Presynaptic and postsynaptic mechanisms underlying auditory neuropathy in patients with mutations in the OTOF or OPA1 gene

Abstract

Abstract Objective: Our objective was to compare acoustically- and electrically-evoked potentials of the auditory nerve in patients with postsynaptic or presynaptic auditory neuropathy with underlying mutations in the OPA1 or OTOF gene. Study design: Transtympanic electrocochleography (ECochG) was recorded from two adult patients carrying the R445H OPA1 mutation, and from five children with mutations in the OTOF gene. Cochlear potentials to clicks or tone-bursts were compared to recordings obtained from 16 normally hearing subjects. Electrically-evoked neural responses recorded through the cochlear implant were also obtained. Results: The cochlear microphonic (CM) was recorded from all subjects, with normal amplitudes. After cancelling the CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls in both groups of patients. Prolonged negative responses were recorded as low as 50–90dB below behavioural threshold in subjects with OTOF mutations whereas in the OPA1 disorder the prolonged potentials were correlated with hearing threshold. A compound action potential (CAP) was superimposed on the prolonged activity at high stimulation intensity in two children with mutations in the OTOF gene while CAPs were absent in the OPA1 disorder. Electrically-evoked compound action potentials (e-CAPs) were only recorded from subjects with OTOF mutations following cochlear implantation. Conclusions: The findings are consistent with abnormal function of distal portions of auditory nerve fibres in patients carrying the OPA1 mutation whereas the low-threshold prolonged potentials recorded from children with mutations in the OTOF gene are consistent with abnormal neurotransmitter release resulting in reduced dendritic activation and impairment of spike initiation.