What is CMT2C?

At a glanceCMT2C is a rare genetic form of Charcot-Marie-Tooth disease caused by overactive TRPV4 channels. It mainly weakens muscles, and unlike most forms of CMT, it often involves the vocal cords, breathing muscles and skeleton [6].

Overview

Charcot-Marie-Tooth disease (CMT) is a group of inherited conditions of the peripheral nerves, the nerves outside the brain and spinal cord. It affects about 1 in 2,500 people worldwide [9].

CMT2C is a form of axonal CMT that damages the nerves for movement and feeling. It can weaken the hands and feet, the vocal cords and the breathing muscles, and it can cause hearing loss that starts in the inner ear [1]. It is caused by changes in a gene called TRPV4 [10].

In type 1 CMT the problem lies in myelin (the nerve's insulation) and nerve signals are slowed. In type 2 CMT the axon itself (the nerve's wire) is damaged and signal strength is reduced [9]. CMT2C belongs to the second group [6].

A way to picture itThink of the nerves to your arms, legs, voice box and breathing muscles as long electrical cables. In type 1 CMT the cables' insulation is damaged. In type 2, which includes CMT2C, the wire inside is damaged, so less signal gets through [9]. In CMT2C the cause is a tiny gate in the surface of cells, made by the TRPV4 gene, that opens too much and lets in too much calcium [6]. The Understanding CMT2C guide explains this with pictures.

Many names, one genetic cause

CMT2C has collected many names over the years, which can make it hard to search for. They all describe the same condition [100].

• CMT2C or CMT type 2C: Charcot-Marie-Tooth disease type 2C [1]. Orphanet's full name is “autosomal dominant Charcot-Marie-Tooth disease type 2C” [1].
• Charcot-Marie-Tooth disease axonal type 2C: the name used by the US Genetic and Rare Diseases Information Center and NORD, which point out that it is an axonal form [100].
• HMSN 2C or HMSN IIC: hereditary motor and sensory neuropathy type 2C, the older name used in the original reports [11].
• Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis: the title of the first description, in 1994 [13].
• Charcot-Marie-Tooth neuropathy type 2C and Charcot-Marie-Tooth disease type 2, TRPV4-related: names used in medical databases and genetic test listings [154].
• TRPV4-related neuromuscular disease or TRPV4 neuropathy: the gene-based name used in recent research, including the 2025 registry paper [3].

Related names. Two more conditions caused by the same gene are usually labeled as spinal muscular atrophy: scapuloperoneal SMA (SPSMA) and congenital distal SMA (CDSMA). They were first described as separate conditions because people had different patterns of weakness, but the three names likely describe one disease whose forms overlap and often cannot be clearly told apart [6]. Despite their names, neither is the better-known spinal muscular atrophy, which is caused by changes in a different gene, SMN1 [157]. Every spelling of all three names is listed below, and Symptoms and outlook describes how each one shows up.

Every spelling, and what the words mean

CMT2C Charcot-Marie-Tooth disease type 2C

The name this site uses. It describes weakness of the hands and feet, often with weakness of the voice and breathing muscles too [6].

Also written as [154]

• CMT 2C, CMT type 2C
• Charcot-Marie-Tooth disease axonal type 2C
• Charcot-Marie-Tooth neuropathy type 2C
• Autosomal dominant Charcot-Marie-Tooth disease type 2C
• Charcot-Marie-Tooth disease type 2, TRPV4-related
• HMSN 2C, HMSN IIC, HMSN2C
• Hereditary motor and sensory neuropathy type 2C (type IIC)
• Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis, the title of its first description in 1994 [13]
• TRPV4 neuropathy
• TRPV4-related neuromuscular disease [3]

SPSMA Scapuloperoneal spinal muscular atrophy

The name used when weakness shows mainly in the shoulder girdle and lower leg muscles, without loss of feeling [6].

Also written as [155]

• Scapuloperoneal SMA
• Spinal muscular atrophy, scapuloperoneal form
• Neurogenic scapuloperoneal amyotrophy, New England type
• Scapuloperoneal neuronopathy

CDSMA Congenital distal spinal muscular atrophy

The name used when leg weakness is present from birth, often with tight knees and hips (contractures) and clubfoot on both sides [6].

Also written as [156]

• Congenital distal SMA
• Distal hereditary motor neuronopathy type 8 (dHMN8, HMN8)
• Distal hereditary motor neuropathy type VIII
• Congenital nonprogressive distal spinal muscular atrophy
• Congenital benign spinal muscular atrophy with contractures

What the words mean

CMT or HMSN

Charcot-Marie-Tooth disease, also called hereditary motor and sensory neuropathy: a group of inherited conditions that damage the nerves for movement (motor) and feeling (sensory) [9].

Type 2, or axonal

The axon, the long wire that carries each nerve signal, is damaged, and this makes the signal weaker [9].

TRPV4

The gene behind all three conditions. It makes a channel, a tiny gate in the surface of cells that lets calcium in [23].

Spinal muscular atrophy (SMA)

Weakness and wasting of muscles caused by the loss of the nerve cells that control movement [157]. The better-known SMA is caused by a different gene, SMN1 [157].

Scapuloperoneal

The shoulder blade (scapula) and the lower leg (peroneal): the muscles SPSMA tends to weaken [6].

Congenital distal

Present from birth (congenital), and affecting the muscles farthest from the center of the body (distal) [6].

A short history

• 1994: a hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis was described [13].
• 2003: the gene was mapped to chromosome 12q23-24 [11].
• 2010: three papers published together in Nature Genetics identified TRPV4 as the cause and showed that CMT2C shares its gene with two conditions labeled spinal muscular atrophy [12].
• 2024 to 2025: a mouse study pointed to blood vessel lining cells as a driver of disease [15], results from the largest patient registry were published [3], and the first TRPV4 inhibitor designed for CMT2C entered human testing [16].

Genetics and inheritance

• Autosomal dominant. One changed copy of TRPV4 is enough to cause the condition. Each child of an affected parent has a 50% chance of inheriting the variant [6].
• Where the changes sit. The common neuromuscular variants are p.Arg186Gln, p.Arg232Cys, p.Arg269Cys, p.Arg269His, p.Arg315Trp, p.Arg316Cys and p.Arg316His. They cluster on one surface of a part of the protein called the ankyrin repeat domain [6]. In the registry, 94% of mutations were in this domain, and R269H (p.Arg269His) was the most common [3]. TRPV4 variants explains how to read these names.
• Symptoms are not always obvious. Signs can be so mild that the person and their doctors do not recognize them [6], and they are easily put down to other causes such as aging. Noticeable symptoms can also begin later in life: onset ranges from birth to after age 80 [6]. Which symptoms appear, when they start and how severe they become “cannot be accurately predicted” [6].
• Severity varies, even in one family. A US study described “marked clinical variations” among people with TRPV4 variants [18]. For my own variant, p.Arg186Gln, a published letter describes a child with severe congenital disease who inherited it from a mother with no recognized symptoms [19].
• New variants happen. De novo (new) variants are common in the most severe forms [6]. Across CMT generally, about 10% of cases result from new variants [9].
• Why do relatives differ? This is not settled. A 2025 report of a woman carrying a TRPV4 variant in only some of her cells (mosaicism) suggested that the level and location of mosaicism may contribute to variable severity [20].

What this means for families: genetic counseling by qualified professionals is recommended [6], and my own test report recommended it too.

Diagnosis

• Genetic testing confirms it. The diagnosis is established by finding a pathogenic (disease-causing) or likely pathogenic TRPV4 variant in someone with the characteristic clinical and nerve test findings. Sequence analysis detects essentially all such variants [6].
• Nerve tests show an axonal pattern. Nerve conduction studies show smaller motor responses with normal conduction speeds, and EMG (a test of the electrical activity in muscles) shows mainly chronic neurogenic changes, a sign of long-standing nerve damage [6].
• Clues that point to TRPV4. In someone with axonal CMT, any of these should prompt TRPV4 testing: vocal cord paralysis, weakness and wasting around the shoulder blades, skeletal dysplasia (abnormal bone development) or hearing loss [18].
• Uncertain variants are a real issue. A 2025 study showed that telling benign from disease-causing TRPV4 variants takes combined clinical, structural and cell-based evidence [22].
• Tests that show how far it reaches. After diagnosis, recommended evaluations include a camera examination of the vocal folds (video laryngoscopy), breathing tests (pulmonary function testing and dynamic chest radiographs), sleep studies, a hearing assessment and X-rays of the skeleton (skeletal radiographs) [6].

My own experience: my variant was confirmed by targeted TRPV4 sequencing in 2020.

How common is it?

Nobody knows precisely, and the published estimates conflict.

• Orphanet puts the prevalence at under 1 in 1,000,000 [1].
• TRPV4 changes account for an estimated 1 to 3.5% of cases of CMT2 and related motor neuropathies [6]. In one US study, 2 of 62 unrelated CMT2 patients (3.2%) had TRPV4 mutations [18].
• The company developing ABS-0871 estimates that about 2,500 people in the United States have CMT2C, a figure that does not come from a peer-reviewed source [4].

Next: Symptoms and outlook