Abstract Details

Mutations in TRPV4 cause a spectrum of neuromuscular disease, including Charcot-Marie-Tooth disease type 2C and related forms of spinal muscular atrophy. Case reports demonstrate a diversity in the age of onset, disease severity, and phenotype, including pure neuromuscular disease or mixed neuromuscular and skeletal disease.

Clinical trials for transient receptor potential vanilloid 4 (TRPV4)-associated neuromuscular disease have been limited by the lack of natural history data and clearly defined endpoints to assess treatment response. We sought to characterize the natural history of TRPV4-associated neuromuscular disease through a standardized patient questionnaire and neurologic exam.

Twenty-seven patients with TRPV4-associated neuromuscular disease completed a questionnaire that assessed motor, sensory, respiratory, and skeletal symptoms and underwent a neurologic exam, including calculation of the validated CMT Exam Score (CMTES). Descriptive statistics were used to assess phenotypic patterns, frequency of disease manifestations, and disease progression. Pearson correlation coefficients were used to describe association.

The median age of onset was 1 year (range 0-50 years), with 19 congenital-onset (70%) and 8 adult-onset (30%) patients. Stridor and vocal cord weakness were reported by 59.3% and 40.7% of patients, respectively. Diagnoses of skeletal dysplasia (25.9%), scoliosis (70.4%), and arthrogryposis (33.3%) were also common. Patients reported weakness primarily in the hands (74.1%) and feet (70.4%) with lower frequencies noted in the shoulders (59.3%) and hips (48.2%). CMTES was found to have a weak positive association with age (r = 0.34).

This represents the largest study of TRPV4-associated neuromuscular disease using a patient questionnaire. Promising therapeutic possibilities for TRPV4-associated neuromuscular disease are being explored in mouse models, increasing the need for clinical trial readiness. The initial data suggest that CMTES, along with respiratory and skeletal symptoms, may provide a meaningful endpoint for congenital and adult-onset patients. This questionnaire represents part of a larger study that will include ongoing yearly longitudinal follow-up.