Charcot-Marie-Tooth Disease Axonal Type 2C

Mendelian MONDO:0011633 Pathograph 9 Show in embeddings browser Charcot-Marie-Tooth Disease Hereditary Motor and Sensory Neuropathy Channelopathy

Charcot-Marie-Tooth disease type 2C is an autosomal dominant axonal neuropathy caused by heterozygous missense variants in the ankyrin-repeat domain of TRPV4, a calcium-permeable cation channel. It was recognised as a distinct clinical entity long before its gene was found, on the strength of a feature no other CMT2 subtype has: vocal cord and diaphragm paralysis accompanying the limb neuropathy. Two things about it are unusual enough to be the reason the entry exists. First, the mechanism is a channel gain of function, not a loss: mutant TRPV4 localises normally but raises resting intracellular calcium to cytotoxic levels, and in transfected cells the resulting death is reversed by a TRPV channel antagonist - a rare instance of an inherited axonal degeneration that is pharmacologically reversible in vitro. Second, the laryngeal and diaphragmatic involvement does not track limb severity: patients with the worst muscle weakness may have minimal respiratory symptoms and vice versa, so respiratory risk cannot be inferred from the neurological examination. The same ankyrin-domain residues also produce scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy, while TRPV4 variants elsewhere in the protein cause skeletal dysplasias with no neuropathy at all.

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1
Inheritance
6
Pathophys.
7
Phenotypes
3
Hypotheses
2
Gaps
9
Pathograph
1
Genes
3
Medical Actions
1
Models
1
References
1
Deep Research
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Both inherited and de novo heterozygous variants are described. Expressivity is markedly variable, including for the defining laryngeal feature. On penetrance the sources disagree in a way worth preserving: the 2002 European family was reported as highly penetrant, but GeneReviews states across the TRPV4 neuromuscular disorders that phenotype and severity cannot be accurately predicted because of reduced penetrance and highly variable expressivity. This entry does not assert high penetrance generally; the family-level observation is recorded as such.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:21288981 SUPPORT Human Clinical
"The R316H is a novel de novo mutation found in a patient with CMT2C phenotype."
Documents a de novo occurrence, establishing that the disease is not exclusively familial.
PMID:12062259 SUPPORT Human Clinical
"In this family the disease has high penetrance, variable severity and apparently the most severe limb muscle involvement in the youngest generation."
Reports high penetrance alongside variable severity in a multigenerational family.
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Mechanistic Hypotheses

3
Non-cell-autonomous degeneration via endothelial barrier breakdown
trpv4_endothelial_non_cell_autonomous CANONICAL
Evidence balance 1 support
The account with the strongest in vivo support. Knock-in mice carrying the same ankyrin-domain substitutions found in patients develop weakness and regional motor neuron loss, and deleting the mutant allele specifically from endothelial cells rescues them, while deleting it from neurons, glia or muscle does not. The proximate lesion is focal breakdown of the blood-spinal cord barrier, driven by gain of mutant channel function in neural vascular endothelial cells. On this account motor neuron death is a consequence of vascular barrier failure rather than of channel activity in the neuron itself.
Pathograph links
TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant -> Endothelial Blood-CNS Barrier Breakdown
Endothelial Blood-CNS Barrier Breakdown -> Motor-Predominant Axonal Degeneration
Show evidence (1 reference)
PMID:38776392 SUPPORT Model Organism
"Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes."
The cell-type-specific rescue experiment, which is what makes this a claim about the driving cell type rather than about where the channel happens to be expressed.
Neuron-autonomous cytotoxic calcium overload
trpv4_neuron_autonomous_calcium_toxicity ALTERNATIVE
Evidence balance 2 support
The account this entry's pathophysiology chain models in detail: mutant channel activity raises intracellular calcium to cytotoxic levels and kills the cell directly, with the death reversible by channel blockade. It rests on transfected-cell work rather than on in vivo genetics, and the cell-type-specific rescue above argues that in the intact animal the neuron is not the cell in which the decisive channel activity occurs. The two are not mutually exclusive - calcium toxicity is the proximate cause of cell death in whichever cell type carries the decisive activity - but an entry that modelled only the neuronal version would misstate where the lesion begins.
Pathograph links
TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant -> Cytotoxic Intracellular Calcium Elevation
Show evidence (2 references)
PMID:21288981 SUPPORT In Vitro
"Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red."
The transfected-cell basis of this account, and the reason it is ALTERNATIVE rather than CANONICAL: the experiment establishes calcium toxicity in a cell line, not that the neuron is the driving cell type in vivo.
PMID:20037587 SUPPORT In Vitro
"Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy"
Links the TRPV4 mutations to altered calcium homeostasis as the proposed pathogenic mechanism. Supports the calcium-toxicity account without establishing which cell type carries the decisive activity, which is why this group remains ALTERNATIVE.
Reduced channel surface expression and haploinsufficiency
trpv4_reduced_surface_expression ⚠ DEPRECATED
⚠ Overturned model — shown for reference, not as current mechanism

DisMech records superseded hypotheses explicitly rather than deleting them, so that claims still circulating in reviews, textbooks and older diagnostic criteria can be checked against an assessment. This model is not part of the disease mechanism DisMech asserts.

Citation volume does not decide standing here. A hypothesis may retain more supporting than refuting citations simply because the supporting literature accumulated for decades before the refutation landed; where the two conflict, DisMech follows the more recent and more direct evidence. Supporting citations below are retained for the historical record.

Evidence balance 2 support
A directly opposed reading of the same variants, and the entry records it because the disagreement is real rather than settled. The 2010 gene-discovery study found that R269H, R315W and R316C reduced or abolished cell-surface expression and produced decreased stimulus-dependent channel activity in HeLa cells, and proposed haploinsufficiency as the likely pathomechanism - the opposite direction to the gain-of-function reading this entry otherwise adopts. The weight of later evidence favours gain of function, particularly the in vivo endothelial work, but a curator reading only the GOF papers would not know this was ever in question.
Show evidence (2 references)
PMID:20037588 SUPPORT In Vitro
"Based on our results using HeLa cells as a heterologous expression system, we suggest that the mutations described here lead to decreased stimulus-dependent TRPV4 channel activity."
The authors' own directional conclusion, opposite to the gain-of-function reading. Graded IN_VITRO because it is a heterologous-expression result.
PMID:20037588 SUPPORT In Vitro
"Haploinsufficiency can be considered the most likely underlying pathomechanism, although we cannot fully exclude adverse interaction of wild-type and mutant TRPV4 subunits."
States the haploinsufficiency proposal explicitly, including the authors' own hedge.
?

Discussions and Knowledge Gaps

2
What determines whether a TRPV4 ankyrin-repeat-domain variant produces CMT2C, scapuloperoneal spinal muscular atrophy, congenital distal spinal muscular atrophy, or no neuropathy at all, given that the same residues and even the same variant can yield different phenotypes?
KNOWLEDGE GAP trpv4_ankyrin_domain_phenotype_discordance
Attached to
pathophysiology#TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant
TRPV4 genotype-phenotype relationships are discordant at two levels. Within the neuromuscular group, the same variant can present as phenotypic CMT2C with vocal cord paresis in one individual and as undifferentiated CMT2 in another from the same family, so the laryngeal feature that defines the entity is not genotype-determined. Across the wider spectrum, TRPV4 variants outside the ankyrin domain cause skeletal dysplasias with no neuropathy, and affected individuals typically have either neuromuscular or skeletal manifestations rather than both. A calcium-toxicity model explains why an ankyrin-domain gain of function kills neurons, but not why it kills these neurons in this pattern, nor why other gain-of-function variants spare neurons entirely and hit cartilage instead. Modifier genes, cell-type-specific channel regulation and differential expression are all candidates; none is established.
Show evidence (2 references)
PMID:21288981 SUPPORT Human Clinical
"Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis."
The within-genotype discordance at the heart of this gap.
PMID:24830047 SUPPORT Other
"Affected individuals typically have either neuromuscular or skeletal manifestations, although overlapping phenotypes can occur."
States the neuromuscular/skeletal dichotomy across the TRPV4 spectrum that any candidate mechanism would have to explain.
Does systemic TRPV4 antagonism, which rescues symptomatic knock-in mice, benefit human CMT2C, given that the mouse disease is lethal and vascular-dominant while the human disease is chronic and usually non-lethal?
HUMAN MODEL MISMATCH trpv4_channel_blockade_human_translation
Attached to
pathophysiology#Endothelial Blood-CNS Barrier Breakdown pathophysiology#Cytotoxic Intracellular Calcium Elevation
Systemic administration of a TRPV4-specific antagonist abrogates the barrier impairment and markedly rescues symptomatic mutant mice, so the open question is not whether channel blockade works in an animal but whether the animal is the right animal. The knock-in mice show early lethality and a vascular-dominant phenotype, whereas human CMT2C is a chronic, slowly progressive neuropathy in which patients characteristically survive to adulthood - so a rescue measured against early death in mice does not straightforwardly predict benefit against decades of axonal loss in people. The reversibility of the barrier lesion is the encouraging part; the severity mismatch is the caveat.
Show evidence (2 references)
PMID:38776392 SUPPORT Model Organism
"Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice."
The in vivo rescue, which is what moves the open question from "does blockade work at all" to "does this model predict humans".
PMID:38776392 SUPPORT Model Organism
"TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss."
Graded PARTIAL because it supports the mismatch rather than the therapeutic claim: early lethality is not a feature of human CMT2C, and it is the severity gap that makes the translation uncertain.
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Pathophysiology

6
TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant
Heterozygous missense variants clustering in the intracellular N-terminal ankyrin repeat domain of TRPV4 - R232C, R269H, R315W, R316C, R316H, S542Y among them - produce a channel that reaches the membrane normally but is inappropriately active. The direction of the defect is the substantive claim: mutant protein subcellular localisation is normal in transfected cells, so this is not a trafficking or expression failure, and the functional data point to gain rather than loss of channel function.
Neuron-autonomous cytotoxic calcium overload Non-cell-autonomous degeneration via endothelial barrier breakdown
TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: MISSENSE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
calcium channel activity GO:0005262 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcium channel activity (GO:0005262), qualified as gain of function. GO:0005262 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Cytotoxic Intracellular Calcium Elevation Neuron-autonomous cytotoxic calcium overload
Endothelial Blood-CNS Barrier Breakdown Non-cell-autonomous degeneration via endothelial barrier breakdown
Show evidence (3 references)
PMID:21288981 SUPPORT Human Clinical
"Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains."
Localises the causal variants to the ankyrin repeat domain across a 17-family CMT2C cohort. Graded HUMAN_CLINICAL because this is sequencing of human families, not a cell-based assay; the sibling item below, from the same paper, is IN_VITRO because it reports a transfected-cell localisation experiment.
PMID:20037587 SUPPORT In Vitro
"Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins."
Independent support for the gain-of-function direction, from a different group than the Klein cohort, and covering the CMT2C-causing mutants specifically. Worth having because the direction of the functional defect is contested in this disease - see the reduced-surface-expression hypothesis group.
PMID:21288981 SUPPORT In Vitro
"Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells."
Rules out mislocalisation as the mechanism, which is what makes the gain-of-function reading rather than a loss-of-function one the supported interpretation. Graded IN_VITRO because the localisation was assessed in transfected cell lines.
Cytotoxic Intracellular Calcium Elevation
Cells expressing the mutant channel carry increased intracellular calcium and die. The calcium elevation is the proximate toxic species: blocking the channel prevents the death, which is what distinguishes a causal calcium overload from an incidental one.
calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↑ INCREASED calcium ion homeostasis GO:0055074 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated calcium ion homeostasis (GO:0055074). GO:0055074 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Motor-Predominant Axonal Degeneration
Show evidence (2 references)
PMID:21288981 SUPPORT In Vitro
"Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red."
Reports the calcium elevation, the resulting cell death, and its reversal by channel blockade - the three observations this node depends on. Graded IN_VITRO because the work is in transfected cells.
PMID:21288981 SUPPORT In Vitro
"Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important."
The authors' own directional conclusion, which is what licenses the GAIN_OF_FUNCTION modifier used upstream rather than a loss-of-function reading.
Endothelial Blood-CNS Barrier Breakdown
Gain of mutant channel function in neural vascular endothelial cells alters tight junction structure and produces focal disruption of the blood-spinal cord barrier. In knock-in mice this is the step that actually drives motor neuron loss: deleting the mutant allele from endothelium rescues the phenotype, while deleting it from neurons, glia or muscle does not. The node is curated because without it the entry asserts a neuron-autonomous chain that the strongest in vivo evidence contradicts. Its evidence is entirely murine, and the human relevance is the open question recorded in the mismatch discussion below.
Non-cell-autonomous degeneration via endothelial barrier breakdown
neural vascular endothelial cell CL:0000071 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural vascular endothelial cell, annotated with blood vessel endothelial cell (CL:0000071). CL:0000071 is a cell type from the Cell Ontology.
Animal models
Trpv4 R269C and R232C knock-in mice Mouse recapitulates Focal blood-spinal cord barrier disruption with altered endothelial tight junction structure, attributable to the mutant channel in endothelial cells specifically.
Downstream
Motor-Predominant Axonal Degeneration Non-cell-autonomous degeneration via endothelial barrier breakdown
Show evidence (2 references)
PMID:38776392 SUPPORT Model Organism
"Symptomatic mutant mice exhibited focal disruptions of blood-spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure."
The barrier lesion and its localisation to endothelial cells, which is what this node models.
PMID:38776392 SUPPORT Model Organism
"Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non-cell autonomous manner by precipitating focal breakdown of the BSCB."
The authors' conclusion that degeneration is non-cell-autonomous, which is the claim this node adds to the entry.
Motor-Predominant Axonal Degeneration
Neuronal loss produces a motor-predominant, non-length-dependent axonal neuropathy. Two features distinguish it from a generic dying-back neuropathy and both matter clinically: it is not length-dependent, so proximal and cranial-nerve-innervated territories are vulnerable rather than merely distal ones, and it is motor-greater-than-sensory rather than purely motor - the sensory component is what separates CMT2C from the allelic distal hereditary motor neuronopathies.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Trpv4 R269C and R232C knock-in mice Mouse partially recapitulates Weakness and regional motor neuron loss are reproduced, but with early lethality that human CMT2C does not show.
Downstream
Laryngeal and Diaphragmatic Denervation
Distal Limb Weakness and Sensory Loss
Show evidence (2 references)
PMID:21115951 SUPPORT Human Clinical
"Two multigenerational families had a motor greater than sensory axonal neuropathy associated with variable vocal cord paresis."
Establishes the motor-greater-than-sensory axonal pattern, including the sensory involvement that distinguishes CMT2C from a pure motor neuronopathy.
PMID:24830047 SUPPORT Other
"These neuromuscular disorders are characterized by a motor-predominant, non-length-dependent peripheral neuropathy or motor neuronopathy with a wide range in age of onset, from congenital to late adult."
The GeneReviews characterisation, supporting the non-length-dependent quality specifically. Graded OTHER because GeneReviews is expert consensus review rather than a primary study, and note its scope is the TRPV4 neuromuscular group rather than CMT2C alone.
Laryngeal and Diaphragmatic Denervation
Denervation of the larynx and diaphragm produces vocal cord paresis, voice change, inspiratory stridor and orthopnoea, and is the feature that defined CMT2C as a clinical entity before its gene was known. It ranges from absent to severe enough to require permanent tracheostomy, and - the point with real clinical consequence - its severity is independent of limb involvement.
Show evidence (2 references)
PMID:12062259 SUPPORT Human Clinical
"Vocal cord paralysis is unrelated to the degree of muscular weakness and patients with the most severe muscle involvement have absent or minimal respiratory symptoms."
The dissociation this node asserts, stated directly: respiratory risk cannot be inferred from limb severity.
PMID:21115951 SUPPORT Human Clinical
"The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects."
Gives the range of laryngeal severity within TRPV4-confirmed CMT2C families, including the tracheostomy-requiring extreme.
Distal Limb Weakness and Sensory Loss
The CMT limb phenotype: distal weakness and wasting with sensory loss, variable in severity between and within families, and in the first European family apparently more severe in the youngest generation.
Show evidence (1 reference)
PMID:21115951 SUPPORT Human Clinical
"The other family had a more severe, progressive, motor neuropathy with sensory loss, but less remarkable short stature and an R315W mutation in TRPV4."
Documents progressive motor neuropathy with sensory loss in a TRPV4-confirmed CMT2C family.
⬡

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 Axonal Type 2C 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

7
Ear 1
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures."
Listed by GeneReviews among the common additional features of the TRPV4 neuromuscular disorders. Same scope caveat as above.
Musculoskeletal 3
Distal Muscle Weakness VERY_FREQUENT HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as course progressive. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:21115951 SUPPORT Human Clinical
"The other family had a more severe, progressive, motor neuropathy with sensory loss"
Reports the progressive motor neuropathy that produces the limb weakness.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures."
Listed by GeneReviews among the common additional features. Same scope caveat as above.
Joint Contractures HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures."
Names joint contractures among the common additional features. Same group-level scope caveat as the other features drawn from this sentence.
Respiratory 1
Respiratory Insufficiency from Diaphragm Weakness HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"Additional common features include laryngeal dysfunction (i.e., vocal fold paresis causing voice change and/or inspiratory stridor), diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural hearing loss, and joint contractures."
The GeneReviews feature list. Note its scope is the TRPV4 neuromuscular group as a whole, not CMT2C specifically, so this supports the feature occurring in this disease group rather than a CMT2C-specific frequency. Graded OTHER as expert consensus review.
Growth 1
Short Stature OCCASIONAL HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21115951 SUPPORT Human Clinical
"One family with mild neuropathy also manifested pronounced short stature, more than 2 SD below the average height for white Americans. There was one instance of dolichocephaly."
Documents pronounced short stature in one of two families, which is also why the frequency is recorded as OCCASIONAL rather than higher: the other family had less remarkable stature.
Other 1
Vocal Cord Paresis FREQUENT HP:0001604 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vocal cord paresis (HP:0001604). HP:0001604 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21115951 SUPPORT Human Clinical
"The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects."
Documents the phenotype and its full severity range. Recorded as FREQUENT rather than VERY_FREQUENT because the same source reports it as absent in some affected individuals, and the R232C family in the Klein cohort contained members with and without it.
🧬

Genetic Associations

1
TRPV4
Gene: TRPV4 hgnc:18083 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPV4 (hgnc:18083). hgnc:18083 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (3 references)
PMID:21288981 SUPPORT Human Clinical
"TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis."
Establishes causality and, in the same breath, the within-genotype phenotypic variability that the notes describe.
PMID:20037588 SUPPORT In Vitro
"The arginine missense substitutions R269H, R315W and R316C disrupt one of these repeats, which allowed us to identify a new 315RR repeat that appears to affect proper TRPV4 channel maturation."
The source of the R269H, R315W and R316C substitutions named in the notes above, and of the structural account of why these particular arginines matter.
PMID:12062259 SUPPORT Human Clinical
"Charcot-Marie-Tooth disease type 2C is clinically and genetically different from Charcot-Marie-Tooth disease type 2A, B, D, E and F, and is not allelic with distal hereditary motor neuronopathy type VII."
The pre-gene linkage evidence establishing CMT2C as a separate entity, which is the historical basis for curating it as its own disease.
💊

Medical Actions

3
Orthoses and Mobility Support
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Ankle-foot and knee-ankle-foot orthoses, shoes with good ankle support, surgery for severe foot deformities, mobility devices and exercise as tolerated. Symptomatic management, which is what exists for this disease.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"For neuromuscular disorders, additional treatment includes special shoes with good ankle support, shoe orthotics, ankle-foot orthoses / knee-ankle-foot orthoses, surgery for severe foot deformities, mobility devices, and exercise as tolerated"
The GeneReviews management protocol for the neuromuscular arm. Scope caveat as elsewhere in this entry: GeneReviews covers all three TRPV4 neuromuscular phenotypes together.
Laryngeal Surgery for Vocal Cord Paresis
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Vocal fold lateralization or tracheostomy in individuals with severe laryngeal involvement. This is the intervention the entry's defining phenotype leads to.
Mechanism Target:
Laryngeal and Diaphragmatic Denervation — Relieves the airway consequence of laryngeal denervation. It does not act on the channel or the degeneration.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"laryngeal surgery for vocal cord paresis (in some individuals, vocal fold lateralization or tracheostomy); speech therapy; and respiratory therapy including noninvasive ventilatory support as needed"
Names the laryngeal and respiratory interventions. Same GeneReviews scope caveat.
Avoidance of Neurotoxic Medications and Respiratory Infection
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
GeneReviews names specific circumstances to avoid, and one of them is unusually consequential here: upper respiratory tract infection can swell the vocal folds and worsen upper airway obstruction in a patient whose folds are already paretic. Diabetes and neurotoxic drugs are to be avoided as additional insults to an already compromised nerve.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"For neuromuscular disorders, avoid diabetes and neurotoxic medications; upper respiratory tract infections can cause vocal fold swelling and worsen upper airway obstruction."
The agents-and-circumstances-to-avoid guidance, including the respiratory-infection interaction with vocal fold paresis.
🔬

Diagnosis

2
Molecular Genetic Testing with Characteristic Neurophysiology
Diagnosis rests on characteristic clinical and neurophysiologic findings plus a heterozygous TRPV4 pathogenic variant. The neurophysiology is what separates this from demyelinating CMT: the neuropathy is axonal, so compound muscle action potential amplitudes are reduced while conduction velocities remain normal or near-normal.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"The diagnosis of an autosomal dominant TRPV4-related disorder is established in a proband who has characteristic clinical and neurophysiologic findings, radiographic findings in the skeletal dysplasias, and a heterozygous TRPV4 pathogenic variant identified by molecular genetic testing."
The diagnostic criteria. Note the sentence is about TRPV4-related disorders as a group; the axonal electrophysiology detail in this node's description is standard for CMT2 and is not asserted by this quote.
Surveillance for Laryngeal and Respiratory Involvement
Because laryngeal and diaphragmatic severity does not track limb severity, respiratory and laryngeal surveillance has to be scheduled independently of the neurological examination rather than triggered by it.
Show evidence (1 reference)
PMID:24830047 SUPPORT Other
"For neuromuscular disorders, annual neurologic examination, physical therapy assessment, otolaryngology evaluation of laryngeal function, dynamic breathing chest radiograph, pulmonary function tests, sleep study, hearing assessment, and musculoskeletal evaluation"
The surveillance schedule, which is the concrete answer to the "warrants independent surveillance" claim the respiratory phenotype makes.
🐁

Animal Models

1
Trpv4 R269C and R232C knock-in mice
Knock-in of two patient substitutions into the endogenous mouse Trpv4 gene. The decisive experiments are the conditional deletions: removing the mutant allele from endothelium rescues, removing it from neurons, glia or muscle does not.
Species
Mouse
Genotype
Trpv4 R269C or R232C knock-in at the endogenous locus
Publication
PMID:38776392
Pathograph links
Endothelial Blood-CNS Barrier Breakdown recapitulates fidelity: high Focal blood-spinal cord barrier disruption with altered endothelial tight junction structure, attributable to the mutant channel in endothelial cells specifically.
Readouts
Blood-spinal cord barrier integrity
Direction: DECREASED
Interpretation: Direct measure of the barrier lesion this node models.
Show evidence (1 reference)
PMID:38776392 SUPPORT Model Organism
"Symptomatic mutant mice exhibited focal disruptions of blood-spinal cord barrier (BSCB) integrity"
The measurement itself.
Phenotypic response to systemic TRPV4 antagonist
Direction: RESTORED
Interpretation: The rescue arm. Establishes that the barrier lesion is reversible pharmacologically, which is what makes the human translation question worth asking rather than idle.
Show evidence (1 reference)
PMID:38776392 SUPPORT Model Organism
"Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice."
Reports both the barrier and the phenotypic rescue.
Show evidence (1 reference)
PMID:38776392 SUPPORT Model Organism
"Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes."
The cell-type-specific rescue that makes this model informative about where the lesion begins, not merely that it occurs.
Motor-Predominant Axonal Degeneration partially recapitulates fidelity: moderate Weakness and regional motor neuron loss are reproduced, but with early lethality that human CMT2C does not show.
Limitations: The mouse disease is more severe and differently shaped than the human one: knock-in mice die early and their phenotype is vascular-dominant, whereas human CMT2C is a chronic, slowly progressive neuropathy whose defining features are vocal cord and diaphragm involvement with normal or near-normal lifespan. The model is therefore strong evidence about mechanism and weak evidence about natural history, and a therapeutic rescue measured against early murine death should not be read as predicting benefit against decades of human axonal loss.
Readouts
Regional motor neuron number
Direction: DECREASED
Interpretation: The degenerative endpoint, reproduced in the model.
Show evidence (1 reference)
PMID:38776392 SUPPORT Model Organism
"TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss."
Reports the motor neuron loss, and in the same sentence the early lethality that grounds the limitation above.
{ }

Source YAML

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name: Charcot-Marie-Tooth Disease Axonal Type 2C
creation_date: "2026-08-28T00:20:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 2C is an autosomal dominant axonal neuropathy
  caused by heterozygous missense variants in the ankyrin-repeat domain of
  TRPV4, a calcium-permeable cation channel. It was recognised as a distinct
  clinical entity long before its gene was found, on the strength of a feature
  no other CMT2 subtype has: vocal cord and diaphragm paralysis accompanying the
  limb neuropathy. Two things about it are unusual enough to be the reason the
  entry exists. First, the mechanism is a channel gain of function, not a loss:
  mutant TRPV4 localises normally but raises resting intracellular calcium to
  cytotoxic levels, and in transfected cells the resulting death is reversed by
  a TRPV channel antagonist - a rare instance of an inherited axonal
  degeneration that is pharmacologically reversible in vitro. Second, the
  laryngeal and diaphragmatic involvement does not track limb severity: patients
  with the worst muscle weakness may have minimal respiratory symptoms and vice
  versa, so respiratory risk cannot be inferred from the neurological
  examination. The same ankyrin-domain residues also produce scapuloperoneal
  spinal muscular atrophy and congenital distal spinal muscular atrophy, while
  TRPV4 variants elsewhere in the protein cause skeletal dysplasias with no
  neuropathy at all.
parents:
  - Charcot-Marie-Tooth Disease
  - Hereditary Motor and Sensory Neuropathy
  - Channelopathy
synonyms:
  - CMT2C
  - HMSN2C
  - hereditary motor and sensory neuropathy type IIC
  - Charcot-Marie-Tooth disease type 2C with vocal cord paresis
disease_term:
  preferred_term: Charcot-Marie-Tooth disease axonal type 2C
  term:
    id: MONDO:0011633
    label: Charcot-Marie-Tooth disease axonal type 2C
references:
  - reference: PMID:24830047
    title: "Autosomal Dominant TRPV4-Related Disorders."
    tags:
      - GeneReviews
notes: >-
  Boundary with the neighbouring TRPV4 entries, which is the modelling question
  this entry has to answer. TRPV4 neuromuscular disease is already partly
  curated in kb/ as Distal_Hereditary_Motor_Neuronopathy_Autosomal_Dominant,
  which discusses HMSN2C within the TRPV4 allelic series, and as
  Scapuloperoneal_Spinal_Muscular_Atrophy. Neither carries MONDO:0011633. CMT2C
  is separable from those on a definitional rather than a merely clinical
  ground: it has sensory involvement, and a distal hereditary *motor*
  neuronopathy by definition does not. The three phenotypes overlap clinically
  and arise from the same residues, so this entry cross-references rather than
  duplicating them, and the shared calcium-toxicity mechanism is stated here in
  full because the project's convention for conserved mechanisms is duplication
  with consistency checking rather than inheritance.

  GeneReviews baseline. PMID:24830047, Autosomal Dominant TRPV4-Related
  Disorders, is the expert-curated reference for this gene and is tagged in the
  references block. Its Clinical Characteristics section covers all three
  neuromuscular phenotypes together rather than CMT2C alone, so features it
  lists - laryngeal dysfunction, diaphragm weakness, scoliosis, sensorineural
  hearing loss, joint contractures - are curated here as phenotypes of the
  TRPV4 neuromuscular group with that scope stated in each explanation, rather
  than being silently attributed to CMT2C specifically.
inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Both inherited and de novo heterozygous variants are described.
      Expressivity is markedly variable, including for the defining laryngeal
      feature. On penetrance the sources disagree in a way worth preserving: the
      2002 European family was reported as highly penetrant, but GeneReviews
      states across the TRPV4 neuromuscular disorders that phenotype and
      severity cannot be accurately predicted because of reduced penetrance and
      highly variable expressivity. This entry does not assert high penetrance
      generally; the family-level observation is recorded as such.
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The R316H is a novel de novo mutation found in a patient with CMT2C
          phenotype.
        explanation: >-
          Documents a de novo occurrence, establishing that the disease is not
          exclusively familial.
      - reference: PMID:12062259
        reference_title: >-
          Charcot-Marie-Tooth disease type 2C: a distinct genetic entity.
          Clinical and molecular characterization of the first European family.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          In this family the disease has high penetrance, variable severity and
          apparently the most severe limb muscle involvement in the youngest
          generation.
        explanation: >-
          Reports high penetrance alongside variable severity in a
          multigenerational family.
mechanistic_hypotheses:
  - hypothesis_group_id: trpv4_endothelial_non_cell_autonomous
    hypothesis_label: Non-cell-autonomous degeneration via endothelial barrier breakdown
    status: CANONICAL
    description: >-
      The account with the strongest in vivo support. Knock-in mice carrying the
      same ankyrin-domain substitutions found in patients develop weakness and
      regional motor neuron loss, and deleting the mutant allele specifically
      from endothelial cells rescues them, while deleting it from neurons, glia
      or muscle does not. The proximate lesion is focal breakdown of the
      blood-spinal cord barrier, driven by gain of mutant channel function in
      neural vascular endothelial cells. On this account motor neuron death is a
      consequence of vascular barrier failure rather than of channel activity in
      the neuron itself.
    evidence:
      - reference: PMID:38776392
        reference_title: >-
          Gain-of-function mutations of TRPV4 acting in endothelial cells drive
          blood-CNS barrier breakdown and motor neuron degeneration in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Genetic deletion of the mutant Trpv4 allele from endothelial cells
          (but not neurons, glia, or muscle) rescued these phenotypes.
        explanation: >-
          The cell-type-specific rescue experiment, which is what makes this a
          claim about the driving cell type rather than about where the channel
          happens to be expressed.
  - hypothesis_group_id: trpv4_neuron_autonomous_calcium_toxicity
    hypothesis_label: Neuron-autonomous cytotoxic calcium overload
    status: ALTERNATIVE
    description: >-
      The account this entry's pathophysiology chain models in detail: mutant
      channel activity raises intracellular calcium to cytotoxic levels and
      kills the cell directly, with the death reversible by channel blockade.
      It rests on transfected-cell work rather than on in vivo genetics, and the
      cell-type-specific rescue above argues that in the intact animal the
      neuron is not the cell in which the decisive channel activity occurs. The
      two are not mutually exclusive - calcium toxicity is the proximate cause
      of cell death in whichever cell type carries the decisive activity - but
      an entry that modelled only the neuronal version would misstate where the
      lesion begins.
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Cells transfected with R232C and R316H displayed increased
          intracellular Ca(2+) levels and reversible cell death by the TRPV
          channel antagonist, ruthenium red.
        explanation: >-
          The transfected-cell basis of this account, and the reason it is
          ALTERNATIVE rather than CANONICAL: the experiment establishes calcium
          toxicity in a cell line, not that the neuron is the driving cell type
          in vivo.
      - reference: PMID:20037587
        reference_title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Our findings link mutations in TRPV4 to altered calcium homeostasis
          and peripheral neuropathies, implying a pathogenic mechanism and
          possible options for therapy
        explanation: >-
          Links the TRPV4 mutations to altered calcium homeostasis as the
          proposed pathogenic mechanism. Supports the calcium-toxicity account
          without establishing which cell type carries the decisive activity,
          which is why this group remains ALTERNATIVE.
  - hypothesis_group_id: trpv4_reduced_surface_expression
    hypothesis_label: Reduced channel surface expression and haploinsufficiency
    status: DEPRECATED
    description: >-
      A directly opposed reading of the same variants, and the entry records it
      because the disagreement is real rather than settled. The 2010
      gene-discovery study found that R269H, R315W and R316C reduced or
      abolished cell-surface expression and produced decreased stimulus-dependent
      channel activity in HeLa cells, and proposed haploinsufficiency as the
      likely pathomechanism - the opposite direction to the gain-of-function
      reading this entry otherwise adopts. The weight of later evidence favours
      gain of function, particularly the in vivo endothelial work, but a curator
      reading only the GOF papers would not know this was ever in question.
    evidence:
      - reference: PMID:20037588
        reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Based on our results using HeLa cells as a heterologous expression
          system, we suggest that the mutations described here lead to decreased
          stimulus-dependent TRPV4 channel activity.
        explanation: >-
          The authors' own directional conclusion, opposite to the
          gain-of-function reading. Graded IN_VITRO because it is a
          heterologous-expression result.
      - reference: PMID:20037588
        reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Haploinsufficiency can be considered the most likely underlying
          pathomechanism, although we cannot fully exclude adverse interaction
          of wild-type and mutant TRPV4 subunits.
        explanation: >-
          States the haploinsufficiency proposal explicitly, including the
          authors' own hedge.
pathophysiology:
  - name: TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant
    biological_scale: MOLECULAR
    description: >-
      Heterozygous missense variants clustering in the intracellular
      N-terminal ankyrin repeat domain of TRPV4 - R232C, R269H, R315W, R316C,
      R316H, S542Y among them - produce a channel that reaches the membrane
      normally but is inappropriately active. The direction of the defect is the
      substantive claim: mutant protein subcellular localisation is normal in
      transfected cells, so this is not a trafficking or expression failure, and
      the functional data point to gain rather than loss of channel function.
    genes:
      - preferred_term: TRPV4
        term:
          id: hgnc:18083
          label: TRPV4
    molecular_functions:
      - preferred_term: calcium channel activity
        term:
          id: GO:0005262
          label: calcium channel activity
        modifier: GAIN_OF_FUNCTION
    genetic_context:
      functional_impact_category: GAIN_OF_FUNCTION
      allele_type: MISSENSE
      zygosity: HETEROZYGOUS
    downstream:
      - target: Cytotoxic Intracellular Calcium Elevation
        hypothesis_groups:
          - trpv4_neuron_autonomous_calcium_toxicity
      - target: Endothelial Blood-CNS Barrier Breakdown
        hypothesis_groups:
          - trpv4_endothelial_non_cell_autonomous
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Two TRPV4 mutations R232C and R316H from 17 CMT2C families were
          identified in the ankyrin repeat domains.
        explanation: >-
          Localises the causal variants to the ankyrin repeat domain across a
          17-family CMT2C cohort. Graded HUMAN_CLINICAL because this is
          sequencing of human families, not a cell-based assay; the sibling item
          below, from the same paper, is IN_VITRO because it reports a
          transfected-cell localisation experiment.
      - reference: PMID:20037587
        reference_title: "Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Functional analysis revealed that increased calcium channel activity
          is a distinct property of both SPSMA- and CMT2C-causing mutant
          proteins.
        explanation: >-
          Independent support for the gain-of-function direction, from a
          different group than the Klein cohort, and covering the
          CMT2C-causing mutants specifically. Worth having because the direction
          of the functional defect is contested in this disease - see the
          reduced-surface-expression hypothesis group.
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Both mutant TRPV4 proteins had normal subcellular localization in
          HEK293 and HeLa cells.
        explanation: >-
          Rules out mislocalisation as the mechanism, which is what makes the
          gain-of-function reading rather than a loss-of-function one the
          supported interpretation. Graded IN_VITRO because the localisation was
          assessed in transfected cell lines.
  - name: Cytotoxic Intracellular Calcium Elevation
    biological_scale: CELLULAR
    description: >-
      Cells expressing the mutant channel carry increased intracellular calcium
      and die. The calcium elevation is the proximate toxic species: blocking
      the channel prevents the death, which is what distinguishes a causal
      calcium overload from an incidental one.
    biological_processes:
      - preferred_term: calcium ion transmembrane transport
        term:
          id: GO:0070588
          label: calcium ion transmembrane transport
        modifier: INCREASED
      - preferred_term: calcium ion homeostasis
        term:
          id: GO:0055074
          label: calcium ion homeostasis
        modifier: DYSREGULATED
    downstream:
      - target: Motor-Predominant Axonal Degeneration
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Cells transfected with R232C and R316H displayed increased
          intracellular Ca(2+) levels and reversible cell death by the TRPV
          channel antagonist, ruthenium red.
        explanation: >-
          Reports the calcium elevation, the resulting cell death, and its
          reversal by channel blockade - the three observations this node
          depends on. Graded IN_VITRO because the work is in transfected cells.
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of
          loss-of-function appears to be pathologically important.
        explanation: >-
          The authors' own directional conclusion, which is what licenses the
          GAIN_OF_FUNCTION modifier used upstream rather than a
          loss-of-function reading.
  - name: Endothelial Blood-CNS Barrier Breakdown
    biological_scale: TISSUE
    description: >-
      Gain of mutant channel function in neural vascular endothelial cells
      alters tight junction structure and produces focal disruption of the
      blood-spinal cord barrier. In knock-in mice this is the step that actually
      drives motor neuron loss: deleting the mutant allele from endothelium
      rescues the phenotype, while deleting it from neurons, glia or muscle does
      not. The node is curated because without it the entry asserts a
      neuron-autonomous chain that the strongest in vivo evidence contradicts.
      Its evidence is entirely murine, and the human relevance is the open
      question recorded in the mismatch discussion below.
    cell_types:
      - preferred_term: neural vascular endothelial cell
        term:
          id: CL:0000071
          label: blood vessel endothelial cell
    downstream:
      - target: Motor-Predominant Axonal Degeneration
        hypothesis_groups:
          - trpv4_endothelial_non_cell_autonomous
    evidence:
      - reference: PMID:38776392
        reference_title: >-
          Gain-of-function mutations of TRPV4 acting in endothelial cells drive
          blood-CNS barrier breakdown and motor neuron degeneration in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Symptomatic mutant mice exhibited focal disruptions of blood-spinal
          cord barrier (BSCB) integrity, associated with a gain of function of
          mutant TRPV4 channel activity in neural vascular endothelial cells
          (NVECs) and alterations of NVEC tight junction structure.
        explanation: >-
          The barrier lesion and its localisation to endothelial cells, which is
          what this node models.
      - reference: PMID:38776392
        reference_title: >-
          Gain-of-function mutations of TRPV4 acting in endothelial cells drive
          blood-CNS barrier breakdown and motor neuron degeneration in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Together, our findings show that mutant TRPV4 channels can drive motor
          neuron degeneration in a non-cell autonomous manner by precipitating
          focal breakdown of the BSCB.
        explanation: >-
          The authors' conclusion that degeneration is non-cell-autonomous,
          which is the claim this node adds to the entry.
  - name: Motor-Predominant Axonal Degeneration
    biological_scale: TISSUE
    description: >-
      Neuronal loss produces a motor-predominant, non-length-dependent axonal
      neuropathy. Two features distinguish it from a generic dying-back
      neuropathy and both matter clinically: it is not length-dependent, so
      proximal and cranial-nerve-innervated territories are vulnerable rather
      than merely distal ones, and it is motor-greater-than-sensory rather than
      purely motor - the sensory component is what separates CMT2C from the
      allelic distal hereditary motor neuronopathies.
    cell_types:
      - preferred_term: motor neuron
        term:
          id: CL:0000100
          label: motor neuron
    biological_processes:
      - preferred_term: neuron apoptotic process
        term:
          id: GO:0051402
          label: neuron apoptotic process
        modifier: INCREASED
    downstream:
      - target: Laryngeal and Diaphragmatic Denervation
      - target: Distal Limb Weakness and Sensory Loss
    evidence:
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Two multigenerational families had a motor greater than sensory
          axonal neuropathy associated with variable vocal cord paresis.
        explanation: >-
          Establishes the motor-greater-than-sensory axonal pattern, including
          the sensory involvement that distinguishes CMT2C from a pure motor
          neuronopathy.
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          These neuromuscular disorders are characterized by a
          motor-predominant, non-length-dependent peripheral neuropathy or motor
          neuronopathy with a wide range in age of onset, from congenital to
          late adult.
        explanation: >-
          The GeneReviews characterisation, supporting the non-length-dependent
          quality specifically. Graded OTHER because GeneReviews is expert
          consensus review rather than a primary study, and note its scope is
          the TRPV4 neuromuscular group rather than CMT2C alone.
  - name: Laryngeal and Diaphragmatic Denervation
    biological_scale: TISSUE
    description: >-
      Denervation of the larynx and diaphragm produces vocal cord paresis, voice
      change, inspiratory stridor and orthopnoea, and is the feature that defined
      CMT2C as a clinical entity before its gene was known. It ranges from
      absent to severe enough to require permanent tracheostomy, and - the point
      with real clinical consequence - its severity is independent of limb
      involvement.
    evidence:
      - reference: PMID:12062259
        reference_title: >-
          Charcot-Marie-Tooth disease type 2C: a distinct genetic entity.
          Clinical and molecular characterization of the first European family.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Vocal cord paralysis is unrelated to the degree of muscular weakness
          and patients with the most severe muscle involvement have absent or
          minimal respiratory symptoms.
        explanation: >-
          The dissociation this node asserts, stated directly: respiratory risk
          cannot be inferred from limb severity.
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The vocal cord paresis varied from absent to severe, requiring
          permanent tracheotomy in 2 subjects.
        explanation: >-
          Gives the range of laryngeal severity within TRPV4-confirmed CMT2C
          families, including the tracheostomy-requiring extreme.
  - name: Distal Limb Weakness and Sensory Loss
    biological_scale: ORGANISM
    description: >-
      The CMT limb phenotype: distal weakness and wasting with sensory loss,
      variable in severity between and within families, and in the first
      European family apparently more severe in the youngest generation.
    evidence:
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The other family had a more severe, progressive, motor neuropathy with
          sensory loss, but less remarkable short stature and an R315W mutation
          in TRPV4.
        explanation: >-
          Documents progressive motor neuropathy with sensory loss in a
          TRPV4-confirmed CMT2C family.
phenotypes:
  - name: Vocal Cord Paresis
    category: Respiratory
    description: >-
      The defining feature of CMT2C. Ranges from clinically absent to severe
      enough to require permanent tracheostomy, and its severity is independent
      of limb involvement.
    phenotype_term:
      preferred_term: Vocal cord paresis
      term:
        id: HP:0001604
        label: Vocal cord paresis
    frequency: FREQUENT
    evidence:
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The vocal cord paresis varied from absent to severe, requiring
          permanent tracheotomy in 2 subjects.
        explanation: >-
          Documents the phenotype and its full severity range. Recorded as
          FREQUENT rather than VERY_FREQUENT because the same source reports it
          as absent in some affected individuals, and the R232C family in the
          Klein cohort contained members with and without it.
  - name: Distal Muscle Weakness
    category: Neuromuscular
    phenotype_term:
      preferred_term: Distal muscle weakness
      term:
        id: HP:0002460
        label: Distal muscle weakness
      clinical_course: PROGRESSIVE
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          The other family had a more severe, progressive, motor neuropathy with
          sensory loss
        explanation: >-
          Reports the progressive motor neuropathy that produces the limb
          weakness.
  - name: Respiratory Insufficiency from Diaphragm Weakness
    category: Respiratory
    description: >-
      Diaphragm weakness presenting as orthopnoea. Together with laryngeal
      dysfunction this is the main determinant of morbidity, and because it does
      not track limb severity it warrants independent surveillance.
    phenotype_term:
      preferred_term: Respiratory insufficiency
      term:
        id: HP:0002093
        label: Respiratory insufficiency
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Additional common features include laryngeal dysfunction (i.e., vocal
          fold paresis causing voice change and/or inspiratory stridor),
          diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural
          hearing loss, and joint contractures.
        explanation: >-
          The GeneReviews feature list. Note its scope is the TRPV4
          neuromuscular group as a whole, not CMT2C specifically, so this
          supports the feature occurring in this disease group rather than a
          CMT2C-specific frequency. Graded OTHER as expert consensus review.
  - name: Sensorineural Hearing Impairment
    category: Auditory
    phenotype_term:
      preferred_term: Sensorineural hearing impairment
      term:
        id: HP:0000407
        label: Sensorineural hearing impairment
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Additional common features include laryngeal dysfunction (i.e., vocal
          fold paresis causing voice change and/or inspiratory stridor),
          diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural
          hearing loss, and joint contractures.
        explanation: >-
          Listed by GeneReviews among the common additional features of the
          TRPV4 neuromuscular disorders. Same scope caveat as above.
  - name: Scoliosis
    category: Skeletal
    phenotype_term:
      preferred_term: Scoliosis
      term:
        id: HP:0002650
        label: Scoliosis
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Additional common features include laryngeal dysfunction (i.e., vocal
          fold paresis causing voice change and/or inspiratory stridor),
          diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural
          hearing loss, and joint contractures.
        explanation: >-
          Listed by GeneReviews among the common additional features. Same scope
          caveat as above.
  - name: Short Stature
    category: Growth
    description: >-
      Present in some but not all CMT2C families, and pronounced in one S542Y
      family. This is the point where the neuromuscular and skeletal halves of
      the TRPV4 phenotype spectrum meet.
    phenotype_term:
      preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:21115951
        reference_title: "CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          One family with mild neuropathy also manifested pronounced short
          stature, more than 2 SD below the average height for white Americans.
          There was one instance of dolichocephaly.
        explanation: >-
          Documents pronounced short stature in one of two families, which is
          also why the frequency is recorded as OCCASIONAL rather than higher:
          the other family had less remarkable stature.
  - name: Joint Contractures
    category: Musculoskeletal
    description: >-
      Listed by GeneReviews among the common additional features of the TRPV4
      neuromuscular disorders. Added because the same GeneReviews sentence is
      already quoted three times in this entry for its other items, and omitting
      the fourth was inconsistent rather than deliberate.
    phenotype_term:
      preferred_term: Joint contracture
      term:
        id: HP:0034392
        label: Joint contracture
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Additional common features include laryngeal dysfunction (i.e., vocal
          fold paresis causing voice change and/or inspiratory stridor),
          diaphragm weakness (orthopnea), scoliosis, bilateral sensorineural
          hearing loss, and joint contractures.
        explanation: >-
          Names joint contractures among the common additional features. Same
          group-level scope caveat as the other features drawn from this
          sentence.
genetic:
  - name: TRPV4
    relationship_type: CAUSATIVE
    gene_term:
      preferred_term: TRPV4
      term:
        id: hgnc:18083
        label: TRPV4
    notes: >-
      Causal variants cluster in the intracellular N-terminal ankyrin repeat
      domain: R232C, R269H, R315W, R316C, R316H and S542Y are reported. R269H,
      R315W and R316C come from the two 2010 gene-discovery papers cited below,
      which is where the variant spectrum in this note originates. The same
      residues also cause scapuloperoneal spinal muscular atrophy and congenital
      distal spinal muscular atrophy, and the same variant can present as either
      phenotypic CMT2C or as undifferentiated CMT2 within one family - so a
      TRPV4 ankyrin-domain variant predicts TRPV4 neuromuscular disease but does
      not predict which of the three phenotypes a given individual will have.
    inheritance:
      - name: Autosomal dominant inheritance
        inheritance_term:
          preferred_term: Autosomal dominant inheritance
          term:
            id: HP:0000006
            label: Autosomal dominant inheritance
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          TRPV4 ankyrin domain alterations including a novel de novo mutation
          cause axonal CMT2. Individuals with the same mutation may have
          nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis.
        explanation: >-
          Establishes causality and, in the same breath, the within-genotype
          phenotypic variability that the notes describe.
      - reference: PMID:20037588
        reference_title: "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The arginine missense substitutions R269H, R315W and R316C disrupt one
          of these repeats, which allowed us to identify a new 315RR repeat that
          appears to affect proper TRPV4 channel maturation.
        explanation: >-
          The source of the R269H, R315W and R316C substitutions named in the
          notes above, and of the structural account of why these particular
          arginines matter.
      - reference: PMID:12062259
        reference_title: >-
          Charcot-Marie-Tooth disease type 2C: a distinct genetic entity.
          Clinical and molecular characterization of the first European family.
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Charcot-Marie-Tooth disease type 2C is clinically and genetically
          different from Charcot-Marie-Tooth disease type 2A, B, D, E and F, and
          is not allelic with distal hereditary motor neuronopathy type VII.
        explanation: >-
          The pre-gene linkage evidence establishing CMT2C as a separate entity,
          which is the historical basis for curating it as its own disease.
discussions:
  - discussion_id: trpv4_ankyrin_domain_phenotype_discordance
    kind: KNOWLEDGE_GAP
    prompt: >-
      What determines whether a TRPV4 ankyrin-repeat-domain variant produces
      CMT2C, scapuloperoneal spinal muscular atrophy, congenital distal spinal
      muscular atrophy, or no neuropathy at all, given that the same residues
      and even the same variant can yield different phenotypes?
    attaches_to:
      - pathophysiology#TRPV4 Ankyrin-Repeat Domain Gain-of-Function Variant
    rationale: >-
      TRPV4 genotype-phenotype relationships are discordant at two levels. Within
      the neuromuscular group, the same variant can present as phenotypic CMT2C
      with vocal cord paresis in one individual and as undifferentiated CMT2 in
      another from the same family, so the laryngeal feature that defines the
      entity is not genotype-determined. Across the wider spectrum, TRPV4
      variants outside the ankyrin domain cause skeletal dysplasias with no
      neuropathy, and affected individuals typically have either neuromuscular
      or skeletal manifestations rather than both. A calcium-toxicity model
      explains why an ankyrin-domain gain of function kills neurons, but not why
      it kills these neurons in this pattern, nor why other gain-of-function
      variants spare neurons entirely and hit cartilage instead. Modifier genes,
      cell-type-specific channel regulation and differential expression are all
      candidates; none is established.
    evidence:
      - reference: PMID:21288981
        reference_title: "TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: >-
          Individuals with the same mutation may have nondistinct CMT2 or have
          phenotypic CMT2C with vocal cord paresis.
        explanation: >-
          The within-genotype discordance at the heart of this gap.
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          Affected individuals typically have either neuromuscular or skeletal
          manifestations, although overlapping phenotypes can occur.
        explanation: >-
          States the neuromuscular/skeletal dichotomy across the TRPV4 spectrum
          that any candidate mechanism would have to explain.
  - discussion_id: trpv4_channel_blockade_human_translation
    kind: HUMAN_MODEL_MISMATCH
    prompt: >-
      Does systemic TRPV4 antagonism, which rescues symptomatic knock-in mice,
      benefit human CMT2C, given that the mouse disease is lethal and
      vascular-dominant while the human disease is chronic and usually
      non-lethal?
    attaches_to:
      - pathophysiology#Endothelial Blood-CNS Barrier Breakdown
      - pathophysiology#Cytotoxic Intracellular Calcium Elevation
    rationale: >-
      Systemic administration of a TRPV4-specific antagonist abrogates the
      barrier impairment and markedly rescues symptomatic mutant mice, so the
      open question is not whether channel blockade works in an animal but
      whether the animal is the right animal. The knock-in mice show early lethality and a vascular-dominant
      phenotype, whereas human CMT2C is a chronic, slowly progressive neuropathy
      in which patients characteristically survive to adulthood - so a rescue
      measured against early death in mice does not straightforwardly predict
      benefit against decades of axonal loss in people. The reversibility of the
      barrier lesion is the encouraging part; the severity mismatch is the
      caveat.
    evidence:
      - reference: PMID:38776392
        reference_title: >-
          Gain-of-function mutations of TRPV4 acting in endothelial cells drive
          blood-CNS barrier breakdown and motor neuron degeneration in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Systemic administration of a TRPV4-specific antagonist abrogated
          channel-mediated BSCB impairments and provided a marked phenotypic
          rescue of symptomatic mutant mice.
        explanation: >-
          The in vivo rescue, which is what moves the open question from
          "does blockade work at all" to "does this model predict humans".
      - reference: PMID:38776392
        reference_title: >-
          Gain-of-function mutations of TRPV4 acting in endothelial cells drive
          blood-CNS barrier breakdown and motor neuron degeneration in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          TRPV4 mutant mice exhibited weakness, early lethality, and regional
          motor neuron loss.
        explanation: >-
          Graded PARTIAL because it supports the mismatch rather than the
          therapeutic claim: early lethality is not a feature of human CMT2C,
          and it is the severity gap that makes the translation uncertain.
animal_models:
  - name: Trpv4 R269C and R232C knock-in mice
    species: Mouse
    genotype: Trpv4 R269C or R232C knock-in at the endogenous locus
    publication: PMID:38776392
    description: >-
      Knock-in of two patient substitutions into the endogenous mouse Trpv4
      gene. The decisive experiments are the conditional deletions: removing the
      mutant allele from endothelium rescues, removing it from neurons, glia or
      muscle does not.
    modeled_mechanisms:
      - target: Endothelial Blood-CNS Barrier Breakdown
        relationship: RECAPITULATES
        fidelity: HIGH
        description: >-
          Focal blood-spinal cord barrier disruption with altered endothelial
          tight junction structure, attributable to the mutant channel in
          endothelial cells specifically.
        readouts:
          - name: Blood-spinal cord barrier integrity
            target: Endothelial Blood-CNS Barrier Breakdown
            direction: DECREASED
            interpretation: >-
              Direct measure of the barrier lesion this node models.
            evidence:
              - reference: PMID:38776392
                reference_title: >-
                  Gain-of-function mutations of TRPV4 acting in endothelial
                  cells drive blood-CNS barrier breakdown and motor neuron
                  degeneration in mice.
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  Symptomatic mutant mice exhibited focal disruptions of
                  blood-spinal cord barrier (BSCB) integrity
                explanation: >-
                  The measurement itself.
          - name: Phenotypic response to systemic TRPV4 antagonist
            target: Endothelial Blood-CNS Barrier Breakdown
            direction: RESTORED
            interpretation: >-
              The rescue arm. Establishes that the barrier lesion is reversible
              pharmacologically, which is what makes the human translation
              question worth asking rather than idle.
            evidence:
              - reference: PMID:38776392
                reference_title: >-
                  Gain-of-function mutations of TRPV4 acting in endothelial
                  cells drive blood-CNS barrier breakdown and motor neuron
                  degeneration in mice.
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  Systemic administration of a TRPV4-specific antagonist
                  abrogated channel-mediated BSCB impairments and provided a
                  marked phenotypic rescue of symptomatic mutant mice.
                explanation: >-
                  Reports both the barrier and the phenotypic rescue.
        evidence:
          - reference: PMID:38776392
            reference_title: >-
              Gain-of-function mutations of TRPV4 acting in endothelial cells
              drive blood-CNS barrier breakdown and motor neuron degeneration in
              mice.
            supports: SUPPORT
            evidence_source: MODEL_ORGANISM
            snippet: >-
              Genetic deletion of the mutant Trpv4 allele from endothelial cells
              (but not neurons, glia, or muscle) rescued these phenotypes.
            explanation: >-
              The cell-type-specific rescue that makes this model informative
              about where the lesion begins, not merely that it occurs.
      - target: Motor-Predominant Axonal Degeneration
        relationship: PARTIALLY_RECAPITULATES
        fidelity: MODERATE
        description: >-
          Weakness and regional motor neuron loss are reproduced, but with early
          lethality that human CMT2C does not show.
        limitations: >-
          The mouse disease is more severe and differently shaped than the human
          one: knock-in mice die early and their phenotype is vascular-dominant,
          whereas human CMT2C is a chronic, slowly progressive neuropathy whose
          defining features are vocal cord and diaphragm involvement with normal
          or near-normal lifespan. The model is therefore strong evidence about
          mechanism and weak evidence about natural history, and a therapeutic
          rescue measured against early murine death should not be read as
          predicting benefit against decades of human axonal loss.
        readouts:
          - name: Regional motor neuron number
            target: Motor-Predominant Axonal Degeneration
            direction: DECREASED
            interpretation: >-
              The degenerative endpoint, reproduced in the model.
            evidence:
              - reference: PMID:38776392
                reference_title: >-
                  Gain-of-function mutations of TRPV4 acting in endothelial
                  cells drive blood-CNS barrier breakdown and motor neuron
                  degeneration in mice.
                supports: SUPPORT
                evidence_source: MODEL_ORGANISM
                snippet: >-
                  TRPV4 mutant mice exhibited weakness, early lethality, and
                  regional motor neuron loss.
                explanation: >-
                  Reports the motor neuron loss, and in the same sentence the
                  early lethality that grounds the limitation above.
treatments:
  - name: Orthoses and Mobility Support
    description: >-
      Ankle-foot and knee-ankle-foot orthoses, shoes with good ankle support,
      surgery for severe foot deformities, mobility devices and exercise as
      tolerated. Symptomatic management, which is what exists for this disease.
    therapeutic_modality: DEVICE
    treatment_term:
      preferred_term: physical therapy
      term:
        id: NCIT:C15302
        label: Physical Therapy
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          For neuromuscular disorders, additional treatment includes special
          shoes with good ankle support, shoe orthotics, ankle-foot orthoses /
          knee-ankle-foot orthoses, surgery for severe foot deformities,
          mobility devices, and exercise as tolerated
        explanation: >-
          The GeneReviews management protocol for the neuromuscular arm. Scope
          caveat as elsewhere in this entry: GeneReviews covers all three TRPV4
          neuromuscular phenotypes together.
  - name: Laryngeal Surgery for Vocal Cord Paresis
    description: >-
      Vocal fold lateralization or tracheostomy in individuals with severe
      laryngeal involvement. This is the intervention the entry's defining
      phenotype leads to.
    therapeutic_modality: SURGERY
    treatment_term:
      preferred_term: surgical procedure
      term:
        id: NCIT:C15329
        label: Surgical Procedure
    target_mechanisms:
      - target: Laryngeal and Diaphragmatic Denervation
        description: >-
          Relieves the airway consequence of laryngeal denervation. It does not
          act on the channel or the degeneration.
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          laryngeal surgery for vocal cord paresis (in some individuals, vocal
          fold lateralization or tracheostomy); speech therapy; and respiratory
          therapy including noninvasive ventilatory support as needed
        explanation: >-
          Names the laryngeal and respiratory interventions. Same GeneReviews
          scope caveat.
  - name: Avoidance of Neurotoxic Medications and Respiratory Infection
    description: >-
      GeneReviews names specific circumstances to avoid, and one of them is
      unusually consequential here: upper respiratory tract infection can swell
      the vocal folds and worsen upper airway obstruction in a patient whose
      folds are already paretic. Diabetes and neurotoxic drugs are to be avoided
      as additional insults to an already compromised nerve.
    therapeutic_modality: BEHAVIORAL
    treatment_term:
      preferred_term: supportive care
      term:
        id: NCIT:C15747
        label: Supportive Care
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          For neuromuscular disorders, avoid diabetes and neurotoxic
          medications; upper respiratory tract infections can cause vocal fold
          swelling and worsen upper airway obstruction.
        explanation: >-
          The agents-and-circumstances-to-avoid guidance, including the
          respiratory-infection interaction with vocal fold paresis.
diagnosis:
  - name: Molecular Genetic Testing with Characteristic Neurophysiology
    description: >-
      Diagnosis rests on characteristic clinical and neurophysiologic findings
      plus a heterozygous TRPV4 pathogenic variant. The neurophysiology is what
      separates this from demyelinating CMT: the neuropathy is axonal, so
      compound muscle action potential amplitudes are reduced while conduction
      velocities remain normal or near-normal.
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          The diagnosis of an autosomal dominant TRPV4-related disorder is
          established in a proband who has characteristic clinical and
          neurophysiologic findings, radiographic findings in the skeletal
          dysplasias, and a heterozygous TRPV4 pathogenic variant identified by
          molecular genetic testing.
        explanation: >-
          The diagnostic criteria. Note the sentence is about TRPV4-related
          disorders as a group; the axonal electrophysiology detail in this
          node's description is standard for CMT2 and is not asserted by this
          quote.
  - name: Surveillance for Laryngeal and Respiratory Involvement
    description: >-
      Because laryngeal and diaphragmatic severity does not track limb severity,
      respiratory and laryngeal surveillance has to be scheduled independently
      of the neurological examination rather than triggered by it.
    evidence:
      - reference: PMID:24830047
        reference_title: "Autosomal Dominant TRPV4-Related Disorders."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: >-
          For neuromuscular disorders, annual neurologic examination, physical
          therapy assessment, otolaryngology evaluation of laryngeal function,
          dynamic breathing chest radiograph, pulmonary function tests, sleep
          study, hearing assessment, and musculoskeletal evaluation
        explanation: >-
          The surveillance schedule, which is the concrete answer to the
          "warrants independent surveillance" claim the respiratory phenotype
          makes.
📚

References & Deep Research

References

1
PMID:24830047
Autosomal Dominant TRPV4-Related Disorders.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Charcot-Marie-Tooth Disease Axonal Type 2C (CMT2C) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 32 citations 2026-08-27T23:21:20.584794

Charcot-Marie-Tooth Disease Axonal Type 2C (CMT2C) — Comprehensive Research Report

1. Disease Information

Overview: Charcot-Marie-Tooth disease axonal type 2C (CMT2C), also designated Hereditary Motor and Sensory Neuropathy type IIC (HMSN2C), is an autosomal dominant, motor-predominant, non-length-dependent peripheral neuropathy or motor neuronopathy caused by heterozygous gain-of-function mutations in TRPV4. It is one of three clinically recognized autosomal dominant "TRPV4 neuromuscular disorders" — alongside scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA/CSMA) — which together with a family of TRPV4 skeletal dysplasias constitute the broader "TRPV4-pathy" spectrum (GeneReviews: Autosomal Dominant TRPV4-Related Disorders; Nature Genetics 2010, ng.512; J Hum Genet 2010, jhg201037).

Key identifiers: - OMIM: #606071 — Hereditary Motor and Sensory Neuropathy, Type IIC (HMSN2C) (OMIM 606071); the TRPV4 gene entry is OMIM 605427 (OMIM 605427) - Orphanet: ORPHA:99937 — "Autosomal dominant Charcot-Marie-Tooth disease type 2C" (Orphanet 99937) - MONDO/MedGen: MedGen concept C1853710 (MedGen 342947; GARD) - Gene: TRPV4 (transient receptor potential cation channel subfamily V member 4), chromosome 12q24.11 - Allelic disorders (same gene, different phenotype "bin"):* Scapuloperoneal spinal muscular atrophy (SPSMA, OMIM 181405), congenital distal spinal muscular atrophy (CDSMA/HMND8, OMIM 600175), and a family of TRPV4 skeletal dysplasias (metatropic dysplasia, spondylometaphyseal dysplasia Kozlowski type, brachyolmia, parastremmatic dysplasia)

Synonyms: HMSN2C; CMT2C; hereditary motor and sensory neuropathy type 2C; TRPV4-related axonal neuropathy; CMT2C with vocal cord paresis.

Evidence basis: This is an aggregated disease-level entity, not derived from a single EHR cohort. Curation rests on published case series/family pedigrees, a small number of dedicated CMT2 patient cohorts (USA, European, Australian), the OMIM/Orphanet/GeneReviews synthetic entries, and mechanistic cell/animal-model studies — not large-scale registry or claims data.

2. Etiology

Primary cause: CMT2C is caused entirely by heterozygous, dominantly acting, gain-of-ion-channel-function missense variants in TRPV4 (Deng et al., Nat Genet 2010;42:165–169; Landouré et al., Nat Genet 2010, ng.512). It is a monogenic Mendelian disorder — there is no evidence for polygenic, infectious, or purely environmental causation of the core neuropathy phenotype.

Genetic risk factors: - Causal variants cluster on "the highly positively charged convex surface of the ankyrin repeat domain," targeting strictly conserved arginine residues in three consecutive finger loops of the protein (GeneReviews NBK201366). - Well-validated recurrent pathogenic variants: p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys, p.Arg316His (GeneReviews NBK201366). The founding CMT2C family carried c.806G>A (p.Arg269His) (Deng et al. 2010); another kindred with the founding phenotype carried the paralogous c.805C>T/c.806G>A → R269C/R269H substitutions at the same residue (review, PMC10311707). - Modifier/severity determinants: the same residue can produce markedly different severity; "the degree of baseline calcium elevation correlates with development of mixed [neuropathy + skeletal] phenotypes and sensitivity to pharmacologic channel inhibition" (Nishida/Zhu et al., PMC8935273). No independent trans-acting modifier gene has been established for the neuromuscular phenotype. - Reduced penetrance and highly variable expressivity are intrinsic features — the specific subtype (CMT2C vs. SPSMA vs. CDSMA), age of onset, and severity "cannot be accurately predicted" from genotype alone (GeneReviews NBK201366).

Environmental/lifestyle risk factors: None specific to disease causation are documented (this is a fully penetrant-genotype, non-environmentally-triggered channelopathy). However, several environmental/physiologic exposures exacerbate manifestations in carriers: - Obesity worsens ambulation (GeneReviews NBK201366) - Upper respiratory tract infections can precipitate acute worsening of vocal-fold/airway obstruction via laryngeal edema (GeneReviews NBK201366) - Neurotoxic medications (standard CMT avoid-list) can accelerate neuropathy - Pregnancy: ~50% of women with CMT report increased weakness during pregnancy, typically resolving postpartum; CMT pregnancies show higher rates of placenta previa, abnormal fetal presentation, and preterm delivery, though overall neonatal outcomes are comparable to background populations (GeneReviews NBK201366)

Protective factors: No genetic or environmental protective factors are described in the literature for TRPV4 neuromuscular disease; this contrasts with skeletal-dysplasia TRPV4 alleles, where no protective variants are documented either.

Gene-environment interaction: Not a recognized feature of this disorder; the driving mechanism is cell-autonomous/vascular channel gain-of-function rather than an environmentally modulated genetic susceptibility.

3. Phenotypes

CMT2C exists on a phenotypic continuum with SPSMA and CDSMA. Core features (with suggested HPO terms):

Phenotype Type Frequency/Notes Suggested HPO
Distal limb weakness/atrophy, pes cavus, foot drop Sign Core feature; onset early childhood–age 25 typically, but ranges birth to 8th decade HP:0003693 (Distal amyotrophy), HP:0001761 (Pes cavus), HP:0001771 (Foot drop... use HP:0001269 foot drop analog)
Non-length-dependent, proximal + asymmetric weakness Sign Shoulder abduction weakness, scapular winging, asymmetric knee extension/hip flexion weakness — distinguishes CMT2C from typical length-dependent CMT HP:0003324 (Generalized muscle weakness), HP:0003691 (Proximal muscle weakness), HP:0003691
Vocal fold (cord) paresis/paralysis Sign "Hallmark" feature across all TRPV4 neuromuscular subtypes; bilateral or asymmetric, often worse on left; hoarse voice/inspiratory stridor HP:0001611 (Hoarse voice), HP:0012046 (Vocal cord paralysis), HP:0010307 (Vocal cord paresis)
Diaphragm weakness / respiratory insufficiency Sign Orthopnea, decreased inspiratory/expiratory pressures, sleep apnea incl. central HP:0009088 (Diaphragmatic paralysis/weakness), HP:0002093 (Respiratory insufficiency), HP:0002104 (Apnea)
Sensorineural hearing loss Sign Bilateral, progressive, mild–moderate, childhood–adult onset (locus overlaps DFNA25) HP:0000407 (Sensorineural hearing impairment)
Sensory loss (vibration > pain) Symptom Present in a subset; predominantly motor disease overall HP:0003390 (Loss of proprioception... use HP:0003701 or vibratory), HP:0007099
Kyphoscoliosis / joint contractures / hip dysplasia Sign Ankle, knee, hip contractures common; tethered spinal cord in 7.5% of a 40-patient cohort HP:0002751 (Kyphoscoliosis), HP:0034332 (Joint contracture), HP:0001385 (Hip dysplasia), HP:0002230 (Tethered cord)
Short stature Sign Present in a subset, overlaps skeletal-dysplasia end of spectrum HP:0004322
Bladder dysfunction Sign Incontinence, urinary frequency HP:0000010 (Urinary bladder sphincter dysfunction)
Skin changes Sign Scaliness, dryness, itching, fissures (reported subset) HP:0000962 (Dry skin)

Onset: Highly variable — "usually between early childhood and age 25 years," but documented range is birth to after the 8th decade; some carriers have subtle findings that escape clinical recognition entirely (reduced penetrance) (GeneReviews NBK201366). Course is chronic/progressive in most, but severity and rate vary widely even within one family carrying the identical variant.

Severity/progression: "There is a wide range of phenotypic severity; in the mildest of the autosomal dominant TRPV4-related disorders life span is normal, whereas in the most severe it is shortened" (GeneReviews NBK201366). Suggestive "red flag" combination for clinicians: vocal cord paralysis + scapular weakness/wasting + skeletal dysplasia + hearing loss in a CMT2 patient (Neurology 2015, Neurology 2014 WNL.0000000000000450; NeuroMolecular Medicine 2019).

Quality of life: No CMT2C-specific EQ-5D/SF-36 data were identified; general CMT registry literature documents mobility impairment, orthotic/AFO dependence, and — distinctively for this subtype — impact from laryngeal dysfunction (dysphonia, aspiration risk, airway obstruction) and respiratory limitation, which are less prominent in typical demyelinating/axonal CMT.

4. Genetic/Molecular Information

Causal gene: TRPV4 (HGNC:17728, chr12q24.11); OMIM gene entry *605427.

Variant classification/type: Exclusively missense (with rare splice-site variants reported in ClinVar, e.g., c.2209-5C>T); no whole-gene deletions/duplications have been reported for the autosomal dominant neuromuscular phenotype, and sequence analysis alone identifies essentially 100% of currently known pathogenic variants (GeneReviews NBK201366). ClinVar lists numerous variant-specific submissions explicitly annotated "AND Charcot-Marie-Tooth disease axonal type 2C," e.g. p.Arg774Cys, p.Arg464Cys, p.Arg151Trp, p.Arg315Trp (ClinVar RCV000645535; RCV000645552; RCV000005291).

Functional consequence: Uniformly gain of channel function (not loss of function) — increased constitutive and agonist-evoked Ca²⁺ influx through the mutant channel, producing "cytotoxic hypercalcemia" (Neurology 2011, WNL.0b013e31820f2de3; PMID 21288981). Original functional work: HEK293 cells transfected with mutant TRPV4 (R269H) showed normal plasma-membrane trafficking but markedly increased constitutive and stimulus-evoked channel currents plus cellular toxicity (Deng et al. 2010; Landouré et al. 2010).

Allele frequency: These are rare, largely private, dominant disease-causing missense variants; population allele frequency in gnomAD is expected to be near-absent for pathogenic alleles (no specific carrier-frequency estimate was located in this search — flag as data gap).

Origin: Both inherited (familial, autosomal dominant transmission with 50% recurrence risk) and de novo cases occur; severe skeletal-dysplasia-end phenotypes are typically de novo in unaffected parents, while milder/classic neuromuscular phenotypes are more often inherited (GeneReviews NBK201366). No somatic/mosaic TRPV4 CMT2C cases were identified in this search.

Modifier genes: None specific and validated; phenotypic variability appears largely explained by variant position/severity of channel gain-of-function rather than a distinct modifier locus (see §2).

Structural/mechanistic basis: Cryo-EM structures of TRPV4 in complex with RhoA GTPase show that many disease residues lie at the TRPV4–RhoA interface; disrupting this interface (by mutating either partner) increases TRPV4 channel activity, drives cytoskeletal remodeling, and impairs neurite extension (Deng lab/PMC10290081; PMID 33664271). A second regulatory mechanism involves ubiquitination of intrinsically disordered N- and C-terminal cytosolic regions of TRPV4: neuropathy-causing gain-of-function mutations reduce channel ubiquitination in cellular and Drosophila models, and experimentally increasing mutant-channel ubiquitination partially suppresses channel overactivity (Aisenberg et al., J Biol Chem 2022, PMC9010760).

Epigenetics/chromosomal abnormalities: Not described as relevant to this single-gene channelopathy; no epigenetic or large chromosomal-rearrangement mechanism has been reported.

5. Environmental Information

CMT2C is not primarily environmentally caused, but relevant environmental/exposure modulators of morbidity include: - Upper respiratory infection — precipitates vocal-fold edema and can acutely worsen airway obstruction in patients with baseline vocal-fold paresis (GeneReviews NBK201366) - Neurotoxic drug exposure — standard CMT avoidance list (vincristine and other agents) can worsen underlying axonal neuropathy - Obesity — a modifiable factor worsening ambulatory function - No infectious agent is causally implicated in CMT2C itself (distinct from acquired/inflammatory neuropathies).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular initiating event: Heterozygous missense variant in the ankyrin-repeat domain (or C-terminal region) of TRPV4 disrupts autoinhibitory conformational constraints, including loss of normal TRPV4–RhoA interaction and reduced channel ubiquitination/turnover (PMC10290081; PMC9010760).
  2. Molecular consequence: Constitutive and stimulus-evoked gain of Ca²⁺-channel function — excess Ca²⁺ influx through the nonselective cation channel (Nat Genet 2010; Neurology 2011 PMID 21288981).
  3. Cellular consequence: "Cytotoxic hypercalcemia" — sustained intracellular Ca²⁺ overload causes cytoskeletal/RhoA-pathway dysregulation, impaired neurite extension, and cell process retraction in neuronal/glial cell models (PMID 33664271).
  4. Vascular/barrier consequence (new mechanistic insight, 2024): Knock-in mouse models (R269C, R232C) show that the dominant pathogenic driver is TRPV4 gain-of-function specifically in vascular endothelial cells, causing focal breakdown of the blood–spinal cord barrier (BSCB); genetic deletion of mutant Trpv4 from endothelial cells (but not neurons, glia, or muscle) rescues the motor phenotype, indicating a non-cell-autonomous, endothelial-driven mechanism of motor neuron degeneration (Chen et al., PMC11316273, PMID 38776392).
  5. Tissue/organism consequence: Regional anterior horn cell/motor neuron loss, motor axon degeneration → progressive limb, laryngeal, diaphragmatic, and (in overlap cases) skeletal phenotypes.

Molecular pathways: TRPV4 calcium signaling; RhoA GTPase/cytoskeletal remodeling pathway; ubiquitin-proteasome-linked channel turnover regulation.

Cellular processes: Calcium-dependent cytotoxicity; impaired neurite outgrowth; vascular endothelial barrier dysfunction; (in the skeletal-dysplasia allelic spectrum) altered chondrocyte hypertrophic differentiation — TRPV4 skeletal-dysplasia mutations "suppress the hypertrophic differentiation of human iPSC-derived chondrocytes" (biorxiv preprint referenced in search, distinguishing the skeletal branch mechanistically from the neuromuscular branch).

Suggested ontology terms: - GO biological process: GO:0070588 (calcium ion transmembrane transport), GO:0007584 (response to nutrient — n/a), better: GO:0006816 (calcium ion transport), GO:0007015 (actin filament organization, via RhoA), GO:0007520 (myoblast fusion — n/a) - GO molecular function: GO:0005227 (calcium-activated cation channel activity), GO:0015276 (ligand-gated ion channel activity) - Cell types (CL): CL:0000540 (neuron)/CL:0011031 (spinal cord motor neuron), CL:0002139 (vascular associated smooth muscle... or) CL:0002139/CL:0000115 (endothelial cell), CL:0000499 (stromal cell — n/a)

Biochemical abnormality: Ion channel gain-of-function (not enzyme deficiency); no metabolic pathway defect is implicated.

Immune involvement: None established; this is not an inflammatory/autoimmune neuropathy.

Omics: No large-scale human transcriptomic/proteomic/metabolomic dataset specific to CMT2C patient tissue was identified in this search (data gap). Model-system transcriptomic/functional-genomics data exist chiefly in the Drosophila and mouse knock-in systems described above and in the endothelial-lineage-tracing study (PMC11316273).

7. Anatomical Structures Affected

Organ/system level: - Peripheral nervous system: motor and (secondarily) sensory peripheral nerves; anterior horn cells (motor neuronopathy component) - Larynx: vocal fold/recurrent laryngeal nerve-innervated musculature - Respiratory system: diaphragm, intercostal muscles - Auditory system: cochlea (sensorineural hearing loss) - Musculoskeletal system: distal and (asymmetrically) proximal limb muscles; spine (kyphoscoliosis, tethered cord); joints (contractures, hip dysplasia) - Vasculature: spinal cord microvascular endothelium (per the 2024 mouse mechanism data) — UBERON: blood-spinal cord barrier - Urinary system: bladder (dysfunction reported) - Integument: skin (dryness/fissuring in a subset)

Suggested UBERON terms: UBERON:0001017 (central nervous system) — not primary; UBERON:0002240 (spinal cord), UBERON:0002423 (anterior horn), UBERON:0001519 (larynx), UBERON:0002616 (diaphragm), UBERON:0001846 (cochlea), UBERON:0002471 (skeletal muscle organ), UBERON:0007798 (skeletal system), UBERON:0001981 (blood vessel endothelium).

Tissue/cell level: Lower motor neurons (anterior horn cells); axons of peripheral motor nerves; laryngeal muscles; vascular endothelial cells of the spinal cord microvasculature (mechanistically central per 2024 mouse data); cochlear hair cells/stria vascularis (candidate site for hearing loss, given TRPV4's proposed role transporting K⁺ into the endolymph at the DFNA25 locus).

Subcellular: Plasma membrane (TRPV4 channel localization); cytoskeleton (RhoA-regulated actin remodeling); N-/C-terminal intrinsically disordered cytosolic domains (site of regulatory ubiquitination).

Suggested GO Cellular Component terms: GO:0005886 (plasma membrane), GO:0015629 (actin cytoskeleton).

Laterality: Weakness/wasting and vocal-fold paresis are frequently asymmetric — a distinguishing clinical clue versus typical symmetric length-dependent CMT (GeneReviews NBK201366; left side often more severely affected for vocal fold paresis).

8. Temporal Development

Onset: Extremely variable — "usually between early childhood and age 25 years," documented range birth to 8th decade+ (GeneReviews NBK201366). Onset pattern is generally insidious/chronic rather than acute, though congenital presentations (overlapping CDSMA) exist at the severe end of the spectrum.

Progression: Chronic, generally slowly progressive; disease course pattern is progressive rather than relapsing-remitting. Severity is markedly variable even within a family sharing the identical variant, consistent with variable expressivity. No formalized clinical staging system specific to CMT2C exists (unlike, e.g., cancer staging); severity is generally described qualitatively (mild/moderate/severe) and via CMT-specific functional scales (e.g., CMTNS) in the broader CMT literature.

Duration/course: Chronic, lifelong. Most patients have a normal lifespan; the most severely affected (especially those with significant respiratory/diaphragmatic involvement) may have reduced life expectancy from respiratory complications (GeneReviews NBK201366).

Remission: Not a relapsing-remitting disease; no spontaneous remission pattern is described. Pregnancy-associated worsening typically resolves postpartum (see §2).

Critical periods: Early recognition of laryngeal/respiratory involvement is clinically critical because airway compromise (from vocal-fold paresis plus superimposed URI-related edema) can be acutely life-threatening, making this a key intervention window distinct from the general limb-weakness natural history.

9. Inheritance and Population

Epidemiology: CMT2C is rare among an already-rare disease group. TRPV4 pathogenic variants account for ~1–3.5% of CMT2/hereditary motor neuropathy (HMN) overall (GeneReviews NBK201366). In specific published cohorts: - 13/422 individuals (<1%) with a general CMT2 phenotype carried heterozygous TRPV4 variants; this rose to 9–16% among CMT2 patients selected for additional atypical features (vocal fold weakness, diaphragmatic paresis, skeletal dysplasia) (GeneReviews NBK201366; Neurology 2015, WNL.0000000000000450) - A USA cohort of 62 unrelated CMT2 patients (MFN2/GARS/NEFL/GDAP1-negative) found 2 TRPV4 mutations (R316C, R269C) — ~3.2% (NeuroMolecular Medicine 2019) - Incidence across European/Australian axonal-neuropathy cohorts ranges 0–7%, and data from outside Europe/Australia/USA remain largely unknown (Neurology 2015) - Orphanet epidemiologic class: rare disease (prevalence class consistent with "<1/1,000,000" to "not yet documented" tier typical of CMT2 subtypes; exact Orphanet prevalence class was not directly captured in this search — recommend confirming via a direct Orphanet epidemiology table pull before finalizing).

Inheritance: Autosomal dominant, by definition (OMIM 606071). Recurrence risk to offspring of an affected individual is 50%.

Penetrance: Reduced — not all variant carriers manifest symptoms, and asymptomatic/subclinically affected carriers are documented (GeneReviews NBK201366; MedGen 342947).

Expressivity: Highly variable — same variant can produce anything from a CMT2C-limb phenotype to SPSMA to CDSMA to a mixed neuropathy/skeletal-dysplasia phenotype, even within one family (review PMC10311707).

Genetic anticipation: Not reported as a feature (this is a channelopathy caused by point missense variants, not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the literature reviewed here (data gap).

Founder effects: Not established for CMT2C specifically; the recurrent Arg-residue "hotspot" variants (e.g., R269C/H, R316C/H) likely reflect mutational hotspots at CpG-type or structurally constrained codons rather than a single founder haplotype, though this was not explicitly confirmed in the sources reviewed.

Consanguinity: Autosomal dominant CMT2C does not require consanguinity; however, homozygous TRPV4 mutations have been reported causing the more severe, biallelic congenital distal SMA/arthrogryposis phenotype in a consanguineous setting (Neurology Genetics, NXG.0000000000000312) — a distinct, allelic (not identical) disease entity.

Carrier frequency: Not established at a population level (extremely rare, largely private variants).

Population demographics: No specific ethnic or geographic predilection has been established for CMT2C; cases have been reported across European, North American, and Asian cohorts. Sex ratio: no strong skew reported (autosomal dominant disorder).

10. Diagnostics

Molecular genetic testing (primary/definitive): - Sequence analysis of TRPV4 is first-line, detecting missense, nonsense, splice-site variants, and small indels; identifies ~100% of currently known pathogenic variants; whole-gene deletion/duplication has not been reported in the autosomal dominant neuromuscular phenotype (GeneReviews NBK201366) - Testing modalities: single-gene sequencing, multigene CMT/HMN panels (including the differential-diagnosis gene list below), or phenotype-focused exome analysis

Electrophysiology (EMG/NCV): - Reduced compound motor action potential (CMAP) amplitudes with normal conduction velocities (>40–60 m/s) — consistent with an axonal/neuronopathic rather than demyelinating process - Sensory nerve action potentials (SNAPs): normal, decreased, or absent - EMG: predominantly chronic neurogenic changes (GeneReviews NBK201366)

Other clinical tests: - Laryngoscopy for vocal fold paresis - Pulmonary function testing and dynamic breathing chest radiographs for diaphragm assessment - Sleep study (central/obstructive sleep apnea screening) - Audiologic evaluation (sensorineural hearing loss) - Skeletal imaging when skeletal-dysplasia overlap is suspected - Spinal MRI to evaluate for tethered cord in appropriate clinical settings

Diagnostic criteria: Diagnosis is established by combining "characteristic clinical and neurophysiologic findings" with identification of a heterozygous TRPV4 variant suspected to cause channel gain-of-function (GeneReviews NBK201366).

Differential diagnosis (genes to exclude/consider): ATP7A, BICD2, BSCL2, DCTN1, DYNC1H1, GARS1, HSPB1, HSPB3, HSPB8, IGHMBP2, JAG1, MYH14, PLEKHG5, SETX, SLC5A7, SMN1 (GeneReviews NBK201366) — these overlap clinically as other distal hereditary motor neuropathies/CMT2/SMA-spectrum disorders.

Screening: No population-based newborn screening; genetic counseling and predictive/cascade testing are offered to at-risk relatives given autosomal dominant inheritance and 50% recurrence risk, with the caveat that penetrance/expressivity cannot be predicted.

11. Outcome/Prognosis

  • Survival: Most affected individuals have a normal lifespan. A subset with severe respiratory (diaphragmatic) involvement may have shortened life expectancy secondary to respiratory complications (GeneReviews NBK201366).
  • Morbidity: Chronic motor disability (distal and proximal weakness, foot deformity, need for orthoses/mobility aids), laryngeal dysfunction with aspiration/airway risk, restrictive respiratory impairment, progressive hearing loss, and skeletal complications (scoliosis, contractures, hip dysplasia, tethered cord in ~7.5% of one 40-patient cohort).
  • Complications: Airway obstruction precipitated by intercurrent URI in the context of pre-existing vocal fold paresis is a specifically flagged acute risk. Aspiration pneumonia risk from laryngeal dysfunction. Sleep-disordered breathing (including central sleep apnea).
  • Recovery potential: The underlying motor neuron/axonal loss is not reversible with current standard-of-care (supportive) management; functional improvement is achieved via orthotic/surgical/rehabilitative support rather than disease reversal. The investigational TRPV4-inhibitor pipeline (see §12) specifically aims to change this by targeting the causal channel gain-of-function.
  • Prognostic factors: Variant identity/position (correlating with degree of baseline Ca²⁺ elevation) predicts development of mixed neuropathy-skeletal phenotypes and in vitro sensitivity to pharmacologic channel inhibition — a mechanistic biomarker relevant to future trial stratification (PMC8935273).

12. Treatment

There is currently no approved disease-modifying therapy; management is supportive/multidisciplinary, though a mechanistically targeted therapeutic is in active clinical development.

Multidisciplinary supportive care (NCIT terms suggested in parentheses): - Orthotic/mobility support: supportive shoes, orthotics, ankle-foot orthoses/knee-ankle-foot orthoses; orthopedic surgery for severe foot deformity (NCIT:C16186, Orthopedic Surgical Procedure); mobility aids and exercise as tolerated (NCIT:C15302, Physical Therapy) - Laryngeal management: vocal fold lateralization surgery or tracheostomy in severe airway compromise; speech therapy (NCIT:C15329, Surgical Procedure; speech-language therapy term) - Respiratory management: noninvasive ventilatory support, pulmonary function monitoring (NCIT:C15747, Supportive Care) - Spinal/orthopedic management: kyphoscoliosis management; neurosurgical release of tethered spinal cord when symptomatic - Audiology: hearing aids/rehabilitation - Genetic counseling (NCIT:C15240) - Preventive care: avoidance of obesity, avoidance of known neurotoxic medications, prompt treatment of URIs

Experimental/targeted therapeutics (therapeutic_modality: SMALL_MOLECULE, mechanism: TRPV4 channel antagonism): - ABS-0871 (Actio Biosciences) — a novel oral TRPV4 inhibitor purpose-built for TRPV4-positive CMT2C. First-in-human Phase 1 healthy-volunteer trial dosing began March 2025; the drug received FDA Orphan Drug Designation and Rare Pediatric Disease Designation in August 2024. In "novel construct-valid preclinical CMT2C rare disease models," ABS-0871 produced "marked improvements in motor function and mobility compared to untreated controls" (BioSpace press release; CMTAUSA; Actio Biosciences). - Proof-of-concept preclinical rescue: Trpv4 knock-in mice with the severe, rapidly fatal neuromuscular phenotype can be rescued by pharmacologic inhibition of TRPV4 channel activity (GeneReviews NBK201366), providing strong mechanistic rationale for the antagonist approach. - Other TRPV4 antagonist tool/clinical compounds (used in broader TRPV4-pathy research, not CMT2C-specific trials): HC-067047 (a pyrrolocarboxamide research antagonist, IC50 ~48 nM human TRPV4) and GSK2798745 (a spiro-carbamate that advanced to Phase II for heart failure/pulmonary edema indications, demonstrating human tolerability of TRPV4 antagonism as a drug class) (MedChemExpress HC-067047; PMID 34531959). - CMT Research Foundation / HNF natural history study of TRPV4 neuromuscular disease (CMT2C) is ongoing to characterize disease trajectory and support trial readiness (CMTAUSA natural history; HNF TRPV4 program).

Pharmacogenomics: Not applicable/established for this monogenic channelopathy (no drug-metabolism pharmacogenomic modifier reported).

Treatment strategy: Because the causal lesion is a well-characterized channel gain-of-function, the field's guiding treatment algorithm is genotype-directed small-molecule channel antagonism layered on top of standard multidisciplinary supportive/rehabilitative care — a precision-medicine approach analogous to other channelopathies.

13. Prevention

  • Primary prevention: Not applicable in the population sense (autosomal dominant single-gene disorder); the relevant "prevention" lever is reproductive/genetic counseling rather than public-health risk-factor modification.
  • Secondary prevention (early detection):
  • Genetic counseling and predictive testing for at-risk relatives of a known proband (50% recurrence risk), with explicit counseling that reduced penetrance/variable expressivity precludes reliable phenotype prediction
  • Prenatal/preimplantation genetic testing options can be discussed for known familial variants (general reproductive-genetics principle; not specifically documented as routinely used for CMT2C in the sources reviewed)
  • Vigilant surveillance for laryngeal/respiratory involvement in known carriers, given the acute-risk nature of airway compromise
  • Tertiary prevention (complication avoidance in affected individuals): Recommended annual surveillance per GeneReviews includes neurologic exam/PT assessment, otolaryngology evaluation of laryngeal function, dynamic breathing chest radiograph + pulmonary function tests, sleep study, hearing assessment, musculoskeletal evaluation (contractures, hip dysplasia, scoliosis, tethered cord signs), and weight/height/obesity assessment (GeneReviews NBK201366).
  • Agents/circumstances to avoid: Obesity, known neurotoxic medications (per CMT Association neurotoxic drug list), and untreated upper respiratory infections (risk of acute airway compromise from vocal-fold edema).
  • Immunization: No CMT2C-specific vaccine strategy; general recommendation would be routine respiratory-pathogen immunization (e.g., influenza) given baseline respiratory vulnerability, though this is inferred rather than explicitly documented in the sources found.
  • Genetic counseling: Central to prevention/family planning in this dominant disorder; standard NSGC/ACMG genetic-counseling frameworks apply.

14. Other Species / Natural Disease

  • Taxonomy of study organisms: Mus musculus (NCBITaxon:10090), Drosophila melanogaster (NCBITaxon:7227); orthologous Trpv4 gene exists broadly across vertebrates.
  • Naturally occurring disease in other species: No naturally occurring companion-animal or wildlife TRPV4 neuropathy analog was identified in this search (this appears to be a human-specific documented clinical entity to date; OMIA search was not directly performed but no hits surfaced organically — flag as a gap to confirm via a direct OMIA query if veterinary relevance is needed).
  • Orthologous gene: Mouse Trpv4 (MGI ortholog of human TRPV4) is the basis of the knock-in disease models described below; NCBI Gene entries exist for mouse and other model organisms' Trpv4 orthologs.
  • Comparative pathology/evolutionary conservation: The ankyrin-repeat arginine residues mutated in human disease are evolutionarily conserved, which is why mouse knock-in of the orthologous R269C/R232C substitutions faithfully reproduces a severe motor phenotype (see below) — supporting deep functional conservation of the TRPV4 channel-gating mechanism across mammals.
  • Zoonotic potential/transmission: Not applicable — this is a non-infectious monogenic channelopathy.

15. Model Organisms

Mouse (mammalian genetic knock-in models): - Trpv4^R269C and Trpv4^R232C knock-in mice (endogenous locus, disease-causing missense knock-ins) exhibit weakness, early lethality, and regional motor neuron loss, closely recapitulating the severe end of the human phenotype spectrum (Chen et al. 2024, PMC11316273; PMID 38776392). - Symptomatic mutant mice show focal disruption of blood–spinal cord barrier (BSCB) integrity, linked to endothelial-cell-autonomous TRPV4 gain-of-function. - Key causal/rescue experiment: Conditional genetic deletion of the mutant Trpv4 allele specifically from vascular endothelial cells (but not from neurons, glia, or muscle) rescues the motor and survival phenotypes — establishing endothelial cells, not neurons, as the primary disease-driving cell type in this model (PMC11316273). - Separately, GeneReviews notes that Trpv4 knock-in mice with a "severe, rapidly progressive fatal neuromuscular phenotype" can be rescued by pharmacologic TRPV4 channel inhibition, directly supporting the small-molecule antagonist therapeutic strategy now in human trials (GeneReviews NBK201366). - Limitations: As with many gain-of-function knock-in models, the mouse phenotype (early lethality, prominent vascular/BSCB pathology) is more acute/severe than the typical chronic, slowly progressive human CMT2C course — the vascular-barrier mechanism's relative contribution in human disease (versus a purely cell-autonomous neuronal mechanism) remains an area of active investigation, representing a human-model translational-fidelity open question worth flagging as a HUMAN_MODEL_MISMATCH-type knowledge gap for KB curation (rodent lethality/BSCB phenotype vs. the typically non-lethal, chronic human trajectory).

Cellular/heterologous models: - HEK293 cells transiently transfected with mutant TRPV4 constructs (the original functional-validation system) — demonstrate increased constitutive/evoked Ca²⁺ channel currents and cytotoxicity for CMT2C-associated variants (Deng et al. 2010; Landouré et al. 2010; PMID 21288981). - Structural biology: Cryo-EM of purified TRPV4–RhoA complexes used to map the disease-residue interface and mechanistically explain gain-of-function (PMC10290081).

Invertebrate models: - Drosophila melanogaster models expressing neuropathy-causing TRPV4 mutants have been used to study the ubiquitination-dependent regulatory mechanism, showing reduced channel ubiquitination and channel overactivity that can be experimentally suppressed by enhancing ubiquitination (Aisenberg et al., PMC9010760; grant description at Grantome F31-NS105404).

Applications: These models collectively support (1) confirmation of the gain-of-function pathomechanism, (2) identification of endothelial cells as an unexpected primary disease-driving cell type, (3) a druggable regulatory node (ubiquitination of channel IDRs), and (4) preclinical proof-of-concept for pharmacologic TRPV4 antagonism as a rational, mechanism-based therapeutic strategy now advancing into human Phase 1 trials (ABS-0871).

Summary of Key Evidence Gaps for Curation

  1. No formal prevalence/incidence rate-per-100,000 figure was located specifically for CMT2C (only relative frequency within CMT2 cohorts, 1–3.5% to ~16% in enriched subgroups) — recommend using Orphanet's own epidemiology table (ORPHA:99937) directly if a numeric prevalence class is required.
  2. No germline mosaicism or founder-effect data specific to TRPV4 CMT2C were found.
  3. No large-scale human transcriptomic/proteomic dataset from patient-derived tissue was identified (model-organism/cell-line data dominate the molecular-profiling literature).
  4. No veterinary/naturally-occurring animal disease analog was found (distinguishing this from many other monogenic channelopathies with OMIA entries).
  5. The apparent tension between the acute/lethal, endothelial-driven mouse knock-in phenotype and the typically chronic, non-lethal human course is a candidate HUMAN_MODEL_MISMATCH worth explicit curation.

Sources

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