Inherited hearing impairment affects one in 2,000 newborns. Nonsyndromic prelingual forms are inherited mainly as autosomal recessive traits, for which 16 genes are currently known. Mutations in the genes encoding connexins 26 and 30 account for up to 50% of these cases. However, the individual contribution of the remaining genes to the whole remains undetermined. In addition, for most of the genes there is a need for studies on genotype-phenotype correlations, to identify distinctive clinical features which may direct the molecular diagnosis to specific genes. Here we present a mutation analysis and a genotype-phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). A total of 37 subjects with mutations in OTOF were studied clinically. They were phenotypically homogeneous, having profound hearing impairment with very early onset, as shown by pure-tone audiometry and auditory brainstem responses. Magnetic resonance imaging and computed tomography did not reveal any inner ear malformation. Unexpectedly, transient evoked otoacoustic emissions (TEOAEs) were present, either bilaterally or unilaterally in 11 subjects. Altogether, clinical data of these subjects met the diagnostic criteria of auditory neuropathy. A total of 10 subjects had been successfully provided with cochlear implants. The results of our study indicate that genetic diagnosis of subjects with auditory neuropathy and profound hearing impairment should be directed to the otoferlin gene. Our data are of concern to universal screening programs which use TEOAEs as the first detection test for hearing impairment in newborns, since this technique may overlook a nonnegligible proportion of cases.

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.

Results showed that some degree of hearing preservation was possible in 15718 patients. All subjects showed statistically significant benefit on all three speech perception tests over time. These significant benefits were also reflected in the subjective benefit outcomes.

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For speech testing in quiet, bimodal scores were significantly better than for HA alone and CI alone conditions (p < 0.01). For speech and noise (S0N0) at 0° azimuth the scores were significantly better in the bimodal condition than for CI alone (p = 0.01), indicating binaural summation. When noise was presented to the HA side (S0NHA) bimodal scores were significantly better than for CI alone (p < 0.01 and p < 0.05, respectively), suggesting a significant binaural squelch effect. Sound localization ability was significantly improved in the bimodal condition compared with the CI alone condition (p = 0.002).

Patients: Five hundred ten individuals from 8 hospitals that met the American Academy of Otolaryngology-Head and Neck Surgery diagnostic criteria for definitive Ménière's disease. Intervention: Conservative treatment. Main Outcome Measure: Frequency and duration of episodes of definitive vertigo during follow-up. Results: Ménière's disease affects both sexes and both ears equally, with onset generally in the fourth decade

In all, 36% of subjects demonstrated preservation of thresholds to within 10 dB of preoperative thresholds across the frequency range (0.25, 0.5, 1.0, 2.0 and 4.0 KHz) and for the low frequency range (0.25-1.0 KHz). Approximately two-thirds of subjects demonstrated preservation of preoperative thresholds to within 20 dB. Preservation of low frequency thresholds post-implant was shown to correlate moderately with cochleostomy site, being more likely for subjects with a site anterior-inferior to the round window but also possible with inferior locations; weakly with cochleostomy size, being more likely when smaller than 1.2 mm; and also with the use of Healon as a sealant and lubricant. Preservation of hearing thresholds across up to 4000 Hz was shown to correlate weakly with the use of suction following opening of the endostium and with bone dust contamination, both having a negative effect upon preservation, while no correlation was observed with the preservation of thresholds for low frequencies alone.

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