Abnormal cochlear potentials recorded by transtympanic electrocochleography from patients with auditory neuropathy due to mutations in the Otoferlin or OPA1 gene

Background: Auditory neuropathy (AN) is a disorder characterized by disruption of auditory nerve activity resulting from lesions involving auditory nerve fibres, inner hair cells (IHCs) and/or the synapses with nerve fibres with preservation of outer hair cell (OHC) function. Clinical criteria for diagnosis include impairment of speech perception beyond that expected for the hearing loss, absence or marked abnormality of auditory brainstem potentials and preserved OHC activities (otoacoustic emissions and/or cochlear microphonic, CM). Abnormal neurotransmitter release from IHCs has been proposed as the mechanism underlying the picture of AN in patients with mutation in the OTOF gene (pre-synaptic AN), while disruption of synchrony at the level of auditory nerve fibers may underlie AN in OPA1 mutation (post-synaptic AN). Study design: Transtympanic electrocochleography was recorded from 6 children with OTOF mutation and 3 adults with mutation in the OPA1 gene. Cochlear potentials to clicks were compared to recordings obtained from 16 normally hearing children. Results: CM was recorded with normal amplitudes from all subjects. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls in both groups of patients. Low-amplitude compound action potentials (CAPs) were superimposed on the prolonged responses only in 3 subjects with OTOF mutation. Adaptation to rapid stimulus rates reduced both amplitude and duration of the prolonged potentials, consistent with neural generation. These potentials were recorded as low as 50-90 dB below behavioural thresholds in subjects with OTOF mutation whereas patients with OPA1 mutation showed a close correlation between prolonged potentials and behavioural threshold. After cochlear implantation electrically-evoked CAPs (ECAPs) were recorded only from subjects with OTOF mutation. Conclusions: In patients with OTOF mutation the prolonged potentials are consistent with alteration in neurotransmitter release resulting in reduced dendritic activation and impairment of spike initiation. The correlation of the prolonged potentials with behavioural threshold in subjects with OPA1 mutation together with the absence of ECAPs point to altered function of distal portions of auditory nerve with slowed conduction velocity and impaired synchrony of auditory nerve firing.