Symptoms and outlook

At a glanceCMT2C is primarily motor: it mainly causes weakness, which can be uneven and does not always start in the feet [6]. In the TRPV4 registry, 79% of people had difficulty walking [3]. Voice problems are a hallmark of the condition and breathing can be affected too, so yearly voice, breathing, sleep and hearing checks are part of recommended care [6]. In mild forms lifespan is normal [6].

Symptoms, with numbers

The figures below come from the Inherited Neuropathy Consortium registry: 68 people with pathogenic (disease-causing) TRPV4 variants, of whom 40 completed a TRPV4-specific questionnaire [3]. They describe a group of research participants, so they may not match any one person's experience.

When it starts. Onset has two peaks: 54% of people had symptoms within the first 2 years of life, with a second, smaller peak at 34 to 48 years [3]. Onset can range from birth to after age 80 [6].

Note on the numbers: the registry paper mixes two sources. Figures with counts come from registry records (68 people analyzed). Figures without counts come from the questionnaire (40 respondents), and the paper does not say how many people answered each question. That is why scoliosis appears as both 64% and 39% [3].

The BiPAP and CPAP rows show which machines registry participants said they use, not which machine is right for them. CPAP alone does not help weak breathing muscles or treat the under-breathing they cause [307]. CPAP and weak breathing muscles explains the difference.

What bothers people most. Registry participants named speech and breathing problems (22%) and leg weakness (21%) as their most bothersome symptoms [3].

The pattern of weakness. Weakness in CMT2C can be non-length-dependent and asymmetric. That means it does not always start in the feet and work upward, and it can affect one side more than the other. It can include shoulder weakness, shoulder blades that stick out (winging), and uneven weakness in straightening the knees and bending the hips, alongside high arches, wasting of the lower legs and foot drop [6].

Voice and breathing. Problems with the voice box (laryngeal dysfunction) are described as “a hallmark of TRPV4-related neuromuscular disease”. They can be severe on both sides or uneven, and their severity does not track limb weakness [6]. Breathing problems arise from diaphragm weakness, and difficulty breathing when lying flat or sleep apnea can occur [6].

Sensation. Most people report no sensory symptoms, yet examination often finds reduced vibration sense [3]. CMT2C is best described as primarily motor [6].

Hearing. When hearing loss occurs, it is sensorineural (coming from the inner ear or the hearing nerve), on both sides, progressive, and mild to moderate [6].

The TRPV4 spectrum

Changes in TRPV4 cause a family of conditions [6]:

• Neuromuscular conditions: CMT2C, scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal spinal muscular atrophy (CDSMA) [6].
• Skeletal conditions (mild to severe): familial digital arthropathy with brachydactyly, brachyolmia, spondylometaphyseal dysplasia Kozlowski type, spondyloepimetaphyseal dysplasia Maroteaux type, and metatropic dysplasia [6].

The three neuromuscular labels “likely represent an overlapping spectrum of disease and can often not be clearly distinguished” [6].

• SPSMA features slowly progressive weakness of the shoulder girdle and lower leg muscles, without sensory involvement [6].
• CDSMA is present from birth, with leg weakness that is non-progressive or slowly progressive, knee and hip contractures often present at birth, and severe clubfoot on both sides [6].
• Overlap with bone. In the registry, 20% of participants reported a skeletal dysplasia (a disorder of bone growth) [3], and at least 19 variants are associated with both neuromuscular and skeletal features [6].

Outlook and monitoring

• Lifespan. In mild forms lifespan is normal. In severe forms it can be shortened by respiratory complications [6].
• Course. The disease can be so mild that it goes unrecognized, or it can be life-threatening. Congenital forms may plateau for long periods or progress in adulthood [6].
• Rate of change. Among 13 registry patients examined more than once over 2 to 9 years, the CMT Examination Score (a severity score where higher means more affected) rose by an average of 0.81 points per year. Age correlated poorly with severity [3]. This is based on only a few patients, and the authors note that standard CMT scales miss key features of this disease [3].

Recommended yearly checks [6]:

• Neurological examination
• Physical therapy assessment of the feet for bracing and orthotics
• Ear, nose and throat review with laryngoscopy (a camera examination of the vocal folds)
• Breathing tests (spirometry and dynamic chest radiographs) and a sleep study
• Hearing assessment
• Musculoskeletal check for contractures, hip dysplasia, scoliosis and tethered cord
• Weight and height at each visit

A symptom tracker is here to help you keep track between visits, on screen or printed.

How CMT2C differs from other CMT types

These figures come from the paper’s separate comparison with CMT1A, so they differ from the registry counts above [3].

Age predicts severity less well in TRPV4 disease than in CMT2A or CMTX1 [3]. In practice, standard CMT care focused on the feet and hands is not enough for CMT2C, because recommended monitoring also includes yearly voice, breathing, sleep and hearing checks [6].

Voice and breathing: the two hallmarks

The registry paper compared people with TRPV4 disease and a CMT1A group only on the legs, arms, walking and sensation, not on voice or breathing [3]. I found no study that compares voice and breathing between CMT2C and other CMT types in the same way, so the figures below come from different kinds of studies. Treat them as a rough picture, not a like-for-like comparison.

The CMT2C figures come from the registry questionnaire (40 respondents) [3]. The other figures come from a review of case reports, one CMT2A study and a patient organization's guidance, so the numbers cannot be compared directly.

Your next steps

• Print the symptom tracker
• Plan your care team
• Sign up for studies open to you now

Next: How CMT2C works