TRPV4 Mutations Are a Significant Cause of Childhood-Onset Neuropathies with Vocal Fold Paresis and/or Skeletal Dysplasia (S26.005)

OBJECTIVE: To evaluate the frequency of TRPV4 mutations in patients with various types of inherited peripheral neuropathy. BACKGROUND: TRPV4 mutations have been identified in patients with Charcot-Marie-Tooth type 2 (CMT2), scapuloperoneal spinal muscular atrophy (SSMA) and distal hereditary motor neuropathy (dHMN) often associated with additional features such as vocal fold paresis and skeletal dysplasia. DESIGN/METHODS: We screened the TRPV4 gene in 151 French unrelated patients with peripheral neuropathy for potentially pathogenic mutations. Ninety-five patients had dominant CMT2 without additional signs, and 56 patients, including 36 patients with dHMN, 13 with CMT2 and 7 with SSMA, presented with at least one additional feature such as vocal fold paresis and skeletal dysplasia. RESULTS: No deleterious mutation was identified in patients with dominant CMT2 without additional signs (0/95). However, 6/56 patients (11%) with additional signs presented pathogenic TRPV4 mutations. Investigation of affected relatives allowed us to study a total of 9 patients. The Arg232Cys mutation was found in 5 dHMN patients and 1 SSMA patient from 4 families, the Arg315Trp mutation in 2 dHMN patients from 1 family, and the new Arg232Ser mutation in 1 CMT2 patient. One mutation arose de novo , and the remainder segregated in families. Foot deformities were observed in 9/9 patients, vocal fold paresis and kyphoscoliosis in 7/9 patients, and chondrodysplasia in 2/9 patients. Vocal fold paresis had a wide range of clinical manifestations including stridor, dysphonia, exertional dyspnea, and sleep apnea. In all cases, symptoms began in childhood. CONCLUSIONS: In our study, we found TRPV4 mutations in 11% of patients presenting with dHMN/CMT2/SSMA associated with vocal fold paresis and/or skeletal dysplasia. TRPV4 should be systematically screened in patients with childhood-onset neuropathy and additional features such as dysphonia, stridor, exertional dyspnea, sleep apnea and skeletal dysplasia. Disclosure: Dr. Echaniz-Laguna has nothing to disclose. Dr. Dubourg has nothing to disclose. Dr. Carre-Pigeon has nothing to disclose. Dr. Chaigne has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Latour has nothing to disclose. Dr. Eymard has received personal compensation for activities with Biomarin. Dr. Stojkovic has received personal compensation for activities with BIOGENIDEC, BAYER SCHERING PHARMA, TEVA, MERCK, SANOFI and LFB as consultant and congress expenses.