Clinical and Molecular Characterization of Auditory Neuropathy
Auditory Neuropathy (AN) is diagnosed when the auditory brainstem response (ABR) is absent and outer hair cells (OHC) function normally, which indicates that the lesion lies in the inner hair cells (IHC), their afferent nerve’s synapse or the auditory nerve. While the presence of non-syndromic recessive multiplex families is relatively rare, it suggests that a recessive gene accounts for a certain percentage of AN individuals. This research was undertaken to test the hypothesis that non-syndromic recessive AN (NSRAN) is genetic. Upon completion of a genome search, a candidate gene, otoferlin (OTOF), was discovered and screened. OTOF has various isoforms, some brain-specific and others cochlear-specific, expressed only in adult mouse IHC. Upon finding OTOF mutations in three of the four original NSRAN families, another hypothesis was developed to explain the somewhat conflicting clinical data. Previous OTOF mutation reports didn’t examine OHC function and, therefore, couldn’t rule-out or diagnose AN. Published OTOF mutations consisted of homozygous “knock-out” mutations. These NSRAN mutations and published non-syndromic recessive deafness (NSRD) OTOF mutations led to the hypothesis that NSRAN, as opposed to non-AN NSRD, is due to at least one OTOF mutation changing but not “knocking-out” the cochlear-specific isoform. To test this hypothesis, 33 NSRAN and NSRD families were screened for OTOF mutations. Six pathogenic mutations, frameshift, splice-site, nonsense and missense, were discovered in five NSRAN families. “Knock-out” mutations were found in both alleles of two NSRAN families. These results, while proving that NSRAN is due to OTOF mutations, disproved the hypothesis that NSRAN requires a cochlear-specific isoform mutation. One patient with non-syndromic AN was found to have Mohr-Tranebjaerg Syndrome (MTS) due to a nonsense mutation, 100C>T (Q34X), in the X-linked gene, TIMM8a. MTS individuals seem non-syndromic until adulthood when other symptoms appear. A temporal bone study of an MTS patient showed near complete loss of spiral ganglion cells, but preservation of the organ of Corti. NSRAN individuals with OTOF mutations benefit from cochlear implantation. No one with MTS is known to have been implanted, but the temporal bone studies suggest they might not benefit. These studies demonstrate the importance of comprehensive clinical analysis for diagnosis.
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