Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype. Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus. Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes (p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal protein binding in neurons. Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2, encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal branching and influences connectivity in neurons

Corrigendum: Clinical Features of Headache in Patients With Diagnosis of Definite Vestibular Migraine: The VM-Phenotypes Projects

[This corrects the article DOI: 10.3389/fneur.2018.00395.]

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere’s Disease

Meniere’s disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case–control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661–2.627); p = 1.39 × 10−09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10−11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD

Mathematical methods for measuring the visually enhanced vestibulo-ocular reflex and preliminary results from healthy subjects and patient groups

Background: Visually enhanced vestibulo-ocular reflex (VVOR) is a well-known bedside clinical test to evaluate visuo-vestibular interaction, with clinical applications in patients with neurological and vestibular dysfunctions. Owing to recently developed diagnostic technologies, the possibility to perform an easy and objective measurement of the VVOR has increased, but there is a lack of computational methods designed to obtain an objective VVOR measurement. Objectives: To develop a method for the assessment of the VVOR to obtain a gain value that compares head and eye velocities and to test this method in patients and healthy subjects. Methods: Two computational methods were developed to measure the VVOR test responses: the first method was based on the area under curve of head and eye velocity plots and the second method was based on the slope of the linear regression obtained for head and eye velocity data. VVOR gain and vestibulo-ocular reflex (VOR) gain were analyzed with the data obtained from 35 subjects divided into four groups: healthy (N = 10), unilateral vestibular with vestibular neurectomy (N = 8), bilateral vestibulopathy (N = 12), and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) (N = 5). Results: Intra-class correlation index for the two developed VVOR analysis methods was 0.99. Statistical differences were obtained by analysis of variance statistical method, comparing the healthy group (VVOR mean gain of 1 ± 0) with all other groups. The CANVAS group exhibited (VVOR mean gain of 0.4 ± 0.1) differences when compared to all other groups. VVOR mean gain for the vestibular bilateral group was 0.8 ± 0.1. VVOR mean gain in the unilateral group was 0.6 ± 0.1, with a Pearson's correlation of 0.52 obtained when VVOR gain was compared to the VOR gain of the operated side. Conclusion: Two computational methods to measure the gain of VVOR were successfully developed. The VVOR gain values appear to objectively characterize the VVOR alteration observed in CANVAS patients, and also distinguish between healthy subjects and patients with some vestibular disorders

Relevance of artifact removal and number of stimuli for video head impulse test examination

Objective: To evaluate the effect of artifacts on the impulse and response recordings with the video head impulse test (VHIT) and determine how many stimuli are necessary for obtaining acceptably efficient measurements. Methods: One hundred fifty patients were examined using VHIT and their registries searched for artifacts. We compared several variations of the dataset. The first variation used only samples without artifacts, the second used all samples (with and without artifacts), and the rest used only samples with each type of artifact. We calculated the relative efficiency (RE) of evaluating an increasingly large number of samples (3 to 19 per side) when compared with the complete sample (20 impulses per side). Results: Overshoot was associated with significantly higher speed (p = 0.005), higher duration (p < 0.001) and lower amplitude of the impulses (p = 0.002), and consequent higher saccades’ latency (p = 0.035) and lower amplitude (p = 0.025). Loss of track was associated with lower gain (p = 0.035). Blink was associated with a higher number of saccades (p < 0.001), and wrong way was associated with lower saccade latency (p = 0.012). The coefficient of quartile deviation escalated as the number of artifacts of any type rose, indicating an increment of variability. Overshoot increased the probability of the impulse to lay on the outlier range for gain and peak speed. Blink did so for the number of saccades, and wrong way for the saccade amplitude and speed. RE reached a tolerable level of 1.1 at 7 to 10 impulses for all measurements except the PR score. Conclusions: Our results suggest the necessity of removing artifacts after collecting VHIT samples to improve the accuracy and precision of results. Ten impulses are sufficient for achieving acceptable RE for all measurements except the PR score

A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease.

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

Clinical Features of Headache in Patients With Diagnosis of Definite Vestibular Migraine: The VM-Phenotypes Projects

Migraine is a common neurological disorder characterized by episodic headaches with specific features, presenting familial aggregation. Migraine is associated with episodic vertigo, named Vestibular Migraine (VM) whose diagnosis mainly rely on clinical history showing a temporary association of symptoms. Some patient refers symptoms occurring in pediatric age, defined "episodic symptoms which may be associated with migraine." The aim of this cross sectional observational study was to assess migraine-related clinical features in VM subjects. For the purpose, 279 patients were recruited in different centers in Europe; data were collected by a senior neurologist or ENT specialist through a structured questionnaire. The age of onset of migraine was 21.8 ± 9. The duration of headaches was lower than 24 h in 79.1% of cases. Symptoms accompanying migrainous headaches were, in order of frequency, nausea (79.9%), phonophobia (54.5%), photophobia (53.8%), vomiting (29%), lightheadedness (21.1%). Visual or other auras were reported by 25.4% of subjects. A familial aggregation was referred by 67.4%, while migraine precursors were reported by 52.3% of subjects. Patients reporting nausea and vomiting during headaches more frequently experienced the same symptoms during vertigo. Comparing our results in VM subjects with previously published papers in migraine sufferers, our patients presented a lower duration of headaches and a higher rate of familial aggregation; moreover some common characters were observed in headache and vertigo attacks for accompanying symptoms like nausea and vomiting and clustering of attacks

Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study

tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype.This study has been funded by H2020 MSCA-ITN-2016–722046, the H2020-SC1-2019-848261, and the GNP-182 GENDER-Net Co-Plus Fund (JALE and CRC). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002 (JALE). This project is a part of European School of Interdisciplinary Tinnitus (ESIT) research and Sana Amanat is a PhD student in Biomedicine Program at the University of Granada. CRC received additional funding from Svenska Läkaresällskapet (SLS- 779681 ), Hörselforskningsfonden (503). The data handling for STOP and SweGen cohorts were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX partially funded by the Swedish Research Council through Grant agreement No. 2018-05973 . The time provided by JS was funded by the University of Nottingham, Nottingham Research Fellowship. PM was supported by the BMBF Treat-ION Grant ( 01GM1907 ) and the DFG Research Unit FOR2715 (FNR INTER/DFG/17/ 11583046 ).Ye