RESUMO
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.
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Frequência do Gene , Doença de Meniere , Mutação de Sentido Incorreto , População Branca , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Europa (Continente)/epidemiologia , Efeito Fundador , Ligação Genética , Predisposição Genética para Doença , Doença de Meniere/genética , Doença de Meniere/epidemiologia , Prevalência , População Branca/genética , População EuropeiaRESUMO
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.
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Hipersensibilidade , Doença de Meniere , Transtornos de Enxaqueca , Camundongos , Animais , Humanos , Doença de Meniere/epidemiologia , Doença de Meniere/genética , Doença de Meniere/complicações , Hipersensibilidade/complicações , Hipersensibilidade/epidemiologia , Comorbidade , Transtornos de Enxaqueca/complicações , PropriocepçãoRESUMO
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.
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Anquirinas , Fenótipo , Zumbido , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anquirinas/genética , Doença Crônica , Potenciais Evocados Auditivos do Tronco Encefálico , Psicometria , Zumbido/genética , Zumbido/fisiopatologiaRESUMO
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.
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Implante Coclear , Perda Auditiva Neurossensorial , Doença de Meniere , Humanos , Doença de Meniere/complicações , Doença de Meniere/cirurgia , Vertigem/etiologia , Vertigem/cirurgia , Canais Semicirculares/cirurgia , Audição , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/cirurgiaRESUMO
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.
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Perda Auditiva Neurossensorial , Doença de Meniere , Humanos , Doença de Meniere/complicações , Doença de Meniere/epidemiologia , Vertigem/complicações , Citocinas , Perda Auditiva Neurossensorial/complicações , Síndrome , Imunoglobulina ERESUMO
The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.
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Crowdsourcing , Bases de Dados Genéticas , Genética Populacional/métodos , Genoma Humano , Software , Alelos , Mapeamento Cromossômico , Exoma , Frequência do Gene , Variação Genética , Genômica , Humanos , Internet , Medicina de Precisão/métodos , EspanhaRESUMO
OBJECTIVES: Meniere disease (MD) is defined by a clinical syndrome of recurrent attacks of spontaneous vertigo associated with tinnitus, aural fullness, and sensorineural hearing loss (SNHL). Most patients have unilateral SNHL, but some of them will develop contralateral SNHL during the course of the disease. Several studies have reported a frequency of 2 to 73% SNHL in the second ear, according to the duration of disease and the period of follow-up. We hypothesize that unilateral and bilateral MD are different conditions, the first would initially involve the apical turn of the cochlea, while bilateral MD would affect the entire length of the cochlea. The aim of the study is to search for clinical predictors of bilateral SNHL in MD to build a predictive model of bilateral involvement. DESIGN: A retrospective, longitudinal study including two cohorts with a total of 400 patients with definite MD was carried out. The inception cohort consisted of 150 patients with MD and the validation cohort included 250 cases. All of the cases were diagnosed of unilateral MD according to their hearing loss thresholds. The following variables were assessed as predictors of bilateral SNHL for the two cohorts: sex, age of onset, familiar history of MD, migraine and high-frequency hearing loss (HFHL, defined if hearing threshold >20 dB in two or more consecutive frequencies from 2 to 8 KHz). A descriptive analysis was carried out according to the presence of HFHL in the first audiogram for the main variables. By using multiple logistic regression, we built-up several predictive models for the inception cohort and validated it with the replication cohort and merged dataset. RESULTS: Twenty-three (19.3%) and 78 (41%) of patients with HFHL developed contralateral SNHL during the follow-up, in the inception and validation cohorts, respectively. In the inception cohort, the best predictive model included HFHL in the first audiogram (OR = 6.985, p = 0.063) and the absence of migraine (OR = 0.215, p = 0.144) as clinical predictors for bilateral SNHL [area under the curve (AUC) = 0.641, p = 0.002]. The model was validated in the second cohort (AUC = 0.621, p < 0.001). Finally, we merged both datasets to improve the precision of the model including HFHL in the first audiogram (OR = 3.168, p = 0.001), migraine (OR = 0.482, p = 0.036) and age of onset >35 years old (OR = 2.422, p = 0.006) as clinical predictors (AUC = 0.639, p < 0.001). CONCLUSIONS: A predictive model including the age of onset, HFHL in the first audiogram and migraine can help to assess the risk of bilateral SNHL in MD. This model may have significant implications for clinical management of patients with MD.
Assuntos
Perda Auditiva Neurossensorial , Doença de Meniere , Transtornos de Enxaqueca , Adulto , Perda Auditiva Bilateral , Humanos , Estudos Longitudinais , Doença de Meniere/complicações , Transtornos de Enxaqueca/complicações , Estudos RetrospectivosRESUMO
INTRODUCTION: Meniere's disease (MD) is a rare inner ear disorder with a significant genetic contribution defined by a core phenotype: episodic vertigo, sensorineural hearing loss and tinnitus. It has been mostly described in sporadic cases, familial cases being around 10% of the observed individuals. It is associated with an accumulation of endolymph in the inner ear, but the molecular underpinnings remain largely unknown. The main molecular pathways showing higher differentially expressed genes in the supporting cells of the inner ear are related to cochlea-vestibular innervation, cell adhesion and leucocyte extravasation. In this study, our objective is to find a burden of rare variants in genes that interact with the main signalling pathways in supporting cells of the inner ear in patients with sporadic MD. METHODS: We designed a targeted-sequencing panel including genes related with the main molecular pathways in supporting cells and sequenced 860 Spanish patients with sporadic MD. Variants with minor allele frequencies <0.1 in the gene panel were compared with three independent reference datasets. Variants were classified as loss of function, missense and synonymous. Missense variants with a combined annotation-dependent depletion score of >20 were classified as damaging missense variants. RESULTS: We have observed a significant burden of damaging missense variants in few key genes, including the NTN4 gene, associated with axon guidance signalling pathways in patients with sporadic MD. We have also identified active subnetworks having an enrichment of rare variants in sporadic MD. CONCLUSION: The burden of missense variants in the NTN4 gene suggests that axonal guidance signalling could be a novel pathway involved in sporadic MD.
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Axônios/metabolismo , Perda Auditiva Neurossensorial/genética , Doença de Meniere/genética , Netrinas/genética , Axônios/patologia , Orelha Interna/química , Orelha Interna/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Doença de Meniere/patologia , Pessoa de Meia-Idade , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Netrinas/química , Netrinas/ultraestrutura , Linhagem , Conformação Proteica , Transdução de Sinais/genética , Relação Estrutura-AtividadeRESUMO
Meniere's disease (MD) is a set of uncommon disorders with core phenotype of tinnitus, episodic vertigo, and sensorineural hearing loss. MD shows a genetic predisposition and a family history is found in 10% cases, with an autosomal dominant inheritance pattern. It is a multifactorial condition whose onset and development are triggered by the combined effect of genetic and environmental factors. Histopathological studies have associated MD with the accumulation of endolymph in the cochlea and the vestibular organs. However, endolymphatic hydrops does not fully explain the persistence of tinnitus, hearing loss progression, or the frequency of vertigo attacks.There are several comorbidities associated with MD, such as migraine, anxiety, autoimmune, and autoinflammatory disorders, adding more complexity to the phenotype. This "extended phenotype" can make the diagnosis and clinical management more complex, but it could also lead to a better characterization, understanding, and treatment of MD patients.We have conducted a systematic review on MD to update current knowledge, focusing on its mechanisms, diagnosis, comorbidities, and practical management.
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Interação Gene-Ambiente , Doença de Meniere , Humanos , Doença de Meniere/diagnóstico , Doença de Meniere/etiologia , Doença de Meniere/fisiopatologia , Doença de Meniere/terapiaRESUMO
PURPOSE OF REVIEW: To provide an update on the most frequent peripheral vestibular disorders. RECENT FINDINGS: The on-going classification of vestibular disorders by the Bárány Society represents major progress. The diagnosis of bilateral vestibulopathy (BVP) requires quantitative testing of vestibular function. 'Acute unilateral peripheral vestibulopathy' (AUPVP) is now preferred over 'vestibular neuritis.' Menière's disease is a set of disorders with a significant genetic contribution. The apogeotropic variant of horizontal canal benign paroxysmal positional vertigo (hcBPPV) and anterior canal BPPV (acBPPV) can be distinguished from a central vestibular lesion. Vestibular paroxysmia is now an internationally accepted clinical entity. The diagnosis of SCDS is based on conclusive findings. SUMMARY: Diagnosis of BVP requires significantly reduced vestibular function. The clinical picture of AUPVP depends on how much the vestibular end organs or their innervation are affected. Menière's disease phenotype is a constellation of symptoms. Although diagnostic and therapeutic criteria for pc and hcBPPV are well defined, a number of less frequent and controversial are increasingly diagnosed and can be treated. Diagnosis of vestibular paroxysmia requires that a patient responds to treatment with a sodium channel blocker. The diagnosis of SCDS requires conclusive findings with various methods. There is still a great need for state-of-the-art randomized controlled treatment trials in most peripheral vestibular disorders.
Assuntos
Doenças Vestibulares/diagnóstico , Doenças Vestibulares/fisiopatologia , Vestíbulo do Labirinto/fisiopatologia , HumanosRESUMO
OBJECTIVES: Research on the genetic basis of tinnitus is still in its first steps. A group of scientists dedicated to tinnitus genetics within European Tinnitus Network (TINNET) network recognize that further progress requires multicenter collaborative efforts for defining contributing genes. The purpose of the present work is to provide instructions regarding collection, processing, storage, and shipment of samples intended for genetic studies in auditory research. DESIGN: One part of the recommendations has a general character; another part is of particular importance for auditory healthcare practitioners such as otolaryngology physicians, audiologists, and general practitioners. RESULTS: We provide a set of instructions and various options for obtaining samples. We give advice regarding sample processing, storage, and shipment and define the minimal and essential clinical information that should accompany the samples collected for genetic processing. CONCLUSIONS: These recommendations offer a basis to standardize and optimize collaborations between geneticists and healthcare practitioners specialized in tinnitus and hearing disorders.
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Pesquisa Biomédica , DNA/isolamento & purificação , Perda Auditiva/genética , RNA/isolamento & purificação , Manejo de Espécimes , Zumbido/genética , Coleta de Amostras Sanguíneas , DNA/análise , Genômica , Guias como Assunto , Humanos , Consentimento Livre e Esclarecido , Mucosa Bucal , RNA/análise , SalivaRESUMO
Meniere's Disease (MD) is a complex disorder associated with an accumulation of endolymph in the membranous labyrinth in the inner ear. It is characterized by recurrent attacks of spontaneous vertigo associated with sensorineural hearing loss (SNHL) and tinnitus. The SNHL usually starts at low and medium frequencies with a variable progression to high frequencies. We identified a novel missense variant in the PRKCB gene in a Spanish family with MD segregating low-to-middle frequency SNHL. Confocal imaging showed strong PKCB II protein labelling in non-sensory cells, the tectal cells and inner border cells of the rat organ of Corti with a tonotopic expression gradient. The PKCB II signal was more pronounced in the apical turn of the cochlea when compared with the middle and basal turns. It was also much higher in cochlear tissue than in vestibular tissue. Taken together, our findings identify PRKCB gene as a novel candidate gene for familial MD and its expression gradient in supporting cells of the organ of Corti deserves attention, given the role of supporting cells in K+ recycling within the endolymph, and its apical turn location may explain the onset of hearing loss at low frequencies in MD.
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Perda Auditiva Neurossensorial/genética , Doença de Meniere/genética , Mutação de Sentido Incorreto/genética , Proteína Quinase C beta/genética , Adulto , Animais , Orelha Interna/patologia , Feminino , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Doença de Meniere/fisiopatologia , Órgão Espiral/patologia , Linhagem , Ratos , Zumbido/genética , Zumbido/fisiopatologiaRESUMO
PURPOSE OF REVIEW: The increased availability of next generation sequencing has enabled a rapid progress in the discovery of genetic variants associated with vestibular disorders. We have summarized molecular genetics finding in vestibular syndromes during the last 18 months. RECENT FINDINGS: Genetic studies continue to shed light on the genetic background of vestibular disorders. Novel genes affecting brain development and otolith biogenesis have been associated with motion sickness. Exome sequencing has made possible to identify three rare single nucleotide variants in PRKCB, DPT and SEMA3D linked with familial Meniere disease. Moreover, superior canal dehiscence syndrome might be related with variants in CDH3 gene, by increasing risk of its development. On the other hand, the association between vestibular schwannoma and enlarged vestibular aqueduct with variants in NF2 and SLC26A4, respectively, seems increasingly clear. Finally, the use of mouse models is allowing further progress in the development gene therapy for hearing and vestibular monogenic disorders. SUMMARY: Most of episodic or progressive syndromes show familial clustering. A detailed phenotyping with a complete familial history of vestibular symptoms is required to conduct a genetic study. Progress in these studies will allow us to understand diseases mechanisms and improve their current medical treatments.
Assuntos
Doenças Vestibulares/genética , HumanosRESUMO
BACKGROUND: The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets. RESULTS: PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants. CONCLUSIONS: Our pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.
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Bases de Dados Genéticas , Sequenciamento do Exoma/métodos , Exoma/genética , Doença de Meniere/genética , Mutação , Software , Algoritmos , Biologia Computacional , Heterozigoto , Humanos , Doença de Meniere/patologia , FenótipoRESUMO
OBJECTIVE: The aim of this work was to assess through a questionnaire the features of vertiginous episodes, accompanying symptoms, familial history, and migraine precursors in a sample of 252 subjects with a diagnosis of definite vestibular migraine. BACKGROUND: Migraine is a common neurological disorder characterized by episodic headaches with specific features. About two-thirds of cases run in families, and patients may refer symptoms occurring in infancy and childhood, defined as episodic syndromes that may be associated with migraine. Migraine is associated with episodic vertigo, called vestibular migraine, whose diagnosis mainly relies on clinical history showing a temporary association of symptoms. METHODS: In this cross-sectional multicentric study, 252 subjects were recruited in different centers; a senior specialist through a structured questionnaire assessed features of vestibular symptoms and accompanying symptoms. RESULTS: The age of onset of migraine was 23 years, while onset of vertigo was at 38 years. One hundred and eighty-four subjects reported internal vertigo (73%), while 63 subjects (25%) reported external vertigo. The duration of vertigo attacks was less than 5 minutes in 58 subjects (23%), between 6 and 60 minutes in 55 (21.8%), between 1 and 4 hours in 29 (11.5%), 5 and 24 hours in 44 (17.5%), up to 3 days in 14 (5.5%), and more than 3 days in seven (2.8%); 14 subjects (5.5%) referred attacks lasting from less than 5 minutes and up to 1 hour, nine (3.6%) referred attacks lasting from less than 5 minutes and up to 1 to 4 hours, six (2.4%) referred attacks lasting from less than 5 minutes and up to 5 to 24 hours, and five (2%) cases referred attacks lasting from less than 5 minutes and up to days. Among accompanying symptoms, patients referred the following usually occurring, in order of frequency: nausea (59.9%), photophobia (44.4%), phonophobia (38.9%), vomiting (17.8%), palpitations (11.5%), tinnitus (10.7%), fullness of the ear (8.7%), and hearing loss (4%). In total, 177 subjects referred a positive family history of migraine (70.2%), while 167 (66.3%) reported a positive family history of vertigo. In the sample, 69% of patients referred at least one of the pediatric precursors, in particular, 42.8% of subjects referred motion sickness. The age of onset of the first headache was lower in the subsample with a familial history of migraine than in the total sample. Among the pediatric precursors, benign paroxysmal vertigo - BPV, benign paroxysmal torticollis, and motion sickness were predictive of a lower age of onset of vertigo in adulthood; cyclic vomiting was predictive for vomiting during vertigo attacks in adults. CONCLUSIONS: Our results may indicate that vestibular symptoms in pediatric patients may act as a predisposing factor to develop vestibular migraine at an earlier age in adulthood.
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Transtornos de Enxaqueca , Vertigem , Adulto , Idade de Início , Idoso , Estudos Transversais , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/fisiopatologia , Espanha/epidemiologia , Vertigem/diagnóstico , Vertigem/epidemiologia , Vertigem/fisiopatologia , Adulto JovemRESUMO
Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD.
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Proteínas Associadas à Distrofina/genética , Genes Dominantes , Doença de Meniere/genética , Proteínas Mitocondriais/genética , Mutação , Neuropeptídeos/genética , Animais , Sequência de Bases , Análise Mutacional de DNA , Proteínas Associadas à Distrofina/metabolismo , Exoma , Feminino , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doença de Meniere/metabolismo , Proteínas Mitocondriais/metabolismo , Neuropeptídeos/metabolismo , Linhagem , Ligação Proteica , Transporte Proteico , RatosRESUMO
Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.
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Etnicidade/genética , Evolução Molecular , Exoma/genética , Variação Genética/genética , Perda Auditiva/genética , Perda Auditiva/patologia , Estudos de Casos e Controles , Conexina 26 , Conexinas , Frequência do Gene , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , FilogeniaRESUMO
PURPOSE: Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). METHODS: Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. RESULTS: Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. CONCLUSION: Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017.
Assuntos
Predisposição Genética para Doença , Zumbido/epidemiologia , Zumbido/genética , Gêmeos , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Humanos , Padrões de Herança , Masculino , Pessoa de Meia-Idade , Vigilância da População , Sistema de Registros , Risco , Suécia/epidemiologia , Zumbido/diagnóstico , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adulto JovemRESUMO
PURPOSE OF REVIEW: Recent advances in next generation sequencing techniques (NGS) are increasing the number of novel genes associated with cerebellar and vestibular disorders. We have summarized clinical and molecular genetics findings in neuro-otolology during the last 2 years. RECENT FINDINGS: Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14. Novel mutations in KCNA1 and CACNA1A genes are associated with episodic ataxia type 1 and type 2, respectively. Moreover, new variants in genes such as COCH, MYO7A and POU4F3 are associated with nonsyndromic deafness and vestibular dysfunction. Several susceptibility loci have been linked to familial vestibular migraine, suggesting genetic heterogeneity, but no specific gene has been identified. Finally, loci for complex and heterogeneous diseases such as bilateral vestibular hypofunction or familial Ménière disease have not been identified yet, despite their strong familial aggregation. SUMMARY: Cerebellar and vestibular disorders leading to dizziness or episodic vertigo may show overlapping clinical features. A deep phenotyping including a complete familial history is a key step in performing a reliable molecular genetic diagnosis using NGS. Personalized molecular medicine will be essential to understand disease mechanisms as well as to improve their diagnosis and treatment.