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International audience; Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.

The sound transfer is strongly dependent on the coupling of the prosthesis to the ossicles. This holds for both passive but in particular for active implants. Various principles of coupling and different designs of attaching the implant to ossicle are in use showing a different mechanical behavior concerning stiffness and damping. Pressing a driving rod against the ossicles means a unilateral coupling which needs a particular prestress. Due to the nonlinear transfer behavior of the coupling region and ossicular chain, the actual motions, e.g. of actuator, stapes and umbo are dependent on that prestress. An optimal coupling should allow a stapes motion sufficient to compensate a hearing loss, but should avoid a distorted sound transfer or feedback due to sound radiation from ear drum. The static adjustment influences the sound transfer of the dynamical system essentially. To find an optimal adjustment of the actuator, the dynamical behavior of the actuator itself, of the coupling region and the individual ossicular chain has to be regarded. During surgery the stiffness of the individual chain has to be estimated and the configuration when the actuator touches the ossicles has to be detected very carefully.

Despite the wide variety of ossiculoplasty techniques that are available, success rates are limited. Current use indicates that surgeons prefer ceramic, autograft bone, and plastic pore prostheses. During the past decade, titanium prostheses have been used with great promise. Although their use is not widespread, satisfaction rates are high. An earlier study of ossiculoplasty showed that titanium prostheses were effective in reducing conductive hearing loss. To date, the surgical-handling attributes of titanium middle ear prostheses have not been assessed. We report the results of our survey of 32 otologic surgeons who used the open Tubingen titanium prosthesis for primary and revision ossiculoplasty during tympanoplasty in 400 patients at 12 academic and nonacademic otolaryngology clinics, most of them in Germany. Because the audiometric efficacy of titanium prostheses has been previously reported, our primary outcomes measures included ease of use with respect to the amount of time required to prepare the implants for placement and the surgeons ‘overall impression of the intraoperative handling characteristics of the implants, taking into consideration factors such as positioning, length adjustment, visibility, and the stability of the coupling. Surgeons also compared the properties of the titanium implant with those of gold, ceramic, and autograft implants that they had used in the past. Based on the results of 383 of the 400 ossiculoplasties, our survey revealed that the titanium implant was significantly superior to the others in all measured respects.

Objectives: The aim of the study was to evaluate the safety and feasibility of piezoelectric malleus vibration audiometer (MVA), which presents micromechanical vibrations to the umbo membranae tympani. Study Design: Phase I study performed in a tertiary referral center (University Hospital). Methods: The coupling rod of the MVA was moved slowly through the outer ear canal toward the eardrum with a micromanipulator. Coupling was completed when the rod tip touched the umbo membranae tympani. Basic audiologic measures of sound threshold obtained with direct stimulation of the malleus are presented. We used MANOVA (multivariate repeated measures ANOVA) to investigate the repeatability of MVA thresholds from one day to the other and when decoupling and retracting the coupling rod 2 mm off the umbo. We also selected the MANOVA to test for unwanted bone-conduction threshold shifts after MVA application. We assessed normality of the data by quantile-quantile plots of the residuals. Results: Twenty-eight male and 10 female subjects with normal hearing, 22.2 to 34.6 years old (median age, 27.2 yr) underwent an examination. Thirty-six subjects underwent MVA, because 2 of the 38 subjects who volunteered for the study have not undergone the procedure due to the external auditory canal anatomy preventing application of the MVA. The results show that it is possible to safely and reliably measure thresholds of direct vibration of the ossicular chain. Using pure tone audiograms, no pure tone bone- and/or air-conduction threshold shifts occurred after the procedure. None of the subjects reported any other ear-related symptoms such as vertigo, tinnitus, or dizziness. Geometric mean vibratory displacements at threshold ranged from 0.55 nm at 250 Hz to 0.03 nm at 6 kHz. MANOVA demonstrated a repeatability of MVA thresholds. Conclusion: Malleus vibration audiometry will not allow exact linkage of actual implantable hearing aid. But the present study demonstrates that MVA can provide an audiometric tool for assessing ossicular function and integrity prior to implantation of an electronic hearing amplifier.

The efficient and systematic development of a middle ear prosthesis necessitates the use of computer models for the prosthesis itself and the reconstructed middle ear. The structure and parameters of the computer model have to be verified by specific measurements of the implant and the reconstructed ear. To obtain a realistic model of a reconstructed ear, three steps of modeling and measurements have been carried out. To get a first approach of the coupling elements a mechanical test rig representing a simplified reconstructed middle ear was built. The velocity of the stapedial footplate was measured with a laser Doppler vibrometer. The corresponding computer model was formulated, and the respective parameters were determined using the measured dynamical transfer functions. In the second step, a prosthesis was implanted into a human temporal bone without inner ear. Exciting this system with noise, the velocity of the stapes footplate was measured with the laser Doppler vibrometer. Based on the multibody system approach, a mechanical computer model was generated to describe the spatial motions of the reconstructed ossicular chain. Varying some significant parameters, simulations have been carried out. To describe the dynamical behavior of the system consisting of middle and inner ear, the computer model used in the second step has been enlarged by adding a simplified structure of the inner ear. The results were compared with in situ measurements taken from living humans.