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Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

A total of 424 patients undergoing VS surgery were included in this retrospective study. Patients were divided into two groups according to the existence or absence of a FN palsy during the 8 days following surgery (Groups 1 and 2, respectively). Various parameters were evaluated preoperatively as follows. Quantitative parameters: age; duration of clinical symptoms; pure-tone audiometry (PTA) results; speech reception threshold; speech discrimination score; auditory brainstem response (ABR) results; and transient-evoked otoacoustic emission amplitude. Qualitative parameters: gender; side of the tumor; angle between the tumor and the internal auditory canal (VS/IAC angle) < or = or > 30 degrees; MRI aspect (n = 69); surgical approach; ease of the surgical procedure, the use or non-use of laser dissection; and the histological Antoni's type of the tumor. RESULTS Pre- and perioperative factors that differed significantly between Groups 1 and 2 were as follows. Quantitative factors: tinnitus duration was longer and PTA and ABR results were worse in Group 1. Qualitative factors: heterogenous/cystic MRI aspect, use of retrosisgmoid and middle fossa approaches, easy surgical procedure, dissection without laser and Antoni's type A were more frequently found in Group 1.

Objectives: Because both the vestibulo-ocular and vestibulospinal pathways depend on neurological maturation during childhood, the purpose of this study was to evaluate the vestibulo-ocular reflexes (VOR) and balance parameters of children aged from 6 to 12 years. Methods: 147 healthy children were included in the study. The visual vestibulo-ocular reflex (VVOR) and VOR were recorded during sinusoidal rotation (videonystagmography), with calculation of the gain. The sensory organization on postural control was studied using computerized dynamic posturography (EquiTest®), with equilibrium scores (ES) and sensory organization tests. Results: Data were analyzed according to age groups: group a from 6 to 8 years, group b from 9 to 10 years, and group c from 11 to 12 years. Whereas VVOR gain was comparable in the three groups, VOR gain was lower in groups b and c compared to group a. Global ES increased with age. Analyzing each sensory component for postural control, the only score that increases with age is the vestibular one. Somesthetic and visual scores remained comparable in the three groups. Conclusions: Our results in a large cohort of children confirm previous ones: VOR gain is higher in young children, whereas ES is lower. Moreover, it seems that the 10- to 12-year-old children use their vestibular inputs more compared to younger ones. From these results it can be suggested that both the vestibulo-ocular and vestibulospinal pathways are still maturing between 6 and 12 years.

Introduction: Patients suffering from bilateral vestibular hypofunction (BVH) often experience ataxia as well as visual instability. Even though progress has been made in vestibular testing, insights regarding vestibular deficit in BVH remain incomplete since no method allows evaluation of frequency ranges of vestibular sensors in a continuous way. The aim of our study was to give a detailed description of the level of vestibular deficit in different ranges of vestibular stimulation and an exhaustive evaluation of the functional impact including dynamic visual acuity (DVA) in a cohort of BVH patients in different etiologies.Methods: We prospectively included 20 patients with chronic BVH. All patients underwent clinical evaluation and functional assessment including evaluation of their symptoms related to BVH, quality of life questionnaire and DVA in the horizontal and vertical plane. Patients underwent vestibulo-ocular reflex (VOR) testing using rotatory chair, caloric stimulation and video head impulse (vHIT) in the plane of the 6 canals, and cervical and ocular Vestibular evoked myogenic potentials.Results: Mean rotatory VOR gain was 0.07 (SD = 0.07). Mean rotatory VOR gain during vHIT for the lateral, anterior and posterior canals was respectively < 0.28, < 0.34, and < 0.20. Mean loss of DVA in the 4 directions was >0.30 LogMAR. In our population fall frequency was significantly higher in patients with lower UniPedal Stance Test (UPST), higher Dizziness Handicap Inventory and Ataxia Numeric Scale (ANS) scores, as well as greater loss of upwards DVA. Patients with ototoxic BVH had a significantly higher residual VOR gain during vHIT in the anterior canal plane and lower DHI than other patients. In the general population anterior canal function was significantly higher than lateral or posterior canal function.Conclusions: This study gives extensive descriptive results of residual vestibular function, DVA and quality of life in a population of patients suffering from severe BVH. UPST and ANS are good indicators for fall risk in case of BVH. Gentamicin induced BVH seems to have a lesser impact on quality of life than other etiologies.Anterior semi-circular canal function seems less deteriorated than lateral and posterior function.

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Motion sickness (MS) usually occurs for a narrow band of frequencies of the imposed oscillation. It happens that this frequency band is close to that which are spontaneously produced by postural sway during natural stance. This study examined the relationship between reported susceptibility to motion sickness and postural control. The hypothesis is that the level of MS can be inferred from the shape of the Power Spectral Density (PSD) profile of spontaneous sway, as measured by the displacement of the center of mass during stationary, upright stance. In Experiment 1, postural fluctuations while standing quietly were related to MS history for inertial motion. In Experiment 2, postural stability measures registered before the onset of a visual roll movement were related to MS symptoms following the visual stimulation. Study of spectral characteristics in postural control showed differences in the distribution of energy along the power spectrum of the antero-posterior sway signal. Participants with MS history provoked by exposure to inertial motion showed a stronger contribution of the high frequency components of the sway signal. When MS was visually triggered, sick participants showed more postural sway in the low frequency range. The results suggest that subject-specific PSD details may be a predictor of the MS level. Furthermore, the analysis of the sway frequency spectrum provided insight into the intersubject differences in the use of postural control subsystems. The relationship observed between MS susceptibility and spontaneous posture is discussed in terms of postural sensory weighting and in relation to the nature of the provocative stimulus.

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