Mutational spectrum in patients with dominant non-syndromic hearing loss in Austria.

PURPOSE: Hearing loss (HL) is often monogenic. The clinical importance of genetic testing in HL may further increase when gene therapy products become available. Diagnoses are, however, complicated by a high genetic and allelic heterogeneity, particularly of autosomal dominant (AD) HL. This work aimed to characterize the mutational spectrum of AD HL in Austria. METHODS: In an ongoing prospective study, 27 consecutive index patients clinically diagnosed with non-syndromic AD HL, including 18 previously unpublished cases, were analyzed using whole-exome sequencing (WES) and gene panels. Novel variants were characterized using literature and bioinformatic means. Two additional Austrian medical centers provided AD HL mutational data obtained with in-house pipelines. Other Austrian cases of AD HL were gathered from literature. RESULTS: The solve rate (variants graded as likely pathogenic (LP) or pathogenic (P)) within our cohort amounted to 59.26% (16/27). MYO6 variants were the most common cause. One third of LP/P variants were truncating variants in haploinsufficiency genes. Ten novel variants in HL genes were identified, including six graded as LP or P. In one cohort case and one external case, the analysis uncovered previously unrecognized syndromic presentations. CONCLUSION: More than half of AD HL cases analyzed at our center were solved with WES. Our data demonstrate the importance of genetic testing, especially for the diagnosis of syndromic presentations, enhance the molecular knowledge of genetic HL, and support other laboratories in the interpretation of variants.

Ageing as risk factor for tinnitus and its complex interplay with hearing loss-evidence from online and NHANES data.

BACKGROUND: Tinnitus affects 10 to 15% of the population, but its underlying causes are not yet fully understood. Hearing loss has been established as the most important risk factor. Ageing is also known to accompany increased prevalence; however, the risk is normally seen in context with (age-related) hearing loss. Whether ageing per se is a risk factor has not yet been established. We specifically focused on the effect of ageing and the relationship between age, hearing loss, and tinnitus. METHODS: We used two samples for our analyses. The first, exploratory analyses comprised 2249 Austrian individuals. The second included data from 16,008 people, drawn from a publicly available dataset (NHANES). We used logistic regressions to investigate the effect of age on tinnitus. RESULTS: In both samples, ageing per se was found to be a significant predictor of tinnitus. In the more decisive NHANES sample, there was an additional interaction effect between age and hearing loss. Odds ratio analyses show that per unit increase of hearing loss, the odds of reporting tinnitus is higher in older people (1.06 vs 1.03). CONCLUSIONS: Expanding previous findings of hearing loss as the main risk factor for tinnitus, we established ageing as a risk factor in its own right. Underlying mechanisms remain unclear, and this work calls for urgent research efforts to link biological ageing processes, hearing loss, and tinnitus. We therefore suggest a novel working hypothesis that integrates these aspects from an ageing brain viewpoint.

Phonon Dephasing Dynamics in MoS2.

A variety of quantum degrees of freedom, e.g., spins, valleys, and localized emitters, in atomically thin van der Waals materials have been proposed for quantum information applications, and they inevitably couple to phonons. Here, we directly measure the intrinsic optical phonon decoherence in monolayer and bulk MoS2 by observing the temporal evolution of the spectral interference of Stokes photons generated by pairs of laser pulses. We find that a prominent optical phonon mode E2g exhibits a room-temperature dephasing time of ∼7 ps in both the monolayer and bulk. This dephasing time extends to ∼20 ps in the bulk crystal at ∼15 K, which is longer than previously thought possible. First-principles calculations suggest that optical phonons decay via two types of three-phonon processes, in which a pair of acoustic phonons with opposite momentum are generated.

Can Cochlear Implantation in Older Adults Reverse Cognitive Decline Due to Hearing Loss?

INTRODUCTION: Older adults with late-onset hearing loss are at risk for cognitive decline. Our study addresses the question of whether cochlear implantation (CI) can counteract this potential influence. We investigated whether cognitive performance in older adults with severe and profound hearing loss improves 12 months after CI to a level comparable to controls with normal hearing, matched for age, sex, and education level. DESIGN: This cohort study was performed at two tertiary referral centers. The study included 29 patients, of age between 60 and 80 years, with adult-onset, severe to profound bilateral sensorineural hearing loss and indication for CI (study group), as well as 29 volunteers with age-adjusted hearing abilities, according to the norm curves of ISO-702 9:2000-01, (control group). Before CI and 12 months after CI, participants completed a neurocognitive test battery including tests of global cognition, verbal and figural episodic memory, and executive functions (attentional control, inhibition, and cognitive flexibility). RESULTS: Twelve months after CI, the performance of the study group improved significantly in global cognition, compared to the situation before CI. Differences in verbal episodic memory, figural episodic memory, and executive function were not significant. Moreover, the improvement of the study group was significantly larger only in global cognition compared to the control group. Noninferiority tests on the cognitive performances of the study group after CI revealed that comparable levels to normal hearing controls were reached only in global cognition, figural episodic memory (immediate recall), and attentional control. The improvement in global cognition was significantly associated with speech recognition 3 months after CI, but not with speech recognition 12 months after CI. CONCLUSION: One year after CI, cognitive deficits in older individuals with adult-onset hearing loss, compared to normal-hearing peers, could only improve some cognitive skills.

Cognition in older adults with severe to profound sensorineural hearing loss compared to peers with normal hearing for age.

Objective: Cognitive performance of older adults with severe to profound sensorineural hearing loss and indication for cochlear implantation was evaluated compared to peers with age appropriate hearing.Design: Prospective matched case control study.Study sample: Study group consisted of n = 30 patients aged between 60 and 80 years, with adult onset, severe to profound sensorineural hearing loss on both sides and indication for cochlear implantation. Matched control group consisted of n = 30 peers with age-adjusted hearing abilities, based on age- appropriate norms.Results: Differences in Constructional Praxis and Recall, Trail Making Test A and Stroop were not significant between both groups. However, the differences in Clock Drawing Test, Word Lists and Trail Making Test B were significant. The impairment in TMT B (cognitive flexibility) was mediated via the severity of depressive problems. Cognitive performance was not related to word recognition, the percentage and duration of hearing loss and hearing aid use.Conclusion: Severely hearing-impaired older adults show widespread impairments in cognitive performance.

[Molecular and functional testing in case of hereditary hearing loss associated with the SLC26A4 gene]. / Molekulare und funktionale Abklärung hereditärer Schwerhörigkeiten am Beispiel des SLC26A4-Gens.

Due to development of molecular techniques at hand, the number of genomic sequence variants detected in patient investigations is rising constantly. The number of potentially involved genes in hereditary hearing loss is rising simultaneously.In this overview, current methods for diagnostic workup on a molecular and functional level for variants of the SLC26A4 gene are described. Based on the description of the physiological function of the resulting protein Pendrin, molecular investigations for interpretation of the function are explained. Based on these investigations, the potential clinical consequences of a variant may be predicted more precisely and simplify routine reporting of a proven genotype and a phenotype, at hand. Finally, subsequent clinical investigations necessary, such as perchlorate discharge test, as well as therapeutic options are discussed.

Functional Testing of SLC26A4 Variants-Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria.

The prevalence and spectrum of sequence alterations in the SLC26A4 gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of SLC26A4 and GJB2, coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants. In this group, four uncharacterized sequence alterations within the SLC26A4 coding region were found. Three of these lead to protein variants with abnormal functional and molecular features, while one should be considered with no pathogenic potential. Pathogenic SLC26A4 sequence alterations were only found in 12% of patients. SLC26A4 sequence alterations commonly found in other Caucasian populations were not detected. This survey represents the first study on the prevalence and spectrum of SLC26A4 sequence alterations in an Austrian cohort and further suggests that genetic testing should always be integrated with functional characterization and determination of the molecular features of protein variants in order to unequivocally identify or exclude a causal link between genotype and phenotype.

Emergency CT head and neck imaging: effects of swimmer's position on dose and image quality.

OBJECTIVES: To compare the effects of different arm positions on dose exposure and image quality (IQ) in cervical spine CT after trauma in different patient groups. METHODS: Patients in standard (STD = 126) and in swimmer's position (SWIM = 254) were included. Body mass index (BMI subgroup 1 = underweight to subgroup 4 = obese), anterior-posterior diameter (AP), left-right diameter (LR), area of an ellipse (AoE) and angle between the humeral heads (optimal STD < 3°, optimal SWIM > 10°) were used as grouping criteria. Computed tomography dose index (CTDI) was documented. Two radiologists rated the IQ at three levels (CV1/2, CV4/5, CV7/T1) using a semi-quantitative scale (0 = not diagnostic, 1 = diagnostic with limitations, 2 = diagnostic without limitations). The Mann-Whitney U test correlations of grouping criteria with dose effects and intra-class correlation (ICC) were calculated. RESULTS: ICC was 0.87. BMI grouping showed the strongest correlation with dose effects: CTDI of optimal STD versus optimal SWIM positioning was 3.17 mGy versus 2.46 mGy (subgroup 1), 5.47 mGy versus 3.97 mGy (subgroup 2), 7.35 mGy versus 5.96 mGy (subgroup 3) and 8.71 mGy versus 8.18 mGy (subgroup 4). Mean IQ at CV7/T1 was 1.65 versus 1.23 (subgroup 1), 1.27 versus 1.46 (subgroup 2), 1.06 versus 1.46 (subgroup 3), 0.79 versus 1.5 (subgroup 4). CONCLUSION: Patients with a BMI > 20 kg/m(2) benefited from both potential dose reduction and improved image quality at the critical cervicothoracic junction when swimmer's position was used. KEY POINTS: • BMI is a useful metric for personalized optimization in CT for the c-spine. • Using swimmer's position, patients can benefit from dose reduction. • In some patients a superior image quality can be achieved with swimmer's position. • For swimmer's positioning an angle of more than 10° is optimal.

Elastometry - The biomechanical analysis of the lateral nasal wall.

'Elastometry' is a novel technique that allows for the quantitative assessment of elastic properties of the nasal tissues, providing valuable insights into the dynamic behavior of the external, soft lateral nasal wall. This study aimed to explore the application of 'elastometry' in understanding the biomechanics of the lateral nasal wall and its implications for nasal function in 'elastometry' measurements. After validation of safety and reliability of this method, we investigated mechanical properties of the lateral nasal wall by 'elastometry' using specifically developed measurement forceps with end pieces including sensors applied on 30 healthy volunteers, aged 18 to 82 without a history of severe trauma or surgery. By measuring normal stress and path length between the end pieces the modulus of elasticity was calculated. Among 360 measurements, the mean value determined for healthy female volunteers was E = 0.135 [N/mm2] and for healthy males E = 0.169 [N/mm2], fitting the range reported in the literature. A tendency of an age-related degree of elastic behavior of the lateral nasal wall was observed, whereby a decrease in elasticity with age in female and a slight increase in elasticity with age in male was detected. Our research showed that 'elastometry' is a cost and time-efficient method to calculate the modulus of elasticity, and could be used in conjunction with 4-phase rhinomanometry (4 PR) to extend diagnostic yield.

CT-scans of cochlear implant patients with characteristics of Pendred syndrome.

BACKGROUND: Sensorineural hearing loss (SNHL) in newborns is estimated with an incidence around 1:10,000 per year and is divided into syndromic and non-syndromic forms. In case of present retrocochlear function' cochlear implantation allows speech and cognitive development in affected children, comparable to that of normal hearing children. Pathogenesis of SNHL remains unclear in many cases. Imaging of the temporal bone, such as computed tomography (CT) and magnetic resonance imaging (MRI), can reveal conspicuous findings, e.g. enlarged vestibular aqueduct (EVA) and Mondini malformation (MM) of the cochlea. These malformations can be a clinical sign for Pendred syndrome. METHODS: We screened CT scans of 75 cochlear implant patients for EVA and MM. RESULTS: Six patients were observed to have either EVA alone (n=3), or MM alone (n=2), or a combination of both (n=1). Further malformations of the temporal bone could be found within the whole group, as well. CONCLUSION: Our results confirm the general opinion on EVA and MM, being commonly found in patients with SNHL. A possible association with Pendred syndrome needs to be confirmed by genetic investigations with search for mutations in the SLC26A4 gene and further clinical tests, such as Perchlorate test for surveillance of thyroid function.

Clinical and Molecular Aspects Associated with Defects in the Transcription Factor POU3F4: A Review.

X-linked deafness (DFNX) is estimated to account for up to 2% of cases of hereditary hearing loss and occurs in both syndromic and non-syndromic forms. POU3F4 is the gene most commonly associated with X-linked deafness (DFNX2, DFN3) and accounts for about 50% of the cases of X-linked non-syndromic hearing loss. This gene codes for a transcription factor of the POU family that plays a major role in the development of the middle and inner ear. The clinical features of POU3F4-related hearing loss include a pathognomonic malformation of the inner ear defined as incomplete partition of the cochlea type 3 (IP-III). Often, a perilymphatic gusher is observed upon stapedectomy during surgery, possibly as a consequence of an incomplete separation of the cochlea from the internal auditory canal. Here we present an overview of the pathogenic gene variants of POU3F4 reported in the literature and discuss the associated clinical features, including hearing loss combined with additional phenotypes such as cognitive and motor developmental delays. Research on the transcriptional targets of POU3F4 in the ear and brain is in its early stages and is expected to greatly advance our understanding of the pathophysiology of POU3F4-linked hearing loss.

Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.

The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].

Novel POU3F4 variants identified in patients with inner ear malformations exhibit aberrant cellular distribution and lack of SLC6A20 transcriptional upregulation.

Hearing loss (HL) is the most common sensory defect and affects 450 million people worldwide in a disabling form. Pathogenic sequence alterations in the POU3F4 gene, which encodes a transcription factor, are causative of the most common type of X-linked deafness (X-linked deafness type 3, DFN3, DFNX2). POU3F4-related deafness is characterized by a typical inner ear malformation, namely an incomplete partition of the cochlea type 3 (IP3), with or without an enlargement of the vestibular aqueduct (EVA). The pathomechanism underlying POU3F4-related deafness and the corresponding transcriptional targets are largely uncharacterized. Two male patients belonging to a Caucasian cohort with HL and EVA who presented with an IP3 were submitted to genetic analysis. Two novel sequence variants in POU3F4 were identified by Sanger sequencing. In cell-based assays, the corresponding protein variants (p.S74Afs*8 and p.C327*) showed an aberrant expression and subcellular distribution and lack of transcriptional activity. These two protein variants failed to upregulate the transcript levels of the amino acid transporter gene SLC6A20, which was identified as a novel transcriptional target of POU3F4 by RNA sequencing and RT-qPCR. Accordingly, POU3F4 silencing by siRNA resulted in downregulation of SLC6A20 in mouse embryonic fibroblasts. Moreover, we showed for the first time that SLC6A20 is expressed in the mouse cochlea, and co-localized with POU3F4 in the spiral ligament. The findings presented here point to a novel role of amino acid transporters in the inner ear and pave the way for mechanistic studies of POU3F4-related HL.

Molecular Features of SLC26A4 Common Variant p.L117F.

The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Although segregation and allelic data support the pathogenicity of this variant, former functional tests showed characteristics that were indistinguishable from those of the wild-type protein. Here, we applied a triad of cell-based assays, i.e., measurement of the ion transport activity by a fluorometric method, determination of the subcellular localization by confocal microscopy, and assessment of protein expression levels, to conclusively assign or exclude the pathogenicity of SLC26A4 p.L117F. This protein variant showed a moderate, but significant, reduction in ion transport function, a partial retention in the endoplasmic reticulum, and a strong reduction in expression levels as a consequence of an accelerated degradation by the Ubiquitin Proteasome System, all supporting pathogenicity. The functional and molecular features of human pendrin p.L117F were recapitulated by the mouse ortholog, thus indicating that a mouse carrying this variant might represent a good model of Pendred syndrome/DFNB4.

Mitochondrial Disease and Hearing Loss in Children: A Systematic Review.

OBJECTIVES: Hearing loss is a clinical symptom, frequently mentioned in the context of mitochondrial disease. With no cure available for mitochondrial disease, supportive treatment of clinical symptoms like hearing loss is of the utmost importance. The aim of this study was to summarize current knowledge on hearing loss in genetically proven mitochondrial disease in children and deduce possible and necessary consequences in patient care. METHODS: Systematic literature review, including Medline, Embase, and Cochrane library. Review protocol was established and registered prior to conduction (International prospective register of systematic reviews-PROSPERO: CRD42020165356). Conduction of this review was done in accordance with MOOSE criteria. RESULTS: A total of 23 articles, meeting predefined criteria and providing sufficient information on 75 individuals with childhood onset hearing loss was included for analysis. Both cochlear and retro-cochlear origin of hearing loss can be identified among different types of mitochondrial disease. Analysis was hindered by inhomogeneous reporting and methodical limitations. CONCLUSION: Overall, the findings do not allow for a general statement on hearing loss in children with mitochondrial disease. Retro-cochlear hearing loss seems to be found more often than expected. A common feature appears to be progression of hearing loss over time. However, hearing loss in these patients shows manifold characteristics. Therefore, awareness of mitochondrial disease as a possible causative background is important for otolaryngologists. Future attempts rely on standardized reporting and long-term follow-up. LEVEL OF EVIDENCE: NA Laryngoscope, 132:2459-2472, 2022.

Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review.

Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition.

The Additional Value of Endolymphatic Hydrops Imaging With Intratympanic Contrast for Diagnostic Work-Up-Experience From a Neurotology Center in Austria.

Objective: To illustrate the merit of hydrops imaging during clinical workup of dizziness and balance disorders. Background: Ever since the first description of in-vivo endolymphatic hydrops imaging in 2007, this diagnostic tool has been implemented in an increasing number of centers. The more experience in its clinical application is gathered, the more it is possible to critically assess its potential value for the diagnostic workup. This article intends to provide information about the experience of handling and utilization of endolymphatic hydrops imaging in one of the first centers in Austria. Methods: Retrospective analysis and review of clinical cases. Results: Based on our experience of endolymphatic hydrops imaging (EHI), which was established in cooperation between our departments of radiology and otorhinolaryngology in 2017, we have exclusively used intratympanic application of a contrast agent prior to magnetic resonance imaging, as this approach provides high quality imaging results. In 42.6% of cases, EHI could lead to the diagnosis of MD or HED. Since precise vestibular examination is still necessary, EHI is not a tool to replace the clinical examination but rather to add significantly to the interpretation of the results. Conclusion: Endolymphatic hydrops imaging represents a valuable, safe and well-applicable tool for evaluating cases with inconclusive clinical results. However, its potential additional diagnostic benefits rely on a correct indication based on prior thorough vestibular investigations.

Workforce Considerations, Training, and Certification of Physicians in Europe.

Following recent geopolitical events and unification of Europe, the European Union (EU) is currently confronted with health care workforce shortage and insufficient uniform access to quality care. Aging population, difficulties with physician retention, and mobility of health care professionals are thought to contribute to this problem. Because of the differences in medical education and residency curriculum across the European countries, there is a need for a standardized training and certification. Current government initiatives are geared toward developing common policies and programs across the EU countries to address health care access.

Temporary Explant of a Transcutaneous Bone Conduction Hearing Implant for Imaging of the Pituitary Gland.

OBJECTIVE: Clinical report on feasibility and outcome of a surgical procedure. PATIENT: Nine-year-old child, supplied with a transcutaneous bone conduction hearing implant, requiring magnetic resonance imaging of the head to exclude a tumor of the pituitary gland. INTERVENTION: Temporal removal and subsequent reimplantation of the implant in a single surgical procedure. MAIN OUTCOME MEASURE: Postoperative audiometric results. CONCLUSION: Under specific clinical circumstances, temporary removal of the transcutaneous bone conduction implant described, is technically accomplishable.