CMT2C is caused by certain mutations in the TRPV4 gene. This gene encodes a calcium-permeable ion channel involved in sensory signaling and motor neuron function. Mutations in the TRPV4 gene disrupt normal nerve signaling, leading to an axonal CMT with prominent motor nerve involvement and minimal sensory nerve involvement.
CMT2C is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation to cause this subtype. However, there is an exception with the S94LTRPV4 variant, which, when homozygous (autosomal recessive), causes CMT2C.
Clinical Features
In what is typically diagnosed as CMT2C, TRPV4-related neuromuscular disease most often appears as a motor-predominant axonal neuropathy, with distal muscle weakness and atrophy that may progress over time. Sensory involvement is often mild or absent compared with other forms of axonal CMT.
A distinguishing feature of CMT2C is the frequent involvement of the laryngeal and breathing muscles, which may lead to vocal cord paralysis, changes in voice (very hoarse or very soft), and breathing difficulties. These symptoms can emerge early or later in the disease course and are not present in all individuals. However, they are more commonly associated with CMT2C than with other CMT subtypes.
Age of symptom onset and severity are highly variable. Some individuals develop symptoms in early childhood, while others first notice weakness in adolescence or adulthood. Disease progression may be slow and relatively stable for some, while others experience more pronounced weakness and functional loss.
Because of this variability, CMT2C does not follow a single, predictable course. Instead, it reflects a spectrum of presentations that share common features but differ in severity, timing, and functional impact.
For clarity and consistency, TRPV4-related neuromuscular presentations discussed here are referred to as CMT2C, recognizing that this label reflects a characteristic clinical pattern within a broader TRPV4 disease spectrum rather than a biologically distinct disease.
Vocal Cord and Breathing Involvement
Vocal cord and breathing involvement are more commonly associated with CMT2C than with many other CMT subtypes. In some individuals, weakness affecting the vocal cords or breathing muscles is apparent early, while in others it may be subtle or develop later in the disease course.
Importantly, vocal cord involvement is not always obvious. In addition to producing sound, the vocal cords help regulate airflow during breathing by opening and closing to control how air moves through the airway. When vocal cord movement is reduced, the opening between them may be narrower than normal, limiting airflow and making breathing more difficult.
Breathing difficulties in CMT2C may reflect vocal cord involvement, weakness of the breathing muscles, or both. These changes do not always cause immediate or obvious symptoms. For some individuals, breathing difficulties may become more apparent only in situations that place greater demands on the respiratory system, such as respiratory illness or physical exertion.
Reported symptoms related to vocal cord and breathing involvement may include:
- Hoarse, weak, or unusually soft voice
- Shortness of breath, particularly with exertion or illness
- Noisy breathing or stridor (a high-pitched squeak or squeal that may be heard and felt at the larynx during respiration)
- Reduced vocal cord movement identified on clinical evaluation, sometimes without clear symptoms
Not all individuals with CMT2C experience vocal cord or breathing involvement, and severity can vary widely. However, because these symptoms are reported more frequently in CMT2C and may be underrecognized, appropriate clinical awareness and evaluation are important, even when symptoms appear mild. These symptoms, when considered alongside an appropriate TRPV4 gene mutation, can sometimes be sufficient to confirm a CMT2C diagnosis.
Pattern of Weakness and Functional Impact
Weakness in CMT2C is typically motor-predominant, with little to no sensory nerve involvement, and can affect both distal (farthest from the spine) and proximal (closest to the center of the body) muscles. While weakness in the hands and feet is common, involvement is not strictly length-dependent, and patterns may differ from those seen in many other axonal CMT subtypes.
In some individuals, hand weakness may appear early and affect fine motor tasks such as gripping, writing, and manipulating small objects. Others may notice weakness involving the shoulders, arms, or legs, which can affect lifting, balance, or walking. Muscle atrophy may develop over time and can lead to changes in posture or endurance.
The functional impact of CMT2C weakness varies widely. Some individuals remain highly independent with mild limitations, while others experience more significant challenges with mobility or daily activities. The pattern and progression of weakness are influenced by age of onset, severity, and the specific symptoms present, rather than following a single predictable pattern.
Age of Onset and Variability
The age of symptom onset in CMT2C is highly variable, ranging from infancy to adulthood. Some individuals show signs early in life, while others do not develop noticeable symptoms until adolescence or later. This wide range of onset reflects the variability seen across TRPV4-related neuromuscular disease.
Earlier onset is often associated with greater overall severity, but not necessarily with faster progression over time. In some individuals with infant or early childhood onset, symptoms may be severe early yet show relatively limited progression. Others with later onset may experience milder initial symptoms that gradually change over many years. Because of this variability, age of onset alone does not reliably predict how CMT2C will progress for an individual.
Severity, progression, and functional impact may vary independently, reflecting a broad range of phenotypic expression rather than a single, uniform disease course.
Disease Course
CMT2C can show significant variability in severity and progression. Some individuals experience relatively mild disease, while others develop more pronounced weakness involving the hands, respiratory muscles, or vocal cords. Earlier onset is often associated with increased overall severity, though this does not necessarily predict faster progression over time.
Disease progression in CMT2C is often slow, and the rate and pattern of change vary widely between individuals. Some people experience severe symptoms early that remain relatively stable over many years, while others develop milder symptoms that change gradually over time. Functional impact depends on the specific combination of motor weakness, respiratory involvement, and vocal cord function present.
Life expectancy is often normal. However, in some individuals with more severe disease, particularly when breathing or vocal cord involvement is not appropriately recognized and managed, life expectancy can be reduced. Vocal cord paralysis, especially when the vocal folds are positioned in a narrowed or closed state, can significantly restrict the airway. In these situations, careful respiratory monitoring is essential, and some individuals may require interventions, such as a tracheostomy, to maintain airway safety and support breathing.
Mobility outcomes also vary. Some individuals remain independently ambulatory throughout life, while others may require mobility aids. These can include orthoses such as AFOs or, in more severe cases, long-term or full-time wheelchair use, depending on the severity and pattern of weakness. The need for assistive devices depends on severity, symptom pattern, and overall functional impact rather than following a uniform or predictable course.
This CMT2C record reflects clinical guidance by Stephanie Carmody.
Read More
- Kosmanopoulos GP, Donohue JK, Hoke M, et al.; Inherited Neuropathies Consortium (RDCRN); McCray BA.
TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations. Brain. 2025;148(1):238–251. doi: https://doi.org/10.1093/brain/awae201 - McCray BA, Schindler A, Hoover-Fong JE, Sumner CJ.
Autosomal Dominant TRPV4-Related Disorders. GeneReviews® (NCBI) https://www.ncbi.nlm.nih.gov/books/NBK201366/
TRPV4 Variants Reported in CMT2C
The following TRPV4 variants are recognized as pathogenic in CMT2C based on work from the laboratory of Brett McCray, MD, PhD.
| Variant | Variant Shortform | Classification |
|---|---|---|
| c.278C>T (p.Ser93Phe) | S93F | Pathogenic |
| c.281C>T (p.Ser94Leu) | S94L | Pathogenic – Only When Homozygous |
| c.290C>G (p.Pro97Arg) | P97R | Pathogenic |
| c.557G>A (p.Arg186Gln) | R186Q | Pathogenic |
| c.694C>T (p.Arg232Cys) | R232C | Pathogenic |
| c.695G>C (p.Arg232Pro) | R232C | Pathogenic |
| c.709C>G (p.Arg237Gly) | R237G | Pathogenic |
| c.710G>T (p.Arg237Leu) | R237L | Pathogenic |
| c.710G>A (p.Arg237Gln) | R237Q | Pathogenic |
| c.805C>T (p.Arg269Cys) | R269C | Pathogenic |
| c.806G>A (p.Arg269His) | R269H | Pathogenic |
| c.943C>T (p.Arg315Trp) | R315W | Pathogenic |
| c.946C>T (p.Arg316Cys) | R316C | Pathogenic |
| c.947G>A (p.Arg316His) | R316H | Pathogenic |
| c.1625C>A (p.Ser542Tyr) | S542Y | Pathogenic |
| c.1846C>G (p.Arg616Gly) | R616G | Pathogenic |
| c.1856T>C (p.Leu619Pro) | L619P | Pathogenic |
| c.2355G>T (p.Trp785Cys) | W785C | Pathogenic |
Candidate Variants/VUS
The following TRPV4 variants of unknown or uncertain significance (VUS) are recognized as possible causes for CMT2C based on work from the laboratory of Brett McCray, MD, PhD, but more data are needed to determine pathogenicity.
| Variant | Variant Shortform | Classification |
|---|---|---|
| c.184G>A (p.Asp62Asn) | D62N | Uncertain (VUS) |
| c.395C>T (p.Pro132Leu) | P132L | Uncertain (VUS) |
| c.709C>T (p.Arg237Ter) | R237* | Uncertain (VUS) |
| c.1075G>A (p.Asp359Asn) | D359N | Uncertain (VUS) |
| c.1392C>T (p.Arg464=) | R464= | Uncertain (VUS) |
| c.1514C>T (p.Thr505Met) | T505M | Uncertain (VUS) |
| c.2042G>A (p.Gly681Asp) | G681D | Uncertain (VUS) |
| c.2458G>T (p.Asp820Tyr) | D820Y | Uncertain (VUS) |
Benign TRPV4 Variants
The following TRPV4 variants often surface in genetic test reports but are considered benign based on work from the laboratory of Brett McCray, MD, PhD.
| Variant | Variant Shortform | Classification |
|---|---|---|
| c.58G>A (p.Gly20Arg) | G20R | Benign |
| c.479G>A (p.Arg160Gln) | R160Q | Benign |
| c.535C>T (p.Arg179Cys) | R179C | Benign |
| c.656G>A (p.Arg219His) | R219H | Benign |
| c.670_671delinsCA (p.Arg224Gln) | R224Q | Benign |
| c.742C>T (p.Arg248Cys) | R248C | Benign |
| c.956C>T (p.Ser319Leu) | S319L | Benign |
| c.811C>T (p.Arg271Cys) | R271C | Benign |
| c.812G>A (p.Arg271His) | R271H | Benign |
| c.962G>T (p.Gly321Val) | G321V | Benign |
| c.1439G>T (p.Cys480Phe) | C480F | Benign |
| c.1543G>T (p.Val515Phe) | V515F | Benign |
| c.1634T>A (p.Ile545Asn) | I545N | Benign |
| c.2038A>G (p.Met680Val) | M680V | Benign |
For more information on TRPV4 variants in CMT2C, see CMT2C GeneReviews© below in the Genetic Context section.
