargiannidou, Amanda J Heslegrave, Alexander M Rossor, Henrik Zetterberg, Mary M Reilly, Christina Christodoulou, Roman Chrast, and Kleopas A Kleopa. Gene replacement therapy in a model of charcot-marie-tooth 4c neuropathy. Brain, 142(5):1227-1241, Mar 2019. URL: https://doi.org/10.1093/brain/awz064, doi:10.1093/brain/awz064. This article has 60 citations and is from a highest quality peer-reviewed journal.

  7. (piscosquito2016screeningforsh3tc2 pages 3-4): Giuseppe Piscosquito, Paola Saveri, Stefania Magri, Claudia Ciano, Claudia Gandioli, Michela Morbin, Daniela D. Bella, Isabella Moroni, Franco Taroni, and Davide Pareyson. Screening for sh3tc2 gene mutations in a series of demyelinating recessive charcot‐marie‐tooth disease (cmt4). Journal of the Peripheral Nervous System, 21:142-149, Sep 2016. URL: https://doi.org/10.1111/jns.12175, doi:10.1111/jns.12175. This article has 57 citations and is from a peer-reviewed journal.

  8. (piscosquito2016screeningforsh3tc2 pages 4-6): Giuseppe Piscosquito, Paola Saveri, Stefania Magri, Claudia Ciano, Claudia Gandioli, Michela Morbin, Daniela D. Bella, Isabella Moroni, Franco Taroni, and Davide Pareyson. Screening for sh3tc2 gene mutations in a series of demyelinating recessive charcot‐marie‐tooth disease (cmt4). Journal of the Peripheral Nervous System, 21:142-149, Sep 2016. URL: https://doi.org/10.1111/jns.12175, doi:10.1111/jns.12175. This article has 57 citations and is from a peer-reviewed journal.

  9. (jerath2018charcot–marie–toothdiseasetype pages 1-3): Nivedita U. Jerath, Ami Mankodi, Thomas O. Crawford, Christopher Grunseich, Hasna Baloui, Chioma Nnamdi‐Emeratom, Alice B. Schindler, Terry Heiman‐Patterson, Roman Chrast, and Michael E. Shy. Charcot–marie–tooth disease type 4c: novel mutations, clinical presentations, and diagnostic challenges. Muscle & Nerve, 57:749-755, May 2018. URL: https://doi.org/10.1002/mus.25981, doi:10.1002/mus.25981. This article has 30 citations and is from a peer-reviewed journal.

  10. (jerath2018charcot–marie–toothdiseasetype pages 8-10): Nivedita U. Jerath, Ami Mankodi, Thomas O. Crawford, Christopher Grunseich, Hasna Baloui, Chioma Nnamdi‐Emeratom, Alice B. Schindler, Terry Heiman‐Patterson, Roman Chrast, and Michael E. Shy. Charcot–marie–tooth disease type 4c: novel mutations, clinical presentations, and diagnostic challenges. Muscle & Nerve, 57:749-755, May 2018. URL: https://doi.org/10.1002/mus.25981, doi:10.1002/mus.25981. This article has 30 citations and is from a peer-reviewed journal.

  11. (OpenTargets Search: Charcot-Marie-Tooth disease type 4C-SH3TC2): Open Targets Query (Charcot-Marie-Tooth disease type 4C-SH3TC2, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  12. (schiza2019genereplacementtherapy pages 2-2): Natasa Schiza, Elena Georgiou, Alexia Kagiava, Jean-Jacques Médard, Jan Richter, Christina Tryfonos, Irene Sargiannidou, Amanda J Heslegrave, Alexander M Rossor, Henrik Zetterberg, Mary M Reilly, Christina Christodoulou, Roman Chrast, and Kleopas A Kleopa. Gene replacement therapy in a model of charcot-marie-tooth 4c neuropathy. Brain, 142(5):1227-1241, Mar 2019. URL: https://doi.org/10.1093/brain/awz064, doi:10.1093/brain/awz064. This article has 60 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 13
Resolved 13
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 13
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 34
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

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:

  • MONDO:0011113 (5 mentions) - the report calls it "if available", "MONDO"; MONDO calls it Charcot-Marie-Tooth disease type 4C

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0032456 (1 mention) - the report calls it "Processes: endosomal recycling"; GO calls it endocytic recycling**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0011113 - called "if available", "MONDO"

Prefixes with no resolver

Terms 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: ORPHA.