From Sound to Stability: Lessons Learned From the CRUSH Study on Hearing Loss Progression and Vestibular Phenotype in Usher Syndrome Type 2A

OBJECTIVE: This study aims to analyze the progression of hearing loss using prospectively collected data and describe the vestibular phenotype of Usher syndrome type 2A (USH 2a ). STUDY DESIGN: Longitudinal, prospective, observational natural history study. PATIENTS: Patients with USH2a and USH2A -associated non-syndromic retinitis pigmentosa (nsRP). MAIN OUTCOME MEASURES: Hearing loss progression was measured by pure tone audiometry (PTA) and phoneme scores. Vestibular function was assessed by velocity step tests (VSTs), video head impulse tests (vHITs), caloric reflex tests, and vestibular evoked myogenic potentials (VEMPs). Patient-reported symptoms were assessed by questionnaires (Usher Lifestyle Survey, SF-12, PHQ-9, DHI, and SSQ). RESULTS: Thirty-three patients with USH2a and 2 patients with nsRP were included. PTA 0.5-4kHz thresholds showed a significant decrease of 2.3 dB ( P =0.017) over 4 years. The progression of hearing loss was most pronounced in the mid-to-high frequencies. No significant differences were observed in phoneme scores as measured by the Speech Reception Threshold (SRT). The 2 patients with nsRP had normal hearing. Vestibular evaluation showed abnormal cervical VEMPs in 34% and abnormal ocular VEMPs in 75% of USH2a patients. VSTs, caloric reflex tests, and vHIT results were within normal limits in more than 90% of subjects. Patient questionnaires revealed no major balance problems as indicated by the DHI. CONCLUSIONS: This analysis provides robust evidence of measurable hearing loss progression in PTA 0.5-4kHz thresholds in USH2a patients beyond presbycusis. Speech understanding, as measured by SRT, remains relatively stable. Vestibular evaluation revealed no semicircular canal dysfunction, although VEMP results suggest a potential subclinical otolith organ impairment in USH2a patients.