Natural History of TRPV4-Associated Neuromuscular Disease (S7.009) (2023)

<h3>Objective:</h3> 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. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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. <h3>Results:</h3> 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). <h3>Conclusions:</h3> 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. <b>Disclosure:</b> Mr. Donohue has nothing to disclose. Dr. Peyton has nothing to disclose. Mrs. Thomas has received personal compensation for serving as an employee of Foundation of Peripheral Neuropathy. Mr. Ben-Davies has nothing to disclose. Dr. Sumner has received personal compensation for serving as an employee of Biogen. Dr. Sumner has received personal compensation for serving as an employee of Avexis. Dr. Sumner has received personal compensation for serving as an employee of Roche/Genentech. Dr. Sumner has received personal compensation for serving as an employee of Ionis Pharmaceuticals. Dr. Sumner has received personal compensation for serving as an employee of Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avexis/Novartis. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alnylam. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Proneurotech. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CMTRF. Dr. Sumner has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal Clinical Investigation. Dr. Sumner has received research support from Roche. Dr. Sumner has received intellectual property interests from a discovery or technology relating to health care. Dr. Sumner has received publishing royalties from a publication relating to health care. The institution of Dr. McCray has received research support from NIH. The institution of Dr. McCray has received research support from Johns Hopkins Merkin Peripheral Neuropathy and Nerve Regeneration Center. The institution of Dr. McCray has received research support from Muscular Dystrophy Association. Inherited Neuropathies Consortium Rare Disease Clinical Research Network has nothing to disclose.