Paul Avan

Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy

Auditory neuropathy is a particular type of hearing impairment in which neural transmission of the auditory signal is impaired, while cochlear outer hair cells remain functional. Here we report on DFNB59, a newly identified gene on chromosome 2q31.1–q31.3 mutated in four families segregating autosomal recessive auditory neuropathy. DFNB59 encodes pejvakin, a 352-residue protein. Pejvakin is a paralog of DFNA5, a protein of unknown function also involved in deafness. By immunohistofluorescence, pejvakin is detected in the cell bodies of neurons of the afferent auditory pathway. Furthermore, Dfnb59 knock-in mice, homozygous for the R183W variant identified in one DFNB59 family, show abnormal auditory brainstem responses indicative of neuronal dysfunction along the auditory pathway. Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect.

Patients affected with Fabry disease have an increased incidence of progressive hearing loss and sudden deafness: an investigation of twenty-two hemizygous male patients.

BackgroundFabry disease (FD, OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism due to the deficient activity of alpha-galactosidase A, a lysosomal enzyme. While the progressive systemic deposition of uncleaved glycosphingolipids throughout the body is known to have protean clinical manifestations, few data are available regarding the cochlear involvement.MethodsWe non-invasively investigated cochlear functions in 22 consecutive hemizygous males (age 19–64 years, mean 39) affected with classic FD. Conventional audiometry, tympanometry, ABR audiometry, otoacoustic emissions were performed in all patients, together with medical history record and physical examination as part of an exhaustive baseline evaluation prior to enzyme replacement therapy.ResultsA total of 12 patients (54.5%) with classic FD were found to have abnormal audition. Five patients had progressive hearing loss and seven patients (32%) experienced sudden deafness. In addition, a hearing loss on high-tone frequencies was found in 7 out of the 10 remaining patients without clinical impairment, despite their young age at time of examination. The incidence of hearing loss appeared significantly increased in FD patients with kidney failure (P < 0.01) or cerebrovascular lesions (P < 0.01), whereas there was no correlation with left ventricular hypertrophy. In addition, tinnitus aurium was also found in six patients (27%).ConclusionThis is the first evidence of a high incidence of both progressive hearing loss and sudden deafness in a cohort of male patients affected with classic Fabry disease. The exact pathophysiologic mechanism(s) of the cochlear involvement deserves further studies.

Frequency Specificity of Human Distortion Product Otoacoustic Emissions

The amplitudes and growth functions of distortion product otoacoustic emissions (DPOE) at 2f1-f2, elicited by two primary tones f1 and f2 with a constant frequency ratio f2/f1 = 1.23 and varying geometric mean values 1, 1.5, 2, 4, 6 and 8 kHz, were measured for 25 normal subjects and 50 patients with sensorineural hearing loss. Partial correlations between DPOE amplitudes and auditory thresholds (0.25 to 8 kHz, half-octave steps) were examined. The amplitude of DPOE evoked by low-intensity primary tones (at or below 62 dB SPL) was strongly correlated only with the auditory threshold at their mean frequency, and DPOE disappeared for local hearing losses larger than about 30 dB. Moreover, DPOE amplitudes did not depend on the basal cochlear state. Confounding effects of middle ear transmission and aging were not significant in this set of experiments. When elicited by higher intensities of primary tones (72 dB SPL), DPOE exhibited a more complex and non-local behavior, and their sensitivity to hearing loss decreased. These results suggest that when low-intensity primaries are used, DPOE patterns provide frequency-specific information on the local cochlear state.

Genetic Dissection of the Function of Hindbrain Axonal Commissures

The Robo3 receptor controls midline crossing by axons. Deleting Robo3 in specific commissural neurons with a conditional knockout reveals their contribution to sensory and motor integration, and models human neurological conditions.

Spontaneous and evoked otoacoustic emissions in preterm neonates

Spontaneous (SOEs) and evoked otoacoustic emissions (EOEs) were recorded in a group of preterm neonates (N = 134 ears) in order to study the basic properties of SOEs and EOEs as a function of gestational age. In the study, it was found that: 1. EOEs were recorded in 93% of the tested ears; 2. SOEs were recorded in 61% of the tested ears; 3. there were no statistically significant variations of EOE amplitude with gestational age; 4. EOE spectrum did not vary with age; and 5. the two main factors influencing EOE amplitude were the SOE presence and the fast Fourier transform spectrum, especially the lower limit of the spectrum. Thus, the maturation of outer hair cell properties appears to be complete at 32 weeks of gestational age. Because a number of infants at risk for hearing loss are preterm babies, screening for EOEs, an objective, rapid, and nontraumatic technique, may prove useful in evaluating peripheral auditory dysfunction in preterm neonates.

Middle ear influence on otoacoustic emissions. I: Noninvasive investigation of the human transmission apparatus and comparison with model results

Evoked otoacoustic emissions (EOAEs) are generated within the cochlea in response to external sounds, and they can be acoustically detected in the external auditory meatus after backward propagation through the middle ear. In addition to being used to probe the cochlear mechanisms, they are expected to be sensitive to minute changes in middle ear impedance. Systematic measurements of the changes in the vectorial components of EOAEs were carried out after various manipulations of the human middle ear in order to characterize the influence of stiffness and inertia of the stapes and tympanic-membrane systems. For this purpose, stapedius muscle contractions were elicited by high-level contralateral sound, controlled changes in middle ear pressure (range +/-100 daPa) were produced and the tympanic membrane was loaded with water droplets. A computer model of the middle ear network was implemented using a standard lumped-element electric analog of the middle ear (Zwislockis model). Forward and backward transmission changes were simulated and model predictions were compared to experimental data. Apart from the case of positive middle ear pressures, a close qualitative correspondence was found between model and real-ear results. Each of the effects was characterized by a unique pattern of phase and magnitude changes as a function of frequency, in relation to the mechanical characteristics of the involved subsystem (i.e. stapes stiffness, tympanic-membrane stiffness or mass) and its resonance properties. Owing to their high sensitivity, EOAEs could be helpful for an accurate individual multifrequency analysis of middle ear impedance by comparisons under rest and test conditions.

Usher type 1G protein sans is a critical component of the tip-link complex, a structure controlling actin polymerization in stereocilia

The mechanotransducer channels of auditory hair cells are gated by tip-links, oblique filaments that interconnect the stereocilia of the hair bundle. Tip-links stretch from the tips of stereocilia in the short and middle rows to the sides of neighboring, taller stereocilia. They are made of cadherin-23 and protocadherin-15, products of the Usher syndrome type 1 genes USH1D and USH1F, respectively. In this study we address the role of sans, a putative scaffold protein and product of the USH1G gene. In Ush1g−/− mice, the cohesion of stereocilia is disrupted, and both the amplitude and the sensitivity of the transduction currents are reduced. In Ush1gfl/flMyo15-cre+/− mice, the loss of sans occurs postnatally and the stereocilia remain cohesive. In these mice, there is a decrease in the amplitude of the total transducer current with no loss in sensitivity, and the tips of the stereocilia in the short and middle rows lose their prolate shape, features that can be attributed to the loss of tip-links. Furthermore, stereocilia from these rows undergo a dramatic reduction in length, suggesting that the mechanotransduction machinery has a positive effect on F-actin polymerization. Sans interacts with the cytoplasmic domains of cadherin-23 and protocadherin-15 in vitro and is absent from the hair bundle in mice defective for either of the two cadherins. Because sans localizes mainly to the tips of short- and middle-row stereocilia in vivo, we conclude that it belongs to a molecular complex at the lower end of the tip-link and plays a critical role in the maintenance of this link.

Corticosteroid treatment in nasal polyposis with a three-year follow-up period.

Objectives/Hypothesis The management of nasal polyposis is undoubtedly a controversial subject. The part played by surgery seems to be steadily growing, if the number of published reports dedicated to this approach is any yardstick. Although the medical treatment remains the undisputed therapeutic mainstay, trials dedicated to the long‐term assessment of its overall efficacy are scarce.

Transient‐evoked otoacoustic emissions and high‐frequency acoustic trauma in the guinea pig

Transient-evoked otoacoustic emissions (TEOE) disappear when hearing loss exceeds 40 dB in the range 1-4 kHz, due to impairment of cochlear outer hair cells. Early screening of sensorineural hearing losses is based on this finding. However, little is known as to the frequency specificity of TEOE abnormalities in a damaged cochlea. TEOE were recorded in 18 normally hearing guinea pigs in a range from 1.5 to 5 kHz before and after exposure to loud pure tones (3-10 kHz, 95-105 dB SPL, 1-10 min). The thresholds of eighth-nerve compound action potentials (CAP) were monitored with a round-window electrode; it was confirmed that acoustic overexposure resulted in typical high-frequency threshold elevations (10 to 50 dB). Most TEOE components were found at lower frequencies at which CAP thresholds did not change. However, a significant linear regression was found between their amplitudes and the percentage of basal cochlea with unaltered CAP thresholds (r = 0.69, p < 0.0001). Two alternative hypotheses are proposed to account for this correlation. Either acoustic trauma induced some minute cochlear damage at places tuned to low frequencies and TEOE were more sensitive to it than CAP thresholds, or significant contributions to lower-frequency TEOE came from the most damaged cochlear places tuned to much higher frequencies.

Auditory Screening in Neonates by Means of Transient Evoked Otoacoustic Emissions: A Report of 2,842 Recordings

The principal goal of an early identification program is to identify hearing impairment present at birth, in order to effect appropriate intervention as early as possible. Although recent research provides some evidence for the value of transient evoked otoacoustic emissions (TEOAEs) in neonate hearing screening, data are needed from large-scale clinical evaluations about the value of using TEOAEs for screening not only high-risk but also healthy neonates. A cohort of 1,421 neonates (2,842 ears) from the well-baby nursery was screened with TEOAEs in a 2-stage process. Neonates were referred from the first test prior to being discharged from the hospital. Those who failed were rescreened before the end of the first month. Those who did not pass the second-stage TEOAE screening were referred for diagnostic audiological evaluation for confirmation of hearing loss. Neonates transferred to a neonatal intensive care unit were not included in this study. Two neonates with bilateral sensorineural hearing loss of >40 dB hearing level were identified from this cohort. This study demonstrates the feasibility and the limitations of using TEOAEs as a universal hearing screening tool for all neonates. It confirms that the prevalence of hearing impairment in neonates has to be taken into account, even in a group of children without high-risk criteria. In France, a prevalence of 1.4 per 1,000 would represent 1,000 deaf children born every year, with reference to about 700,000 births per year. This study suggests that such universal screening programs would substantially increase the rate of early-identified infants with significant hearing impairment.