Perceptual Consequences of Cochlear Deafferentation in Humans.

Cochlear synaptopathy, a form of cochlear deafferentation, has been demonstrated in a number of animal species, including non-human primates. Both age and noise exposure contribute to synaptopathy in animal models, indicating that it may be a common type of auditory dysfunction in humans. Temporal bone and auditory physiological data suggest that age and occupational/military noise exposure also lead to synaptopathy in humans. The predicted perceptual consequences of synaptopathy include tinnitus, hyperacusis, and difficulty with speech-in-noise perception. However, confirming the perceptual impacts of this form of cochlear deafferentation presents a particular challenge because synaptopathy can only be confirmed through post-mortem temporal bone analysis and auditory perception is difficult to evaluate in animals. Animal data suggest that deafferentation leads to increased central gain, signs of tinnitus and abnormal loudness perception, and deficits in temporal processing and signal-in-noise detection. If equivalent changes occur in humans following deafferentation, this would be expected to increase the likelihood of developing tinnitus, hyperacusis, and difficulty with speech-in-noise perception. Physiological data from humans is consistent with the hypothesis that deafferentation is associated with increased central gain and a greater likelihood of tinnitus perception, while human data on the relationship between deafferentation and hyperacusis is extremely limited. Many human studies have investigated the relationship between physiological correlates of deafferentation and difficulty with speech-in-noise perception, with mixed findings. A non-linear relationship between deafferentation and speech perception may have contributed to the mixed results. When differences in sample characteristics and study measurements are considered, the findings may be more consistent.

Associations Between Physiological Correlates of Cochlear Synaptopathy and Tinnitus in a Veteran Population.

PURPOSE: Animal models and human temporal bones indicate that noise exposure is a risk factor for cochlear synaptopathy, a possible etiology of tinnitus. Veterans are exposed to high levels of noise during military service. Therefore, synaptopathy may explain the high rates of noise-induced tinnitus among Veterans. Although synaptopathy cannot be directly evaluated in living humans, animal models indicate that several physiological measures are sensitive to synapse loss, including the auditory brainstem response (ABR), the middle ear muscle reflex (MEMR), and the envelope following response (EFR). The purpose of this study was to determine whether tinnitus is associated with reductions in physiological correlates of synaptopathy that parallel animal studies. METHOD: Participants with normal audiograms were grouped according to Veteran status and tinnitus report (Veterans with tinnitus, Veterans without tinnitus, and non-Veteran controls). The effects of being a Veteran with tinnitus on ABR, MEMR, and EFR measurements were independently modeled using Bayesian regression analysis. RESULTS: Modeled point estimates of MEMR and EFR magnitude showed reductions for Veterans with tinnitus compared with non-Veterans, with the most evident reduction observed for the EFR. Two different approaches were used to provide context for the Veteran tinnitus effect on the EFR by comparing to age-related reductions in EFR magnitude and synapse numbers observed in previous studies. These analyses suggested that EFR magnitude/synapse counts were reduced in Veterans with tinnitus by roughly the same amount as over 20 years of aging. CONCLUSION: These findings suggest that cochlear synaptopathy may contribute to tinnitus perception in noise-exposed Veterans. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24347761.

Contralateral inhibition of distortion product otoacoustic emissions in young noise-exposed Veterans.

Although animal models show a clear link between noise exposure and damage to afferent cochlear synapses, the relationship between noise exposure and efferent function appears to be more complex. Animal studies indicate that high intensity noise exposure reduces efferent medial olivocochlear (MOC) reflex strength, whereas chronic moderate noise exposure is associated with a conditioning effect that enhances the MOC reflex. The MOC reflex is predicted to improve speech-in-noise perception and protects against noise-induced auditory damage by reducing cochlear gain. In humans, MOC reflex strength can be estimated by measuring contralateral inhibition of distortion product otoacoustic emissions (DPOAEs). The objective of this study was to determine the impact of military noise exposure on efferent auditory function by measuring DPOAE contralateral inhibition in young Veterans and non-Veterans with normal audiograms. Compared with non-Veteran controls, Veterans with high levels of reported noise exposure demonstrated a trend of reduced contralateral inhibition across a broad frequency range, suggesting efferent damage. Veterans with moderate noise exposure showed trends of reduced inhibition from 3 to 4 kHz but greater inhibition from 1 to 1.5 kHz, consistent with conditioning. These findings suggest that, in humans, the impact of noise exposure on the MOC reflex differs depending on the noise intensity and duration.

Predicting synapse counts in living humans by combining computational models with auditory physiology.

Aging, noise exposure, and ototoxic medications lead to cochlear synapse loss in animal models. As cochlear function is highly conserved across mammalian species, synaptopathy likely occurs in humans as well. Synaptopathy is predicted to result in perceptual deficits including tinnitus, hyperacusis, and difficulty understanding speech-in-noise. The lack of a method for diagnosing synaptopathy in living humans hinders studies designed to determine if noise-induced synaptopathy occurs in humans, identify the perceptual consequences of synaptopathy, or test potential drug treatments. Several physiological measures are sensitive to synaptopathy in animal models including auditory brainstem response (ABR) wave I amplitude. However, it is unclear how to translate these measures to synaptopathy diagnosis in humans. This work demonstrates how a human computational model of the auditory periphery, which can predict ABR waveforms and distortion product otoacoustic emissions (DPOAEs), can be used to predict synaptic loss in individual human participants based on their measured DPOAE levels and ABR wave I amplitudes. Lower predicted synapse numbers were associated with advancing age, higher noise exposure history, increased likelihood of tinnitus, and poorer speech-in-noise perception. These findings demonstrate the utility of this modeling approach in predicting synapse counts from physiological data in individual human subjects.

The Impacts of Noise Exposure on the Middle Ear Muscle Reflex in a Veteran Population.

PURPOSE: Human studies of noise-induced cochlear synaptopathy using physiological indicators identified in animal models (auditory brainstem response [ABR] Wave I amplitude, envelope following response [EFR], and middle ear muscle reflex [MEMR]) have yielded mixed findings. Differences in the population studied may have contributed to the differing results. For example, due to differences in the intensity level of the noise exposure, noise-induced synaptopathy may be easier to detect in a military Veteran population than in populations with recreational noise exposure. We previously demonstrated a reduction in ABR Wave I amplitude and EFR magnitude for young Veterans with normal audiograms reporting high levels of noise exposure compared to non-Veteran controls. In this article, we expand on the previous analysis in the same population to determine if MEMR magnitude is similarly reduced. METHOD: Contralateral MEMR growth functions were obtained in 92 young Veterans and non-Veterans with normal audiograms, and the relationship between noise exposure history and MEMR magnitude was assessed. Associations between MEMR magnitude and distortion product otoacoustic emission, EFR, and ABR measurements collected in the same sample were also evaluated. RESULTS: The results of the statistical analysis, although not conventionally statistically significant, suggest a reduction in mean MEMR magnitude for Veterans reporting high noise exposure compared with non-Veteran controls. In addition, the MEMR appears relatively insensitive to subclinical outer hair cell dysfunction, as measured by distortion product otoacoustic emissions, and is not well correlated with ABR and EFR measurements. CONCLUSIONS: When combined with our previous ABR and EFR findings in the same population, these results suggest that noise-induced synaptopathy occurs in humans. In addition, the findings indicate that the MEMR may be a good candidate for noninvasive diagnosis of cochlear synaptopathy/deafferentation and that the MEMR may reflect the integrity of different neural populations than the ABR and EFR. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.18665645.

Envelope following response measurements in young veterans are consistent with noise-induced cochlear synaptopathy.

Animal studies have demonstrated that noise exposure can lead to the loss of the synapses between the inner hair cells and their afferent auditory nerve fiber targets without impacting auditory thresholds. Although several non-invasive physiological measures appear to be sensitive to cochlear synaptopathy in animal models, including auditory brainstem response (ABR) wave I amplitude, the envelope following response (EFR), and the middle ear muscle reflex (MEMR), human studies of these measures in samples that are expected to vary in terms of the degree of noise-induced synaptopathy have resulted in mixed findings. One possible explanation for the differing results is that synaptopathy risk is lower for recreational noise exposure than for occupational or military noise exposure. The goal of this analysis was to determine if EFR magnitude and ABR wave I amplitude are reduced among young Veterans with a history of military noise exposure compared with non-Veteran controls with minimal noise exposure. EFRs and ABRs were obtained in a sample of young (19-35 years) Veterans and non-Veterans with normal audiograms and robust distortion product otoacoustic emissions (DPOAEs). The statistical analysis is consistent with a reduction in mean EFR magnitude and ABR wave I amplitude (at 90 dB peSPL) for Veterans with a significant history of noise exposure compared with non-Veteran controls. These findings are in agreement with previous ABR wave I amplitude findings in young Veterans and are consistent with animal models of noise-induced cochlear synaptopathy.

Development and Initial Validation of the Lifetime Exposure to Noise and Solvents Questionnaire in U.S. Service Members and Veterans.

Purpose A need exists to investigate the short- and long-term impact of noise exposures during and following military service on auditory health. Currently available questionnaires are limited in their ability to meet this need because of (a) inability to evaluate noise exposures beyond a limited time frame, (b) lack of consensus on scoring, (c) inability to assess impulse exposures (e.g., firearm use), (d) lack of a single questionnaire that assesses both military and nonmilitary exposures, and (e) lack of validity and reliability data. To address these limitations, the Lifetime Exposure to Noise and Solvents Questionnaire (LENS-Q) was developed. The purpose of this report is to describe the development and initial validation of the LENS-Q as a measure of self-reported noise exposure. Method Six hundred ninety participants, consisting of current Service members and recently military-separated (within about 2.5 years) Veterans, completed the LENS-Q, additional study questionnaires, and comprehensive audiometric testing. Noise exposure scores were computed from LENS-Q responses using a simple scoring algorithm that distinguishes between different cumulative levels of exposure and allows for the inclusion of both continuous and impulse noise exposures. Results The LENS-Q demonstrates good construct validity as evidenced by measures of hearing loss, tinnitus, and subjective hearing difficulties all increasing with an increase in noise exposure scores. A logistic regression, adjusting for age and sex, revealed that participants in the highest exposure group were 2.4-3.9 times more likely to experience hearing loss, 2.7-2.8 times more likely to experience tinnitus, and 3.0-3.7 times more likely to report hearing difficulties compared with individuals in the lowest exposure group. Conclusions The LENS-Q captures noise exposure over an individual's lifetime and provides an alternative scoring metric capable of representing exposure to both continuous and impulse noise. Findings suggest that the LENS-Q is a valuable tool for capturing and measuring both military and nonmilitary noise exposure. Supplemental Material https://doi.org/10.23641/asha.14582937.

Subclinical Auditory Dysfunction: Relationship Between Distortion Product Otoacoustic Emissions and the Audiogram.

Purpose Distortion product otoacoustic emissions (DPOAEs) and audiometric thresholds have been used to account for the impacts of subclinical outer hair cell (OHC) dysfunction on auditory perception and measures of auditory physiology. However, the relationship between DPOAEs and the audiogram is unclear. This study investigated this relationship by determining how well DPOAE levels can predict the audiogram among individuals with clinically normal hearing. Additionally, the impacts of age, noise exposure, and the perception of tinnitus on the ability of DPOAE levels to predict the audiogram were evaluated. Method Suprathreshold DPOAE levels from 1 to 10 kHz and pure-tone thresholds from 0.25 to 16 kHz were measured in 366 ears from 194 young adults (19-35 years old) with clinically normal audiograms and middle ear function. The measured DPOAE levels at all frequencies were used to predict pure-tone thresholds at each frequency. Participants were grouped by age, self-reported noise exposure/Veteran status, and self-report of tinnitus. Results Including DPOAE levels in the pure-tone threshold prediction model improved threshold predictions at all frequencies from 0.25 to 16 kHz compared with a model based only on sample mean pure-tone thresholds, but these improvements were modest. DPOAE levels for f 2 frequencies of 4 and 5 kHz were particularly influential in predicting pure-tone thresholds above 4 kHz. However, prediction accuracy varied based on participant characteristics. On average, predicted pure-tone thresholds were better than measured thresholds among Veterans, individuals with tinnitus, and the oldest age group. Conclusions These results indicate a complex relationship between DPOAE levels and the audiogram. Underestimation of pure-tone thresholds for some groups suggests that additional factors other than OHC damage may impact thresholds among individuals within these categories. These findings suggest that DPOAE levels and pure-tone thresholds may differ in terms of how well they reflect subclinical OHC dysfunction. Supplemental Material https://doi.org/10.23641/asha.13564745.

Use of the auditory brainstem response for assessment of cochlear synaptopathy in humans.

Although clinical use of the auditory brainstem response (ABR) to detect retrocochlear disorders has been largely replaced by imaging in recent years, the discovery of cochlear synaptopathy has thrown this foundational measure of auditory function back into the spotlight. Whereas modern imaging now allows for the noninvasive detection of vestibular schwannomas, imaging technology is not currently capable of detecting cochlear synaptopathy, the loss of the synaptic connections between the inner hair cells and afferent auditory nerve fibers. However, animal models indicate that the amplitude of the first wave of the ABR, a far-field evoked potential generated by the synchronous firing of auditory nerve fibers, is highly correlated with synaptic integrity. This has led to many studies investigating the use of the ABR as a metric of synaptopathy in humans. However, these studies have yielded mixed results, leading to a lack of consensus about the utility of the ABR as an indicator of synaptopathy. This review summarizes the animal and human studies that have investigated the ABR as a measure of cochlear synaptic function, discusses factors that may have contributed to the mixed findings and the lessons learned, and provides recommendations for future use of this metric in the research and clinical settings.

Evoked Potentials Reveal Noise Exposure-Related Central Auditory Changes Despite Normal Audiograms.

Purpose Complaints of auditory perceptual deficits, such as tinnitus and difficulty understanding speech in background noise, among individuals with clinically normal audiograms present a perplexing problem for audiologists. One potential explanation for these "hidden" auditory deficits is loss of the synaptic connections between the inner hair cells and their afferent auditory nerve fiber targets, a condition that has been termed cochlear synaptopathy. In animal models, cochlear synaptopathy can occur due to aging or exposure to noise or ototoxic drugs and is associated with reduced auditory brainstem response (ABR) wave I amplitudes. Decreased ABR wave I amplitudes have been demonstrated among young military Veterans and non-Veterans with a history of firearm use, suggesting that humans may also experience noise-induced synaptopathy. However, the downstream consequences of synaptopathy are unclear. Method To investigate how noise-induced reductions in wave I amplitude impact the central auditory system, the ABR, the middle latency response (MLR), and the late latency response (LLR) were measured in 65 young Veterans and non-Veterans with normal audiograms. Results In response to a click stimulus, the MLR was weaker for Veterans compared to non-Veterans, but the LLR was not reduced. In addition, low ABR wave I amplitudes were associated with a reduced MLR, but with an increased LLR. Notably, Veterans reporting tinnitus showed the largest mean LLRs. Conclusions These findings indicate that decreased peripheral auditory input leads to compensatory gain in the central auditory system, even among individuals with normal audiograms, and may impact auditory perception. This pattern of reduced MLR, but not LLR, was observed among Veterans even after statistical adjustment for sex and distortion product otoacoustic emission differences, suggesting that synaptic loss plays a role in the observed central gain. Supplemental Material https://doi.org/10.23641/asha.11977854.

Auditory brainstem response demonstrates that reduced peripheral auditory input is associated with self-report of tinnitus.

Tinnitus is one of the predicted perceptual consequences of cochlear synaptopathy, a type of age-, noise-, or drug-induced auditory damage that has been demonstrated in animal models to cause homeostatic changes in central auditory gain. Although synaptopathy has been observed in human temporal bones, assessment of this condition in living humans is limited to indirect non-invasive measures such as the auditory brainstem response (ABR). In animal models, synaptopathy is associated with a reduction in ABR wave I amplitude at suprathreshold stimulus levels. Several human studies have explored the relationship between wave I amplitude and tinnitus, with conflicting results. This study investigates the hypothesis that reduced peripheral auditory input due to synaptic/neuronal loss is associated with tinnitus. Wave I amplitude data from 193 individuals [43 with tinnitus (22%), 150 without tinnitus (78%)], who participated in up to 3 out of 4 different studies, were included in a logistic regression analysis to estimate the relationship between wave I amplitude and tinnitus at a variety of stimulus levels and frequencies. Statistical adjustment for sex and distortion product otoacoustic emissions (DPOAEs) was included. The results suggest that smaller wave I amplitudes and/or lower DPOAE levels are associated with an increased probability of tinnitus.

Use of non-invasive measures to predict cochlear synapse counts.

Cochlear synaptopathy, the loss of synaptic connections between inner hair cells (IHCs) and auditory nerve fibers, has been documented in animal models of aging, noise, and ototoxic drug exposure, three common causes of acquired sensorineural hearing loss in humans. In each of these models, synaptopathy begins prior to changes in threshold sensitivity or loss of hair cells; thus, this underlying injury can be hidden behind a normal threshold audiogram. Since cochlear synaptic loss cannot be directly confirmed in living humans, non-invasive assays will be required for diagnosis. In animals with normal auditory thresholds, the amplitude of wave 1 of the auditory brainstem response (ABR) is highly correlated with synapse counts. However, synaptopathy can also co-occur with threshold elevation, complicating the use of the ABR alone as a diagnostic measure. Using an age-graded series of mice and a partial least squares regression approach to model structure-function relationships, this study shows that the combination of a small number of ABR and distortion product otoacoustic emission (DPOAE) measurements can predict synaptic ribbon counts at various cochlear frequencies to within 1-2 synapses per IHC of their true value. In contrast, the model, trained using the age-graded series of mice, overpredicted synapse counts in a small sample of young noise-exposed mice, perhaps due to differences in the underlying pattern of damage between aging and noise-exposed mice. These results provide partial validation of a noninvasive approach to identify synaptic/neuronal loss in humans using ABRs and DPOAEs.

Tinnitus and Auditory Perception After a History of Noise Exposure: Relationship to Auditory Brainstem Response Measures.

OBJECTIVES: To determine whether auditory brainstem response (ABR) wave I amplitude is associated with measures of auditory perception in young people with normal distortion product otoacoustic emissions (DPOAEs) and varying levels of noise exposure history. DESIGN: Tinnitus, loudness tolerance, and speech perception ability were measured in 31 young military Veterans and 43 non-Veterans (19 to 35 years of age) with normal pure-tone thresholds and DPOAEs. Speech perception was evaluated in quiet using Northwestern University Auditory Test (NU-6) word lists and in background noise using the words in noise (WIN) test. Loudness discomfort levels were measured using 1-, 3-, 4-, and 6-kHz pulsed pure tones. DPOAEs and ABRs were collected in each participant to assess outer hair cell and auditory nerve function. RESULTS: The probability of reporting tinnitus in this sample increased by a factor of 2.0 per 0.1 µV decrease in ABR wave I amplitude (95% Bayesian confidence interval, 1.1 to 5.0) for males and by a factor of 2.2 (95% confidence interval, 1.0 to 6.4) for females after adjusting for sex and DPOAE levels. Similar results were obtained in an alternate model adjusted for pure-tone thresholds in addition to sex and DPOAE levels. No apparent relationship was found between wave I amplitude and either loudness tolerance or speech perception in quiet or noise. CONCLUSIONS: Reduced ABR wave I amplitude was associated with an increased risk of tinnitus, even after adjusting for DPOAEs and sex. In contrast, wave III and V amplitudes had little effect on tinnitus risk. This suggests that changes in peripheral input at the level of the inner hair cell or auditory nerve may lead to increases in central gain that give rise to the perception of tinnitus. Although the extent of synaptopathy in the study participants cannot be measured directly, these findings are consistent with the prediction that tinnitus may be a perceptual consequence of cochlear synaptopathy.

Auditory Brainstem Response Altered in Humans With Noise Exposure Despite Normal Outer Hair Cell Function.

OBJECTIVES: Recent animal studies demonstrated that cochlear synaptopathy, a partial loss of inner hair cell-auditory nerve fiber synapses, can occur in response to noise exposure without any permanent auditory threshold shift. In animal models, this synaptopathy is associated with a reduction in the amplitude of wave I of the auditory brainstem response (ABR). The goal of this study was to determine whether higher lifetime noise exposure histories in young people with clinically normal pure-tone thresholds are associated with lower ABR wave I amplitudes. DESIGN: Twenty-nine young military Veterans and 35 non Veterans (19 to 35 years of age) with normal pure-tone thresholds were assigned to 1 of 4 groups based on their self-reported lifetime noise exposure history and Veteran status. Suprathreshold ABR measurements in response to alternating polarity tone bursts were obtained at 1, 3, 4, and 6 kHz with gold foil tiptrode electrodes placed in the ear canal. Wave I amplitude was calculated from the difference in voltage at the positive peak and the voltage at the following negative trough. Distortion product otoacoustic emission input/output functions were collected in each participant at the same four frequencies to assess outer hair cell function. RESULTS: After controlling for individual differences in sex and distortion product otoacoustic emission amplitude, the groups containing participants with higher reported histories of noise exposure had smaller ABR wave I amplitudes at suprathreshold levels across all four frequencies compared with the groups with less history of noise exposure. CONCLUSIONS: Suprathreshold ABR wave I amplitudes were reduced in Veterans reporting high levels of military noise exposure and in non Veterans reporting any history of firearm use as compared with Veterans and non Veterans with lower levels of reported noise exposure history. The reduction in ABR wave I amplitude in the groups with higher levels of noise exposure cannot be accounted for by sex or variability in outer hair cell function. This change is similar to the decreased ABR wave I amplitudes observed in animal models of noise-induced cochlear synaptopathy. However, without post mortem examination of the temporal bone, no direct conclusions can be drawn concerning the presence of synaptopathy in the study groups with higher noise exposure histories.

Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea.

The prevalence of hearing loss after damage to the mammalian cochlea has been thought to be due to a lack of spontaneous regeneration of hair cells, the primary receptor cells for sound. Here, we show that supporting cells, which surround hair cells in the normal cochlear epithelium, differentiate into new hair cells in the neonatal mouse following ototoxic damage. Using lineage tracing, we show that new hair cells, predominantly outer hair cells, arise from Lgr5-expressing inner pillar and third Deiters cells and that new hair cell generation is increased by pharmacological inhibition of Notch. These data suggest that the neonatal mammalian cochlea has some capacity for hair cell regeneration following damage alone and that Lgr5-positive cells act as hair cell progenitors in the cochlea.

Vestibular function in families with inherited autosomal dominant hearing loss.

The inner ear contains the developmentally related cochlea and peripheral vestibular labyrinth. Given the similar physiology between these two organs, hearing loss and vestibular dysfunction may be expected to occur simultaneously in individuals segregating mutations in inner ear genes. Twenty-two different genes have been discovered that when mutated lead to non-syndromic autosomal dominant hearing loss. A review of the literature indicates that families segregating mutations in 13 of these 22 genes have undergone formal clinical vestibular testing. Formal assessment revealed vestibular dysfunction in families with mutations in ten of these 13 genes. Remarkably, only families with mutations in the COCH and MYO7A genes self-report considerable vestibular challenges. Families segregating mutations in the other eight genes do not self-report significant balance problems and appear to compensate well in everyday life for vestibular deficits discovered during formal clinical vestibular assessment. An example of a family (referred to as the HL1 family) with progressive hearing loss and clinically-detected vestibular hypofunction that does not report vestibular symptoms is described in this review. Notably, one member of the HL1 family with clinically-detected vestibular hypofunction reached the summit of Mount Kilimanjaro.

In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier.

OBJECTIVES: To evaluate the auditory, vestibular, and retinal characteristics of a large American DFNA11 pedigree with autosomal dominant progressive sensorineural hearing loss that first impacts the low- and mid-frequency auditory range. The pedigree (referred to as the HL2 family) segregates a myosin VIIA (MYO7A) mutation in exon 17 at DNA residue G2164C (MYO7A) that seems to be influenced by a genetic modifier that either rescues or exacerbates the MYO7A alteration. DNA analysis to examine single-nucleotide polymorphisms in 2 candidate modifier genes (ATP2B2 and Wolfram syndrome 1 [WFS1]) is summarized in this report. STUDY DESIGN: Family study. RESULTS: The degree of low- and mid-frequency hearing loss in HL2 family members segregating the MYO7A mutation varies from mild to more severe, with approximately the same number of HL2 family members falling at each end of the severity spectrum. The extent of hearing loss in HL2 individuals can vary between family generations. Differences in the degree of hearing loss in MYO7A HL2 family members may be mirrored by vestibular function in at least 2 of these same individuals. The single-nucleotide polymorphisms examined within ATP2B2 and WFS1 did not segregate with the mild versus more severe auditory phenotype. CONCLUSION: The severity of the auditory and vestibular phenotypes in MYO7A HL2 family members may run in parallel, suggesting a common modifier gene within the inner ear. The putative MYO7A genetic modifier is likely to represent a common polymorphism that is not linked tightly to the MYO7A mutation on the MYO7A allele.

A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings.

BACKGROUND: Low frequency sensorineural hearing loss (LFSNHL) is an uncommon clinical finding. Mutations within three different identified genes (DIAPH1, MYO7A, and WFS1) are known to cause LFSNHL. The majority of hereditary LFSNHL is associated with heterozygous mutations in the WFS1 gene (wolframin protein). The goal of this study was to use genetic analysis to determine if a small American family's hereditary LFSNHL is linked to a mutation in the WFS1 gene and to use VEMP and EcochG testing to further characterize the family's audiovestibular phenotype. METHODS: The clinical phenotype of the American family was characterized by audiologic testing, vestibular evoked myogenic potentials (VEMP), and electrocochleography (EcochG) evaluation. Genetic characterization was performed by microsatellite analysis and direct sequencing of WFS1 for mutation detection. RESULTS: Sequence analysis of the WFS1 gene revealed a novel heterozygous mutation at c.2054G>C predicting a p.R685P amino acid substitution in wolframin. The c.2054G>C mutation segregates faithfully with hearing loss in the family and is absent in 230 control chromosomes. The p.R685 residue is located within the hydrophilic C-terminus of wolframin and is conserved across species. The VEMP and EcochG findings were normal in individuals segregating the WFS1 c.2054G>C mutation. CONCLUSION: We discovered a novel heterozygous missense mutation in exon 8 of WFS1 predicting a p.R685P amino acid substitution that is likely to underlie the LFSNHL phenotype in the American family. For the first time, we describe VEMP and EcochG findings for individuals segregating a heterozygous WFS1 mutation.