Skip to main content
Living With CMT2CHome

Research papers

What the CMT2C research says

At a glanceEvery paper I could find that mentions CMT2C, ranked by how much it tells us about the condition. Each one is explained in plain words, with an honest look at how strong the study is, including how “unaffected” relatives were actually checked. The analyses were written with the help of an AI reader, and every quote in them was then checked against the papers themselves (how this was done). The small labels with an author and a year, such as “Landouré 2010”, open the plain-language explanation of that paper.

271 papers found106 analyzed in depth986 supporting quotes from the papersSearched October 2026

This is a guide to the research, not medical advice. It describes what studies found. Decisions about tests or treatment belong with your own neuromuscular team.

The short version

  • One gene, several names. CMT2C is caused by changes in TRPV4, the gene for a channel that lets calcium into cells. Changes in the same gene cause conditions with other names (scapuloperoneal SMA, congenital distal SMA) and some bone growth conditions. Researchers now describe these as one overlapping spectrum. Landouré 2010Deng 2010Auer-Grumbach 2010McCray 2014
  • Mostly the motor nerves, often more. Weakness is the main problem. Voice, breathing, hearing, spine and hip problems are common in published cases, but not everyone has them. Kosmanopoulos 2025Echaniz-Laguna 2014
  • Severity varies enormously, even within one family. The same gene change has left one relative needing a breathing tube as a baby, while another had a mild problem found late in life. Klein 2003Landouré 2010Aharoni 2011
  • “Unaffected” relatives were not always checked. Some relatives who carry the change seem to stay well. The most carefully checked case is one Spanish family. Several other “unaffected” carriers were never examined or nerve-tested, and some relatives who felt well turned out to have the condition when tested. Berciano 2011Deng 2020Donaghy 1999
  • The channel is probably too active. Most lab work says the faulty channel lets in too much calcium. Blocking it helped in cells, flies and mice. None of these papers reports testing a treatment aimed at the cause in people with CMT2C. McCray 2014Woolums 2020Sullivan 2024
  • The evidence is thin in places. Most papers describe one family or a handful of people. The largest human study included 68 people with a confirmed TRPV4 cause, and only 13 of them had repeat examinations over time. Kosmanopoulos 2025

One gene, many names

Doctors first described CMT2C (then called HMSN IIc) in 1994, in two families with weakness of the limbs, vocal cords and breathing muscles. Dyck 1994 For years it was known only by its symptoms. In 2010, three research groups reported at the same time that changes in TRPV4 cause it. Landouré 2010Deng 2010Auer-Grumbach 2010Nilius 2010

Two of those groups found that the same gene also causes scapuloperoneal spinal muscular atrophy (SPSMA) and congenital distal SMA. One large family included people with all three diagnoses. Deng 2010Auer-Grumbach 2010 A 2010 screening study across Europe and the US described “an unusual spectrum” running from conditions present at birth to adult-onset CMT2C. Zimoń 2010

The same gene also causes several skeletal dysplasias (bone growth conditions). Some people have both bone and nerve problems, and a gene change linked to one kind of problem has also turned up in people with the other. Cho 2012Faye 2019Taga 2022 The label a person receives can depend on which features stand out and which specialist they see. In a French study, most people with a TRPV4 cause had been labeled distal hereditary motor neuropathy, and only one had been labeled CMT2. Echaniz-Laguna 2014

What it can affect

These figures come from small and selected groups, so read them as “this happens, and it is not rare” rather than as your own chances. The largest source, a 2025 registry, likely over-represents severe cases, and many of its figures are self-reported. Kosmanopoulos 2025

AreaWhat the studies reportHow firm
Voice (vocal cords)Vocal fold weakness in 55% of 40 registry questionnaire respondents Kosmanopoulos 2025, and in 94% of 17 people in a French series Echaniz-Laguna 2014. In one large family, 16 of 18 affected people had some vocal cord, diaphragm or rib muscle weakness, and for several a hoarse voice was the only sign. Klein 2003 Voice problems ranged from none to needing a permanent tracheotomy. Chen 2010Common, not universal. Some people with TRPV4 neuropathy have no voice problems. Evangelista 2015
BreathingShortness of breath in 55% and breathing support in 11% of registry respondents. Kosmanopoulos 2025 Breathing failure needing night-time or bilevel support is described in several families. McEntagart 2005Jędrzejowska 2019 The 1994 paper says breathing failure shortened life in severely affected people. Dyck 1994Well documented, but the 1994 statement is about severely affected people in two families.
HearingIn one Dutch family, all four carriers developed hearing loss from the inner ear or hearing nerve, noticed between the ages of 35 and 62 and slowly worsening. Oonk 2014 In one child, the hearing nerve worsened over three years while a standard hearing test stayed normal. Rance 2024 Hearing loss was reported in 24% of the French series. Echaniz-Laguna 2014Real but under-measured. Many papers never tested hearing formally.
Spine, hips and feetScoliosis in 64% of registry questionnaire respondents, though the registry's own table gives 39%. Kosmanopoulos 2025 All four children with TRPV4-related CMT in an Australian clinic had hip dysplasia, and two needed hip surgery. Tan 2025 In one family, scoliosis and clubfoot came from muscle weakness rather than a bone disorder. Aharoni 2011The hip finding rests on four children.
Feeling (sensation)Of registry participants, 68% reported no sensory symptoms, yet examination found reduced pinprick sense in 47%. Kosmanopoulos 2025 In some people, sensory nerve tests were normal early and abnormal years later. Koutsis 2015Chen 2010Aharoni 2011Often present without being noticed.
Shoulders and hips (proximal weakness)Proximal leg weakness on examination in 40% of registry participants, compared with 4% in CMT1A. Kosmanopoulos 2025 Shoulder blade winging and wasting overlap with SPSMA. Koutsis 2015Chen 2023Reasonably consistent.
BladderNine people in the 2010 gene discovery families reported bladder urgency and incontinence. Landouré 2010Few reports.
Sweating and temperatureOne woman with CMT2C could not sweat and struggled to keep cool, with normal heart rate and blood pressure control. Baker 2018A single case.
Other single reportsShort stature in two families Chen 2010, slow wound healing after foot surgery in one child Elhaddad 2026, and tremor that turned out to be a separate condition in one family Louis 2014.One or two families each.

Same change, different lives

Every family study in this collection describes big differences between relatives who carry the same change. In one American family, impairment scores ranged from 8 to 164 points, and symptoms began at 1 month in a granddaughter but at 80 in her grandmother. Klein 2003 A mother had mild weakness late in life while her daughter had severe weakness of all four limbs and breathing failure. Landouré 2010 Among five carriers in one family, two children needed tracheostomies while a 14-year-old brother played sports with a normal voice. Aharoni 2011 In a Polish family, a 56-year-old mother had only mild shoulder blade winging while her daughters were moderately and severely affected. Jędrzejowska 2019

Age explains little of it. In the registry, age was only weakly linked to severity (R² = 0.066). The 13 people with repeat examinations worsened by 0.81 points a year on average, with wide differences between people. Kosmanopoulos 2025

Proposed explanations are mostly untested. Modifier genes (other genes that can make a condition milder or more severe) are often suggested, but no paper here tested them. Berciano 2011 Mosaicism, where a new change is present in only some of a person's cells, is documented in a few people, and one girl with the change in about 30% of her blood DNA was still severely affected. Lee 2025Taga 2022Ragamin 2022 Claims that the condition starts earlier in each generation rest on three people in one family and a single father and son. Klein 2003Biasini 2016 A Polish team found no such pattern across published families. Jędrzejowska 2019

The course over time is uncertain. A father with SPSMA stayed stable for two decades, and his son, very ill as a newborn, was walking with braces by age 5 (only the abstract of this paper was available). Vill 2015 A review of published mixed nerve and bone cases found that 21 of 23 worsened, but published cases tend to be the severe ones. Taga 2022

“Unaffected” relatives: who was actually checked?

When a paper says a relative “carries the change but is unaffected”, that claim is only as good as the check behind it. A relative can be called unaffected because a neurologist examined them and ran nerve conduction tests, or simply because the family said they were fine. This matters: the idea of reduced penetrance (carrying the change without ever showing the condition) rests on these relatives.

Here is how each paper that makes this kind of claim decided who was unaffected.

Examined and nerve-tested, still no signs

The strongest evidence that some carriers stay unaffected.

  • Berciano 2011 Three carriers aged 70, 40 and 9 had a full examination, nerve conduction tests, EMG and lower-leg MRI, all normal. This is the best-checked example. Caveats: the 70-year-old had two leg nerve values just below the normal range, the 9-year-old could still develop signs, and the shoulders and vocal cords were not checked.
  • Klein 2003 The family used strict rules: “unaffected” meant older than 23, no symptoms, a near-zero impairment score and nerve tests in the normal range. One relative classed this way carried the disease-linked DNA, but the paper gives no details about them.
  • Koutsis 2015 A sister is described as “clinically and electrically unaffected”, which suggests an examination and nerve tests, but her age and results are not given.
  • Wang 2024 A father had muscle MRI and EMG without significant abnormalities. His examination is only partly reported.

Examined, but no nerve tests

Mild nerve damage can be missed without nerve conduction tests.

  • Aharoni 2011 A 14-year-old brother was examined and had a normal laryngoscopy, but declined nerve tests, and his ankle reflexes were hard to obtain.
  • Landouré 2010 Two carriers were “not found to be affected during limited examination in their homes”. No nerve tests are described.

Not examined, or the method is not described

These claims cannot tell carriers who are truly unaffected from people with mild or not-yet-started disease.

  • Deng 2020 Three relatives are called non-penetrant. None had a DNA test, and none is described as examined. The paper infers their status from the family tree.
  • Zimoń 2010 Six carriers are called unaffected, and the paper concludes that reduced penetrance is “relatively common”. It does not say how they were checked. Other papers show that three of them are the Spanish carriers that Berciano 2011 later examined in detail. The two papers give different ages for them: 79, 36 and 6 here, compared with 70, 40 and 9 in Berciano 2011, which gives their ages at the 2010 re-examination. Two are the American carriers who had only a “limited examination in their homes” Landouré 2010, and one, aged 69, is not described further.
  • Fawcett 2012 One carrier's son “was asymptomatic but has not been examined”. Another carrier's father had no symptoms, but his EMG showed changes.
  • Berth 2025 Carrier relatives are called “asymptomatic” with no examination or nerve tests described.
  • Cho 2012 A carrier mother is said to have “no neuropathy” without a stated method (only a summary of this paper was available).
  • Velilla 2019Lugo 2023Thibodeau 2017 Parents of children with a two-copy (recessive) form are called healthy, with no neurological examination described.
  • Echaniz-Laguna 2014 Two “asymptomatic carriers” are reported. The abstract does not say how they were checked.

Felt well, but tests found the condition

The reverse lesson: “no symptoms” is not the same as “not affected”.

  • Donaghy 1999 A mother and sister had no symptoms at all, but nerve tests confirmed a neuropathy. The authors urged examining and nerve-testing close relatives. The same British family appears to be described again in McEntagart 2005, which also reports a second family in which a symptom-free relative had mild weakness and reduced reflexes on examination.
  • Klein 2011 A mother and sister with no symptoms had distal weakness on examination and an axonal neuropathy on nerve tests.
  • Chen 2023 A son with no weakness had abnormal nerve tests and EMG.
  • Dyck 1994 The first description of CMT2C already noted sensory loss that people had not noticed themselves.
  • Kosmanopoulos 2025 Most registry participants reported no sensory symptoms, yet examination found reduced feeling in many.
  • Lin 2011 Outside TRPV4, a Taiwanese study found that relatives who “denied to have any neurological symptoms” had mild signs when examined.

What this adds up to: reduced penetrance probably does happen, as the thoroughly checked carriers in the Spanish family show. How often it happens is not known. Several of the “unaffected” carriers in the literature were never examined or nerve-tested, and several “healthy” relatives turned out to be affected when they were.

How often TRPV4 is the cause

TRPV4 changes are a rare cause of CMT overall: under 1% of 422 people with axonal CMT or motor neuropathy in a UK series Fawcett 2012, 2 of 566 people at an Italian center Gentile 2020, none of 36 people with CMT2 in Taiwan Lin 2011, and 2 of 62 people with unexplained CMT2 in Detroit Deng 2020.

They are much more common when the neuropathy comes with vocal cord or skeletal problems. In France, none of 95 people with “pure” CMT2 had one, compared with 12 of 74 (16%) with vocal cord paralysis or skeletal dysplasia. Echaniz-Laguna 2014 In a European and US series, 5 of 14 people whose first sign was vocal fold paralysis had one (36%). Zimoń 2010 Even so, TRPV4 does not explain every family that looks like CMT2C: some had no TRPV4 change. Landouré 2010Klein 2011

Reading a gene result. TRPV4 has many rare variants that turn out to be harmless, so a new variant needs careful checking before it is called the cause. Fawcett 2012Drew 2015 Adding lab tests changed the formal classification of 9 of 19 variants in one study. Berth 2025 An older test method missed a real change in one family for technical reasons, and exome sequencing later found it. Landouré 2012

What goes wrong inside the cell

TRPV4 makes a channel, a small gate in the cell's outer wall that lets calcium in. Most CMT2C changes sit on one outer face of a part of the channel called the ankyrin repeat domain. Inada 2012Sullivan 2015Landouré 2012 Where a change sits does not reliably predict whether it causes nerve disease, bone disease or both. Faye 2019Cho 2012

Too open, most likely. The first studies disagreed: one found the faulty channel did too little, while others found it did too much. Nilius 2010Auer-Grumbach 2010 Most later work found the faulty channels let in extra calcium and damaged cells, and channel blockers prevented this in lab dishes. Landouré 2010Fecto 2011Klein 2011Sullivan 2015 The current clinical summary says gain of function (a channel that works too much) is most likely. McCray 2014 A few changes behaved the other way in lab tests. Fiorillo 2012Thibodeau 2017

A missing brake. A protein called RhoA sits exactly where many neuropathy changes cluster and normally holds the channel closed. Neuropathy changes weaken this hold. McCray 2021Nadezhdin 2023Kwon 2023 Other natural brakes have been described too: a membrane fat called PIP2 Takahashi 2014, small ubiquitin tags Aisenberg 2022 and a partner protein called ARHGEF10 Loder 2026.

How nerves get damaged. In fruit flies, a CMT2C change raised calcium, switched on an enzyme called CaMKII and stalled the movement of mitochondria (the cell's power supply) along nerve fibers, before the fibers degenerated. Woolums 2020 In mice carrying a CMT2C change in their own gene, the damage seemed to start in the lining of small blood vessels in the spinal cord, which began to leak, rather than in the nerve cells themselves. These mice had a severe form that killed them by weaning age, and their limb nerves, sensory nerves and vocal cords were not examined. Sullivan 2024 In lab-grown eye cells given each known disease-causing change, 7 of 22 neuropathy changes weakened the seal between cells, but how much calcium a change let in did not predict this. The company team behind that study calls the link with diagnosis weak. Sampaio 2025

Almost all of this comes from cell lines made to produce large amounts of the channel, from flies and from mice. Very little has been checked in human nerve tissue.

Treatment: where things stand

The clinical summary, last updated in December 2025, says there is no treatment yet that targets the cause, and that care focuses on symptoms through a team of specialists. McCray 2014 Its suggested checks come from the authors' experience rather than trials.

Channel blockers. TRPV4-blocking drugs reduced damage in cells Fecto 2011Sullivan 2015 and in flies Woolums 2020. In mice with two copies of the R269C change, a TRPV4 blocker (GSK2193874), started after symptoms appeared, closed the spinal cord leak, and treated mice lived longer and moved better. These mice had a severe, early-fatal form, the drug was injected twice a day, and no people were studied. The human safety data the authors cite come from trials of a different blocker in other conditions. Sullivan 2024 Some rare changes needed far more blocker in cells than others, which may matter for future trials. Taga 2022 A company's experimental blocker, ABS-0872 (a different compound from ABS-0871), prevented or reversed the weakening of the seal between lab-grown cells for the few changes tested; the paper has no animal or human data, and all its authors work for the company. Sampaio 2025 Several researchers in this field declare links to a company developing TRPV4 treatments. Kosmanopoulos 2025Berth 2025

Getting ready for trials. The registry team found that standard CMT scores may not capture change well, and suggested that future trials measure proximal weakness, walking, vocal fold function and breathing. Kosmanopoulos 2025 A tested scale now exists for measuring CMT in children under five. Mandarakas 2018

Single-person reports. A remote-microphone listening system helped one child follow speech in noise. Rance 2024 One young man with SPSMA trained for about five years without measurable decline. Crisafulli 2025 One child had severe wound breakdown after foot surgery. Elhaddad 2026 Each is one person and cannot show what would happen for others.

What nobody knows yet

  • How often people who carry a TRPV4 change stay unaffected for life.
  • How fast the condition changes in adults. Only 13 people in the largest study had repeat examinations.
  • Why some people get voice, breathing, hearing or bone problems and others with the same change do not.
  • Whether TRPV4 blockers help people. Every result so far is from cells, flies or mice.
  • How common bladder, sweating and hearing problems really are, because few studies test for them.

How CMT2C was pieced together

  1. 1994 Two families described and named HMSN IIc. Dyck 1994
  2. 1996 to 2002 Linkage studies rule out the gene regions for CMT2A, 2B, 2D and distal motor neuropathy type VII, showing that it is a separate condition. Yoshioka 1996Nagamatsu 2000Santoro 2002McEntagart 2002
  3. 1999 A second family: vocal cord palsy at 41, and symptom-free relatives with neuropathy on nerve tests. Donaghy 1999
  4. 2003 The gene is placed on chromosome 12 (12q23-24) in one large family. Klein 2003
  5. 2005 Two more families support that location and narrow it to 66 genes. McEntagart 2005
  6. 2010 TRPV4 is identified, and SPSMA and congenital distal SMA turn out to share the gene. Landouré 2010Deng 2010Auer-Grumbach 2010Zimoń 2010
  7. 2014 The clinical summary for TRPV4 disorders is first published (updated December 2025). McCray 2014
  8. 2020 to 2023 Fly studies and channel structures show how the channel's brake fails. Woolums 2020McCray 2021Kwon 2023
  9. 2024 A TRPV4 blocker, started after symptoms appeared, helped mice with a CMT2C change and a severe, early-fatal form of the disease live longer and move better. Sullivan 2024
  10. 2025 The largest registry study describes 68 people. Kosmanopoulos 2025

The most relevant papers

Ranked by how directly they are about CMT2C, then by how strong the evidence is. Select a title to read its full analysis.

  1. 1TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestationsKosmanopoulos GP, Donohue JK, Hoke M et al. · 2025
  2. 2Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2CLandouré G, Zdebik AA, Martinez TL et al. · 2010
  3. 3Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4Deng HX, Klein CJ, Yan J et al. · 2010
  4. 4Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2CAuer-Grumbach M, Olschewski A, Papić L et al. · 2010
  5. 5The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disordersKlein CJ, Cunningham JM, Atkinson EJ et al. · 2003
  6. 6Autosomal Dominant TRPV4-Related DisordersMcCray BA, Schindler A, Hoover-Fong JE et al. · 2014 (updated December 2025)
  7. 7TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of functionTaga A, Peyton MA, Goretzki B et al. · 2022
  8. 8Incidence and Clinical Features of TRPV4-Linked Axonal Neuropathies in a USA Cohort of Charcot-Marie-Tooth Disease Type 2Deng S, Feely SME, Shi Y et al. · 2020
  9. 9TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathiesKlein CJ, Shi Y, Fecto F et al. · 2011
  10. 10Novel mutations highlight the key role of the ankyrin repeat domain in TRPV4-mediated neuropathySullivan JM, Zimanyi CM, Aisenberg W et al. · 2015

What you can do next

If something here matters to you, these are good places to go next.

Next: Papers explained