Hidden hearing loss in a hereditary peripheral neuropathy: evidence from a mouse model of Charcot Marie Tooth type 1A

Abstract

AbstractHidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound evoked potentials, has been proposed to underlie hearing difficulties in noisy environments. Animal studies showing that HHL is associated with loss of inner hair cell (IHC) synapses in response to mild noise exposures and aging led to most studies of HHL focusing on IHC synaptopathy. More recently we showed that transient auditory nerve (AN) demyelination also causes HHL but without affecting IHC synapses, suggesting that demyelinating peripheral neuropathies could be a second HHL mechanism. To test this in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibit HHL, i.e., normal auditory threshold but reduced amplitudes and longer latencies of sound-evoked compound action potential. The AN structural phenotypes of CMT1A mice are also remarkably similar to those found in mice with transient demyelination, i.e., disorganization of AN heminodes near the IHCs with minor loss of AN fibers. Our results support the hypothesis that mild disruptions of AN myelination can cause HHL, and that heminodal defects contribute to the alterations in action potential amplitudes and latencies seen in these models. Also, these findings suggest that patients with CMT1A or other peripheral neuropathies like Guillain-Barré Syndrome, are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in CMT1A patients might help in the development of robust clinical tests for HHL, which are currently lacking.Significance StatementHidden Hearing Loss (HHL), an auditory disorder estimated to affect 12-15% of the adult population, is believed to impact auditory processing and hearing clarity in individuals with normal audiometric thresholds. Based on animal studies, the loss of inner hair cell synapses is currently considered its primary cause. Here we provide evidence that mild disruptions of auditory nerve myelination, i.e., disorganization of auditory nerve heminodes, can also cause HHL. Our results suggest that patients suffering from Charcot-Marie-Tooth type 1A, the most common hereditary peripheral neuropathy, are likely to experience HHL. Studies of hearing in CMT1A patients might thus help in the development of robust clinical tests for HHL, which are currently lacking.