Christina L. Runge

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13)

We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

Rate of Neural Recovery in Implanted Children with Auditory Neuropathy Spectrum Disorder

Objectives. The study objectives were to compare the rate of neural recovery and speech perception performance in children with auditory neuropathy spectrum disorder (ANSD) and children with sensorineural hearing loss (SNHL) from other etiologies. Study Design. Cohort study. Setting. Academic hospital and cochlear implant center. Subjects and Methods. Ten children with ANSD were matched based on type of implant and age at implantation with peers diagnosed with SNHL. Electrically evoked compound action potential (ECAP) recovery functions were obtained to measure neural refractory behaviors in response to stimulation from the cochlear implant. Speech perception performance was measured using speech recognition thresholds (SRTs) for monosyllable and spondee word stimuli. These outcome measures were compared between groups. Results. There was no difference in average recovery function exponent in children with ANSD compared to children with SNHL. Similarly, there were no differences in average SRTs in quiet and in noise in children with ANSD compared to children with SNHL. Relationships between SRT and recovery rate were not present within groups or for all subjects for SRT in quiet, but a significant relationship was found for all subjects for SRT in noise (P = .04). Conclusions. Dyssynchronous neural activity in ANSD may affect temporal encoding of electrical stimulation from a cochlear implant. As a group, children with ANSD did not demonstrate slower neural recovery compared to those with SNHL, but there was slower neural recovery observed for some subjects. The utility of ECAP recovery functions on optimizing the stimulation rate for individual patients with ANSD requires further investigation.

Patient Outcomes in Magnet-Based Implantable Auditory Assist Devices

IMPORTANCE Magnet-based implantable auditory assist devices (MIAADs) are a recent development in bone-anchored hearing devices. This report increases the number of children studied with specific outcome criteria and provides detailed solutions to avoid device use difficulties in other centers considering this device. OBJECTIVE To assess hearing thresholds, use rates, and complications in children implanted with a MIAAD for conductive hearing loss. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of children implanted with an MIAAD at an ambulatory care quaternary referral center since the Food and Drug Administration approved the Sophono device (Sophono Inc) for use in the United States (May 2011 through January 2013). Ten pediatric patients were implanted for conductive hearing loss (14 ears; mean age at implantation, 9 years [range, 3.8-17.2 years]). Diagnoses included aural atresia (n = 7) and chronic ear disease and cholesteatoma (n = 3). INTERVENTIONS Implantation of MIAAD and management of skin complications. MAIN OUTCOMES AND MEASURES Demographics, hearing thresholds, use rates, and complications were assessed. RESULTS After fitting with the magnetic baseplate and sound processor, the mean (SD) aided pure-tone average was 20.2 (6.0) dB hearing level (HL), with a mean (SD) functional gain of 39.9 (12.4) dB HL. There were no surgical complications. Negative outcomes were assessed following fitting of the sound processor. The skin complication rate was 35.7%, including skin breakdown (n = 2) and pain and erythema (n = 5), which resulted in decreased use of the device for these patients. Intervention included decreasing the magnet strength, graduated wearing schedule, antibiotic ointment, barrier protection, and reoperation for well widening with Alloderm (LifeCell Corporation) placement. Patients without skin complications are consistent users of their device, with an average daily use of 8 to 10 hours. CONCLUSIONS AND RELEVANCE The MIAAD device has equivalent levels of hearing restoration to other previously described methods of intervention for children with conductive hearing loss. This early report indicates high rates of skin difficulties and a need for improved methods of implantation, magnetic baseplate fitting, and device use. We suggest decreased magnet strength at the initial fitting, a graduated wearing schedule, caution with patients who have a history of skin issues from a bone-anchored hearing aid or multiple surgical procedures, and parent counseling regarding potential skin irritation.

Recovery from forward masking in elderly cochlear implant users.

Objective To compare temporal aspects of peripheral neural responses and central auditory perception between groups of younger adult and elderly cochlear implant users. Study Design Cohort study. Setting Academic hospital and cochlear implant center. Patients Adult cochlear implant users aged 28 to 57 years in the younger group (n = 5) and 61 to 89 years (n = 9) in the elderly group. All subjects used Advanced Bionics devices. Intervention Diagnostic. Main Outcome Measures Time constants of neural (i.e., electrically evoked compound action potentials [ECAPs]) and perceptual recovery from forward masking. Interstimulus intervals (ISIs) were varied in both experiments. Results ECAP recovery rates were equivalent between groups, and no correlation was found between ECAP recovery and age. No correlations were found between ECAP recovery and speech perception. Psychophysical recovery was significantly slower in the elderly compared with the younger subjects (p < 0.0005), with a significant effect of age (R2 = 0.70, p < 0.0005). At the longest ISI (240 ms), elderly subjects experienced a mean maximum threshold shift of 35.2% (relative to 1 ms ISI) versus 14.8% for younger subjects. There was a significant positive relationship between psychophysical recovery and consonant-nucleus-consonant word scores (R2 = 0.62, p < 0.001), although no relationship was found with Hearing in Noise Test sentences. Conclusion These findings suggest that difficulties observed in speech perception by elderly CI users may be due to age-related changes in the central rather than peripheral auditory system. With further study, these results may provide information to allow clinicians to assess patients’ temporal processing abilities and facilitate setting program parameters that will maximize their auditory perceptual experience with a cochlear implant.

The role of age on cochlear implant performance, use, and health utility: a multicenter clinical trial.

Objective To use data obtained in a multicenter clinical trial to evaluate factors affecting performance with an implant, with special emphasis on the effect of age on performance. Study design and setting Post hoc analyses of data collected during a multicenter prospective study to evaluate performance with a recently introduced cochlear implant (CI) system conducted at 13 academic centers in the United States. Subjects participated in speech recognition testing in quiet and noise and completed questionnaires regarding health utility and processor use. Patients Thirty-eight adults with moderate to profound hearing loss who ranged in age from 18 to 89 years. Subjects were divided into younger (<65 yr, n = 20) and older (≥65 yr, n = 18) groups for the analyses. Intervention All subjects received a multichannel CI system. Preimplant to postimplant change in speech recognition was evaluated for each group, and the performance of the two groups was compared. Postimplant performance of older subjects who scored greater than 40% preimplant on HINT (Hearing in Noise Test) sentences was also evaluated. Linear regression was used to further evaluate the effects of variables on outcomes. Results Both younger and older subjects demonstrated significant improvement in speech recognition and hearing health utility after receiving a CI, and differences between groups were insignificant. Older subjects who scored greater than 40% preoperatively on HINT sentences demonstrated a significant improvement in speech recognition. Conclusion Both older and younger patients can receive significant improvement in speech recognition and health utility after receiving a CI.

Aiding and Occluding the Contralateral Ear in Implanted Children with Auditory Neuropathy Spectrum Disorder

BACKGROUND The challenges associated with auditory neuropathy spectrum disorder (ANSD) are due primarily to temporal impairment and therefore tend to affect perception of low- to midfrequency sounds. A common treatment option for severe impairment in ANSD is cochlear implantation, and because the degree of impairment is unrelated to degree of hearing loss by audiometric thresholds, this population may have significant acoustic sensitivity in the contralateral ear. Clinically, the question arises as to how we should treat the contralateral ear in this population when there is acoustic hearing-should we plug it, amplify it, implant it, or leave it alone? PURPOSE The purpose of this study was to examine the effects of acute amplification and plugging of the contralateral ear compared to no intervention in implanted children with ANSD and aidable contralateral hearing. It was hypothesized that due to impaired temporal processing in ANSD, contralateral acoustic input would interfere with speech perception achieved with the cochlear implant (CI) alone; therefore, speech perception performance will decline with amplification and improve with occlusion. RESEARCH DESIGN Prospective within-subject comparison. Adaptive speech recognition thresholds (SRTs) for monosyllable and spondee word stimuli were measured in quiet and in noise for the intervention configurations. STUDY SAMPLE Nine children treated at the Medical College of Wisconsin Koss Cochlear Implant Program participated in the study. Inclusion criteria for this study were children diagnosed with ANSD who were unilaterally implanted, had aidable hearing in the contralateral ear (defined as a three-frequency pure-tone average of ≤80 dB HL), had at least 1 yr of cochlear implant experience, and were able to perform the speech perception task. INTERVENTION We compared SRT with the CI alone to SRTs with interventions of cochlear implant with a contralateral hearing aid (CI+HA) and cochlear implant with a contralateral earplug (CI+plug). DATA COLLECTION AND ANALYSIS SRTs were measured and compared within subjects across listening conditions. Within-subject comparisons were analyzed using paired t-tests, and analyses of predictive variables for effects of contralateral intervention were analyzed using linear regression. RESULTS Contrary to the hypothesis, the bimodal CI+HA configuration showed a significant improvement in mean performance over the CI-alone configuration in quiet (p = .04). In noise, SRTs were obtained for six subjects, and no significant bimodal benefit was observed (p = .09). There were no consistent effects of occlusion observed across subjects and stimulus conditions. Degree of bimodal benefit showed a significant relationship with performance with the CI alone, with greater bimodal benefit associated with poorer CI-alone performance (p = .01). This finding, however, was limited by floor effects. CONCLUSIONS The results of this study indicate that children with ANSD who are experienced cochlear implant users may benefit from contralateral amplification, particularly for moderate cochlear implant performers. It is unclear from these data whether long-term contralateral hearing aid use in real-world situations would ultimately benefit this population; however, a hearing aid trial is recommended with assessment of bimodal benefit over time. These data may help inform clinical guidelines for determining optimal hearing configurations for unilaterally implanted children with ANSD, particularly when considering candidacy for sequential cochlear implantation.

A Novel Otoferlin Splice-Site Mutation in Siblings with Auditory Neuropathy Spectrum Disorder

We characterize a novel otoferlin mutation discovered in a sibling pair diagnosed with auditory neuropathy spectrum disorder and investigate auditory nerve function through their cochlear implants. Genetic sequencing revealed a homozygous mutation at the otoferlin splice donor site of exon 28 (IVS28 + 1G>T) in both siblings. Functional investigation showed that the intronic sequence between exons 28 and 29 was retained in the mutated minigenes that were expressed in 293T cells. Auditory nerve compound action potential recovery functions in the siblings demonstrated different rates of neural recovery, with sibling AN1 showing rapid recovery (1.14 ms) and AN2 showing average recovery (0.78 ms) compared to subjects with sensorineural hearing loss (average: adults 0.71 ms, children 0.85 ms). Differences in neural recovery were consistent with speech perception differences between the siblings. Genotype information may indicate site of lesion in hearing loss; however, additional, as yet, unknown factors may impact clinical outcomes and must be considered.

Variant discovery in targeted resequencing using whole genome amplified DNA.

BackgroundNext generation sequencing and advances in genomic enrichment technologies have enabled the discovery of the full spectrum of variants from common to rare alleles in the human population. The application of such technologies can be limited by the amount of DNA available. Whole genome amplification (WGA) can overcome such limitations. Here we investigate applicability of using WGA by comparing SNP and INDEL variant calls from a single genomic/WGA sample pair from two capture separate experiments: a 50 Mbp whole exome capture and a custom capture array of 4 Mbp region on chr12.ResultsOur results comparing variant calls derived from genomic and WGA DNA show that the majority of variant SNP and INDEL calls are common to both callsets, both at the site and genotype level and suggest that allele bias plays a minimal role when using WGA DNA in re-sequencing studies.ConclusionsAlthough the results of this study are based on a limited sample size, they suggest that using WGA DNA allows the discovery of the vast majority of variants, and achieves high concordance metrics, when comparing to genomic DNA calls.

Association of TMTC2 with human nonsyndromic sensorineural hearing loss

IMPORTANCE Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES Sensorineural hearing loss. RESULTS Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10-4). CONCLUSIONS AND RELEVANCE A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

Electrode failure and device failure in adult cochlear implantation

Abstract Objectives To determine the prevalence of cochlear implant electrode failure and the relationship with overall device failure. Methods Electrode status was analyzed in 322 functioning and in-use devices from 366 adult cochlear implant patients currently followed at our center. An additional 21 devices that had been explanted were also analyzed. Electrode failure was defined as unacceptably high impedance alone or in combination with aberrant percepts. Results At least one electrode had been turned off in 173 devices (54%). Most deactivated electrodes were the basal-most and had been turned off to improve sound quality. Of 437 deactivated electrodes, 33 were considered to have failed and were represented in 22 devices. These 22 devices are still in use (mean: 43.0 ± 29.8 months) without further electrode failures or device failure. There were no statistically significant differences in electrode failure rates among device manufacturers. There were 21 devices explanted of which 10 were due to device failure. One of five hard failures and two of three soft failures had deactivated electrodes prior to explantation. Two failures had no electrode data available. Discussion An inherent risk of cochlear implantation, as with all implanted electrical prostheses, is device failure. Failure of individual electrodes has been postulated to represent an early indicator of impending device failure. Our data demonstrate that electrode failure does not necessarily predict impending device failure. Although maps containing deactivated electrodes are fairly common, electrode failure as a reason for bypassing an electrode is rare and is often manageable with programming.