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 Tmc1^N321I/+ 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. Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.

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.

S These results support previous ones with regard to FN risk factors in VS surgery. However, they also provide new preoperative factors that influence postoperative FN function, such as clinical symptoms, the nature of the surgical procedure (use of laser) and ABR results. To determine pre- and perioperative factors influencing facial nerve (FN) outcome in vestibular schwannoma (VS) surgery. 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.

Introduction: An increased number of otic capsule dehiscence (OCD) variants relying on the third window pathomechanism have been reported lately. Therefore, a characterization of the anatomical structures involved and an accurate radiological description of the third window (TW) interface location have become essential for improving the diagnosis and appropriate therapeutic modalities. The purpose of this article is to propose a classification based on clinical, anatomical, and radiological data of third mobile window abnormalities (TMWA) and to discuss the alleged pathomechanism in lesser-known clinical variants.Materials and Methods: The imaging records of 259 patients who underwent, over the last 6 years, a high-resolution CT (HRCT) of the petrosal bone for conductive hearing loss were analyzed retrospectively. Patients with degenerative, traumatic, or chronic infectious petrosal bone pathology were excluded. As cases with a clinical presentation similar to those of a TW syndrome have recently been described in the literature but without these being confirmed radiologically, we thought it necessary to be integrated in a separated branch of this classification as “CT - TMWA.” The same goes for certain intralabyrinthine pathologies also recently reported in the literature, which mimic to some extent the symptoms of a TW pathology. Therefore, we suggest to call them intralabyrinthine TW-like abnormalities.Results: Temporal bone HRCT and, in some cases, 3T MRI of 97 patients presenting symptomatic or pauci-symptomatic, single or multiple, unilateral or bilateral OCD were used to develop this classification. According to the topography and anatomical structures involved at the site of the interface of the TW, a third-type classification of OCD is proposed.Conclusions: A classification reuniting all types of TMWA as the one proposed in this article would allow for a better systematization and understanding of this complex pathology and possibly paves the way for innovative therapeutic approaches. To encompass all clinical and radiological variants of TMWA reported in the literature so far, TMWAs have been conventionally divided into two major subgroups: Extralabyrinthine (or “true” OCD with three subtypes) and Intralabyrinthine (in which an additional mobile window-like mechanism is highly suspected) or TMWA-like subtype. Along these subgroups, clinical forms of OCD with multiple localization (multiple OCD) and those that, despite the fact that they have obvious characteristics of OCD have a negative CT scan (or CT – TMWA), were also included.