TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations

Abstract

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT Examination Scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT type 1A (CMT1A) patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%) and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness and respiratory disease.

Keywords: CMT2C; Charcot-Marie-Tooth disease; TRPV4; hereditary neuropathy; spinal muscular atrophy.

Figure 1

TRPV4-related neuromuscular disease is motor-predominant. (A) Patient age at baseline registration in the patient registry plotted versus Charcot-Marie-Tooth Examination Score (CMTES). (B) Histogram of patient questionnaire responses for age of symptom onset. (C) Histogram of patient questionnaire responses for age of diagnosis. (D and E) Graphs of percentages of patients reporting weakness of regions of the arms (D) and legs (E) from the TRPV4 patient questionnaire. (F) Graph of percentages of patients reporting difficulties with various arm and leg functions. (G and H) Graphs of percentages of patients reporting sensory symptoms (G) or pain (H) in specific body regions.

Figure 2

TRPV4 clinical features are distinct from Charcot-Marie-Tooth disease type 1A (CMT1A). (A) Box and whisker plot of average age at baseline registration for CMT1A and TRPV4 patients. Boxes represent the 25%–75% percentile, and bars represent maximum and minimum values. (B and C) Histogram of leg symptoms (B) and leg strength examination (C) in CMT1A versus TRPV4 patients. (D and E) Histogram of arm symptoms (D) and arm strength examination (E) in CMT1A versus TRPV4 patients. (F) Histogram of sensory symptoms in CMT1A versus TRPV4 patients. (G and H) Histogram of vibration sensation (G) and pinprick sensation (H) in CMT1A versus TRPV4 patients.

Figure 3

TRPV4-related neuromuscular disease progression is variable. (A) Average change in baseline Charcot-Marie-Tooth Examination Score (CMTES) versus year of follow-up for 13 patients from the patient registry. Error bars represent the standard error of the mean. (B–F) Longitudinal CMTES scores over repeated evaluations for individual patients from the patient registry. (G) Age versus CMT Pediatric Scale (CMTPedS) scores for three paediatric patients.

Figure 4

Patient experience is driven by motor and bulbar symptoms. (A) Graph of percentages of patient responses to questions regarding vocal fold and bulbar function and assessments. (B) Graph of percentages of patient responses to questions regarding respiratory function and assessments. (C) Graph of percentages of patient responses to questions regarding skeletal disease. (D) Graph of percentages of patient responses to questions regarding urinary symptoms. (E and F) Pie charts showing the percentages of patient responses to the question of which symptom is the most bothersome (E) and which symptom has the greatest impact on daily life (F).

Figure 5

TRPV4 genotype-phenotype evaluation. (A) Pie chart showing the frequency of specific TRPV4 mutations within patients in the registry. (B) Graph showing average Charcot-Marie-Tooth Examination Score (CMTES) at baseline registration for specific TRPV4 mutations. (C) Graph showing average age of onset for specific TRPV4 mutations. (D–G) Graphs of CMTES arm exam score versus leg exam score (D), CMTES arm exam score versus patient reported sensory symptoms (E), CMTES arm exam score versus vibration score (F) and CMTES arm exam score versus pinprick score (G). Red bar denotes patients with proximal arm weakness. One-way ANOVA, ***P < 0.001, comparing patients weak above the elbows to other groups. (H–K) Graphs comparing patients with or without significant shoulder weakness with respect to frequency of arm and leg weakness (H), difficulties with activities (I), sensory loss (J) and pain (K). Error bars represent the standard error of the mean.

Figure 6

Patients with infantile-onset disease have less sensory involvement and slower progression. (A–C) Graphs of percentages of infantile-onset and non-infantile onset patient responses to questions regarding vocal fold symptoms and progression (A), arm weakness and progression (B) and leg weakness and progression (C). The fraction of each patient cohort with a given symptom is represented by the full height of the coloured bars, and the fraction with progression by the darker portion of the bar. (D) Graph of percentages of infantile-onset and non-infantile onset patients reporting difficulties with various arm and leg functions. Chi-squared test, *P < 0.05 comparing progressing fractions of each group (dark blue and dark red bars). (E and F) Graphs of percentages of infantile-onset and non-infantile onset patients reporting sensory changes (E) and pain (F) in specific body regions. Chi-squared test, *P < 0.05 comparing total fractions of each group (full height of blue and red bars). (G) Charcot-Marie-Tooth Examination Score (CMTES) versus age at registration for infantile-onset and non-infantile onset patients.