Temperature-sensitive auditory neuropathy: long-term follow-up and genotypic correlation.

Abstract

Background: Temperature-sensitive auditory neuropathy (TSAN) is a rare disease and a distinctive subtype of auditory neuropathy, characterized by fluctuating hearing thresholds and speech recognition influenced by body or environmental temperature. It is most associated with biallelic variants in the OTOF gene. Despite growing genetic insights, its long-term natural history remains poorly characterized, and the functional consequences of specific OTOF variants are incompletely understood.

Methods: This retrospective case series included 5 Han Chinese patients with TSAN carrying OTOF variants. Comprehensive audiological evaluations, including auditory brainstem response (ABR), otoacoustic emissions (OAE), cochlear microphonics (CM), pure-tone audiometry, and speech recognition assessment, were performed. Genetic analyses included whole-exome sequencing, Sanger validation, in silico pathogenicity prediction, and structural modeling. Long-term clinical follow-up ranged from 5 to 21 years.

Results: All patients initially presented with mild-to-moderate fluctuating hearing loss, absent ABR, and preserved OAE and/or CM, consistent with AN. Genetic analysis identified 7 rare OTOF variants, including 2 frameshift variants (p. Gln994Valfs*7 and p. Leu795Serfs*5), 1 nonsense variant (p. Arg1134Ter), and 4 missense variants (p. Arg1607Trp, p. Gly541Ser, p. Trp536Cys, and p. Ala1667Asp). Most variants affected evolutionarily conserved residues and were predicted to be deleterious, while structural modeling suggested that the missense variants may alter local protein conformation and stability. Long-term follow-up revealed marked inter-individual variability in auditory outcomes. Several patients achieved near-normal auditory performance without intervention, with Categories of Auditory Performance scores of 7 and Speech Intelligibility Rating scores of 5, whereas others showed persistent speech perception deficits despite only moderate hearing thresholds. Cochlear implantation improved auditory performance in selected patients.

Conclusions: OTOF-related TSAN demonstrated substantial clinical heterogeneity but generally favorable long-term functional outcomes in this cohort. These findings contribute to the characterization of the OTOF mutational landscape in TSAN, highlight the importance of long-term monitoring in this rare disease, and support individualized management strategies guided by both genotype and functional auditory performance.