Phenotypic spectrum of tinnitus patients bearing rare ANK2 gene variants.

PURPOSE: To describe the clinical, audiological, and psychometric features observed in patients with chronic tinnitus and rare variants in the ANK2 gene. METHODS: We report a case series of 12 patients with chronic tinnitus and heterozygous variants in the ANK2 gene. Tinnitus phenotyping included audiological (standard and high-frequency audiometry, Auditory Brainstem Responses (ABR) and Auditory Middle Latency Responses (AMLR)), psychoacoustic and psychometric assessment by a Visual Analog Scale (VAS) for tinnitus annoyance, the Tinnitus Handicap Inventory (THI), the test on Hypersensitivity to Sound (THS-GÜF), the Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) and the Montreal Cognitive Assessment (MoCA). RESULTS: All patients reported a persistent, unilateral noise-type tinnitus, mainly described as white noise or narrowband noise. Seven patients (58%) were considered to have extreme phenotype (THI score > 76), and all patients reported some degree of hyperacusis (THS-GÜF score > 18 in 75% of patients). Seven patients scored MoCA < 26, regardless of the age reported, suggesting a mild cognitive disorder. ABR showed no significant differences in latencies and amplitudes between ears with or without tinnitus. Similarly, the latencies of Pa, Pb waves, and NaPa complex in the AMLR did not differ based on the presence of tinnitus. However, there were statistical differences in the amplitudes of Pa waves in AMLR, with significantly greater amplitudes observed in ears with tinnitus. CONCLUSION: Patients with ANK2 variants and severe tinnitus exhibit an endophenotype featuring hyperacusis, persistent noise-like tinnitus, high-frequency hearing loss, and decreased amplitudes in AMLR. However, anxiety, depression, and cognitive symptoms vary among individuals.

An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population.

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

A Systematic Review on the Genetic Contribution to Tinnitus.

PURPOSE: To assess the available evidence to support a genetic contribution and define the role of common and rare variants in tinnitus. METHODS: After a systematic search and quality assessment, 31 records including 383,063 patients were selected (14 epidemiological studies and 17 genetic association studies). General information on the sample size, age, sex, tinnitus prevalence, severe tinnitus distribution, and sensorineural hearing loss was retrieved. Studies that did not include data on hearing assessment were excluded. Relative frequencies were used for qualitative variables to compare different studies and to obtain average values. Genetic variants and genes were listed and clustered according to their potential role in tinnitus development. RESULTS: The average prevalence of tinnitus estimated from population-based studies was 26.3% for any tinnitus, and 20% of patients with tinnitus reported it as an annoying symptom. One study has reported population-specific differences in the prevalence of tinnitus, the white ancestry being the population with a higher prevalence. Genome-wide association studies have identified and replicated two common variants in the Chinese population (rs2846071; rs4149577) in the intron of TNFRSF1A, associated with noise-induced tinnitus. Moreover, gene burden analyses in sequencing data from Spanish and Swede patients with severe tinnitus have identified and replicated ANK2, AKAP9, and TSC2 genes. CONCLUSIONS: The genetic contribution to tinnitus is starting to be revealed and it shows population-specific effects in European and Asian populations. The common allelic variants associated with tinnitus that showed replication are associated with noise-induced tinnitus. Although severe tinnitus has been associated with rare variants with large effect, their role on hearing or hyperacusis has not been established.

A Systematic Review on Heritability of Sudden Sensorineural Hearing Loss.

OBJECTIVE: To assess the evidence supporting the heritability and genetic basis of sudden sensorineural hearing loss (SSNHL). DATA SOURCE: Records were extracted from PubMed, Scopus, and Cochrane databases. REVIEW METHODS: The protocol was registered on PROSPERO (CRD42022357389) and includes a systematic review on the genetic contribution to SSNHL. The search strategy yielded 1.483 articles from electronic databases. After quality assessment, 34 records were selected, including 369.650 patients with SSNHL from nine prevalence studies, two familial aggregation studies, one twin study, and 22 genetic studies. The prevalence of SSNHL was calculated from data on its incidence from population-based studies (period prevalence). To evaluate the heritability of SSNHL, the sibling recurrence risk ratio (λs) was calculated, by comparing the prevalence of SSNHL among siblings within the same generation to the estimated prevalence in the overall population. Genetic variants were grouped, based on the pathological mechanism related to SSNHL. RESULTS: The prevalence of SSNHL ranged from 0.1% to 0.0003% in America to 0.12%-0.0093% in Asia. The estimated sibling recurrence risk ratio for SSNHL (λs = 20.8-83.3) supports a significant familial aggregation. Although several genetic variants were reported to be associated with SSHL in controlled studies, neither was replicated in an independent cohort. CONCLUSIONS: Evidence supporting heritability of SSNHL is limited to epidemiological studies showing prevalence differences across different populations and familial aggregation. Genetic studies are of low quality and they lack replication cohort to confirm their findings. According to its low prevalence, exome or genome sequencing familial-based studies are needed to identify rare genetic variants in SSNHL. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Epidemiology and genetics of Meniere's disease.

PURPOSE OF REVIEW: This review discusses the recent developments on the understanding of epidemiology and genetics of Meniere's disease. RECENT FINDINGS: Meniere's disease has been shown to be associated with several comorbidities, such as migraine, anxiety, allergy and immune disorders. Recent studies have investigated the relationship between environmental factors and Meniere's disease such as air pollution, allergy, asthma, osteoporosis or atmospheric pressure, reporting specific comorbidities in East Asian population. The application of exome sequencing has enabled the identification of genes sharing rare missense variants in multiple families with Meniere's disease, including OTOG and TECTA and suggesting digenic inheritance in MYO7A . Moreover, knockdown of DTNA gene orthologue in Drosophila resulted in defective proprioception and auditory function. DTNA and FAM136A knockout mice have been studied as potential mouse models for Meniere's disease. SUMMARY: While it has attracted emerging attention in recent years, the study of Meniere's disease genetics is still at its early stage. More geographically and ethnically based human genome studies, and the development of cellular and animal models of Meniere's disease may help shed light on the molecular mechanisms of Meniere's disease and provide the potential for gene-specific therapies.

Treatment of Meniere's disease with simultaneous triple semicircular canal occlusion and cochlear implantation.

OBJECTIVE: Report three cases of simultaneous triple semicircular canal occlusion (TSCO) and cochlear implantation (CI) as the treatment of intractable Meniere's disease (MD). CASE REPORTS: Patients with MD can present occasionally with intractable vertigo and profound sensorineural hearing loss (SNHL). TSCO and CI have been proposed to control vertigo and restore profound deafness in patients with MD separately. However, a few studies have reported simultaneous TSCO and CI in the same surgical procedure for the treatment of MD. In the present study, we described three patients with MD showing incapacitating vertigo and severe SNHL who underwent simultaneous TSCO and CI after examinations of auditory system, vestibular system, and imaging. Their symptoms were significantly alleviated during the follow-up period. CONCLUSION: The combined TSCO and CI remains a viable treatment option which is effective for the control of vertigo as well as the restoring of hearing in patients with MD.

The statistical analysis plan for the unification of treatments and interventions for tinnitus patients randomized clinical trial (UNITI-RCT).

BACKGROUND: Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. METHODS: Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. DISCUSSION: The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

Immune-Related Disorders Associated With Ménière's Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: To analyze evidence supporting an association between immune-related diseases and Ménière's disease (MD) since it has long been thought to be related to autoimmune disorders and allergies. DATA SOURCES: We retrieved records from Pubmed, Web of Science, Scopus, and Cochrane Library to identify studies published between January 2002 and October 2022. REVIEW METHODS: Articles were independently assessed by 2 reviewers and verified by a third reviewer. Published cross-sectional studies, cohort/longitudinal studies, case series, and noncomparative cohort studies were considered eligible for inclusion. We conducted a systematic review and meta-analysis according to a registered protocol on the International Prospective Register of Systematic Reviews and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Selected studies were classified into 2 groups: epidemiological and genetic association studies. Relative frequencies and odds ratios (ORs) for each autoinflammatory/autoimmune disease or genetic marker reported to be associated with MD. RESULTS: Fifteen studies from 6 countries met our inclusion criteria. Nine are epidemiological studies and 6 are genetic association studies. The epidemiological studies were used to perform 3 different meta-analyses. Airway allergic disease and autoimmune thyroid disease showed a significant association with MD (OR = 2.27 [2.08-2.48] and OR = 1.35 [1.25-1.46]); while rheumatoid arthritis did not (OR = 0.63 [0.28-1.41]). Other comorbidities also showed a significant association with MD like chronic obstructive pulmonary disease, vitiligo, fibromyalgia, arthritis, and psoriasis. CONCLUSION: Epidemiological evidence supports an association between MD and immune-related disorders in European and Asian populations, with population-specific effects. The evaluation of thyroid diseases, airway allergic diseases, and other inflammatory diseases should be implemented in the clinical management of MD patients.

Recent advances in understanding molecular bases of Ménière's disease.

Ménière's disease (MD) is a rare syndromic disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities, such as migraine, asthma, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and genetic data, with a difference in comorbidities according to ethnicity. Familial MD is found in 10%, the most commonly found genes being OTOG, MYO7A and TECTA, previously associated with autosomal dominant and recessive SNHL. These findings suggest that proteins involved in the tectorial membrane and stereocilia links are critical in the pathophysiology of MD. Moreover, proinflammatory cytokines may have a role in some patients with MD by promoting a persistent inflammatory status. Preliminary data suggest that sodium intake could be related to the release of cytokines, and this may influence the relapsing course of the condition. The ionic homeostasis of the otolithic and tectorial membranes could be critical in suppressing the innate motility of individual hair cell bundles, and focal detachment of the otolithic, or tectorial membranes may cause random depolarization of hair cells and explain changes in tinnitus loudness or the triggering of vertigo attacks.

Single-cell immune profiling of Meniere Disease patients.

BACKGROUND: Meniere Disease (MD) is an inner ear syndrome, characterized by episodes of vertigo, tinnitus and fluctuating sensorineural hearing loss. The pathological mechanism leading to sporadic MD is still poorly understood, however an allergic inflammatory response seems to be involved in some patients with MD. OBJECTIVE: Decipher an immune signature associated with the syndrome. METHODS: We performed mass cytometry immune profiling on peripheral blood from MD patients and controls. We analyzed differences in state and differences in abundance of the different cellular subsets. IgE levels were quantified through ELISA on supernatant of cultured whole blood. RESULTS: We have identified two clusters of individuals according to the single cell cytokine profile. These clusters presented differences in IgE levels, immune cell population abundance, including a reduction of CD56dim NK-cells, and changes in cytokine expression with a different response to bacterial and fungal antigens. CONCLUSION: Our results support a systemic inflammatory response in some MD patients that show a type 2 response with allergic phenotype, which could benefit from personalized IL-4 blockers.

Types of Inheritance and Genes Associated with Familial Meniere Disease.

Meniere disease (MD) is a rare disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities such as migraine, respiratory allergies, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and familial segregation studies. Familial MD is found in 10% of cases, the most frequently found genes being OTOG, MYO7A, and TECTA, previously associated with autosomal dominant and recessive non-syndromic SNHL. These findings suggest a new hypothesis where proteins involved in the extracellular structures in the apical surface of sensory epithelia (otolithic and tectorial membranes) and proteins in the stereocilia links would be key elements in the pathophysiology of MD. The ionic homeostasis of the otolithic and tectorial membranes could be critical to suppress the innate motility of individual hair cell bundles. Initially, focal detachment of these extracellular membranes may cause random depolarization of hair cells and will explain changes in tinnitus loudness or trigger vertigo attacks in early stages of MD. With the progression of the disease, a larger detachment will lead to an otolithic membrane herniation into the horizontal semicircular canal with dissociation in caloric and head impulse responses. Familial MD shows different types of inheritance, including autosomal dominant and compound recessive patterns and implementation of genetic testing will improve our understanding of the genetic structure of MD.

Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere's disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere's disease, and 38 European-American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere's disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.

Application of Human Stem Cells to Model Genetic Sensorineural Hearing Loss and Meniere Disease.

Genetic sensorineural hearing loss and Meniere disease have been associated with rare variations in the coding and non-coding region of the human genome. Most of these variants were classified as likely pathogenic or variants of unknown significance and require functional validation in cellular or animal models. Given the difficulties to obtain human samples and the raising concerns about animal experimentation, human-induced pluripotent stem cells emerged as cellular models to investigate the interaction of genetic and environmental factors in the pathogenesis of inner ear disorders. The generation of human sensory epithelia and neuron-like cells carrying the variants of interest may facilitate a better understanding of their role during differentiation. These cellular models will allow us to explore new strategies for restoring hearing and vestibular sensory epithelia as well as neurons. This review summarized the use of human-induced pluripotent stem cells in sensorineural hearing loss and Meniere disease and proposed some strategies for its application in clinical practice.

Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease.

Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score > 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease.

Using coding and non-coding rare variants to target candidate genes in patients with severe tinnitus.

Tinnitus is the phantom percept of an internal non-verbal set of noises and tones. It is reported by 15% of the population and it is usually associated with hearing and/or brain disorders. The role of structural variants (SVs) in coding and non-coding regions has not been investigated in patients with severe tinnitus. In this study, we performed whole-genome sequencing in 97 unrelated Swedish individuals with chronic tinnitus (TIGER cohort). Rare single nucleotide variants (SNV), large structural variants (LSV), and copy number variations (CNV) were retrieved to perform a gene enrichment analysis in TIGER and in a subgroup of patients with severe tinnitus (SEVTIN, n = 34), according to the tinnitus handicap inventory (THI) scores. An independent exome sequencing dataset of 147 Swedish tinnitus patients was used as a replication cohort (JAGUAR cohort) and population-specific datasets from Sweden (SweGen) and Non-Finish Europeans (NFE) from gnomAD were used as control groups. SEVTIN patients showed a higher prevalence of hyperacusis, hearing loss, and anxiety when they were compared to individuals in the TIGER cohort. We found an enrichment of rare missense variants in 6 and 8 high-constraint genes in SEVTIN and TIGER cohorts, respectively. Of note, an enrichment of missense variants was found in the CACNA1E gene in both SEVTIN and TIGER. We replicated the burden of missense variants in 9 high-constrained genes in the JAGUAR cohort, including the gene NAV2, when data were compared with NFE. Moreover, LSVs in constrained regions overlapping CACNA1E, NAV2, and TMEM132D genes were observed in TIGER and SEVTIN.

A novel nonsense variant in the CENPP gene segregates in a Swiss family with autosomal dominant low-frequency sensorineural hearing loss.

Low-frequency sensorineural hearing loss (SNHL) is a rare hearing impairment affecting frequencies below 1000 Hz, previously associated with DIAPH1, WSF1, MYO7A, TNC, SLC26A4 or CCDC50 genes. By exome sequencing, we report a novel nonsense variant in CENPP gene, segregating low-frequency SNHL in five affected members in a Swiss family with autosomal dominant inheritance pattern. Audiological evaluation showed up-sloping audiometric configuration with mild-to-moderate losses below 1000 Hz, that progresses to high-frequencies over time. Protein modeling shows that the variant truncates five amino acids at the end, losing electrostatic interactions that alter protein stability. CENPP gene is expressed in the supporting cells of the organ of Corti and takes part as a subunit of the Constitutive Centromere Associated Network in the kinetochore, that fixes the centromere to the spindle microtubules. We report CENPP as a new candidate gene for low-frequency SNHL. Further functional characterization might enable us to elucidate its molecular role in SNHL.

Standardized Clinical Profiling in Spanish Patients with Chronic Tinnitus.

BACKGROUND: Tinnitus is a heterogeneous condition. The aim of this study as to compare the online and hospital responses to the Spanish version of European School for Interdisciplinary Tinnitus Research screening-questionnaire (ESIT-SQ) in tinnitus individuals by an unsupervised age clustering. METHODS: A cross-sectional study was performed including 434 white Spanish patients with chronic tinnitus to assess the demographic and clinical profile through the ESIT-SQ, with 204 outpatients and 230 individuals from an online survey; a K-means clustering algorithm was used to classify both responses according to age. RESULTS: Online survey showed a high proportion of Meniere's disease (MD) patients compared to both the general population and the outpatient cohort. The responses showed statistically significant differences between groups regarding education level, tinnitus-related hearing disorders (MD, hyperacusis), sleep difficulties, dyslipidemia, and other tinnitus characteristics, including duration, type of onset, the report of mitigating factors and the use of treatments. However, these differences were partially confirmed after adjusting for age. CONCLUSIONS: Self-reported tinnitus surveys are a low confidence source for tinnitus phenotyping. Additional clinical evaluation is needed for tinnitus research to reach the diagnosis. Age-based cluster analysis might help to better define clinical profiles and to compare responses in ESIT-SQ among subgroups of patients with tinnitus.