Keita Tsukada

A large cohort study of GJB2 mutations in Japanese hearing loss patients

Tsukada K, Nishio S, Usami S, and the Deafness Gene Study Consortium. A large cohort study of GJB2 mutations in Japanese hearing loss patients.

The responsible genes in Japanese deafness patients and clinical application using Invader assay

Discovery of deafness genes has progressed but clinical application lags because of the genetic heterogeneity. To establish clinical application strategy, we reviewed the frequency and spectrum of mutations found in Japanese hearing loss patients and compared them to those in populations of European ancestry. Screening revealed that in Japanese, mutations in GJB2, SLC26A4, and CDH23, and the mitochondrial 12S rRNA are the major causes of hearing loss. Also, mutations in KCNQ4, TECTA, COCH, WFS1, CRYM, COL9A3, and KIAA1199 were found in independent autosomal dominant families. Interestingly, spectrums of GJB2, SLC26A4, and CDH23 mutations in Japanese were quite different from those in Europeans. Simultaneous screening of multiple deafness mutations based on the mutation spectrum of a corresponding population using an Invader panel revealed that approximately 30% of subjects could be diagnosed. This assay will enable us to detect deafness mutations in an efficient and practical manner in the clinical platform. We conclude that specific racial populations may have unique deafness gene epidemiologies; therefore, ethnic background should be considered when genetic testing is performed. Simultaneous examination of multiple mutations based on a populations spectrum may be appropriate and effective for detecting deafness genes, facilitating precise clinical diagnosis, appropriate counseling, and proper management.

Comparison of the diagnostic value of 3 T MRI after intratympanic injection of GBCA, electrocochleography, and the glycerol test in patients with Meniere's disease

Abstract Conclusion. 3 T MRI after intratympanic injection of gadolinium-based contrast agent (GBCA) is more useful for the diagnosis of endolymphatic hydrops compared with the glycerol test and electrocochleography (ECoG). Objective: To investigate the relationship between 3 T MRI after intratympanic injection of GBCA, the glycerol test, and ECoG in patients with Menieres disease (MD). Methods: A total of 20 patients with MD were evaluated. Diluted gadodiamide (a gadolinium-based contrast agent) was administered to the bilateral tympanic cavity by injection through the tympanic membrane. After 24 h, the endolymphatic hydrops was evaluated by a 3.0 T MR scanner. To investigate cochlear hydrops, the glycerol test and ECoG were carried out in all patients. Results: A positive result was observed in 11 patients (55%) in the glycerol test and in 12 patients (60%) by ECoG. The incidence of positive findings when evaluating the same patients with both the glycerol test and ECoG increased to 75%. Nineteen of 20 (95%) patients showed positive results for 3 T MRI.

Semi-quantitative evaluation of endolymphatic hydrops by bilateral intratympanic gadolinium-based contrast agent (GBCA) administration with MRI for Meniere's disease

Conclusion: Bilateral intratympanic administration of a gadolinium-based contrast agent (GBCA) in MRI was successfully performed and proved to be beneficial in the semi-quantitative evaluation of endolymphatic hydrops. Such image-based diagnosis will lead to re-revaluation and reclassification of the diagnostic criteria for Menieres disease (MD). Objective: To visualize endolymphatic hydrops semi-quantitatively in patients with MD, by using bilateral intratympanic GBCA administration with MRI. Patients and methods: A total of 13 patients were evaluated, including 12 with MD and one with acute low-tone sensorineural hearing loss. Diluted gadodiamide (a kind of GBCA) was administered to the bilateral tympanic cavity by injection through the tympanic membrane. After 24 h, the endolymphatic hydrops was evaluated with a 3.0 T MR scanner. The areas enhanced by gadodiamide were measured semi-quantitatively. Results: Three-dimensional, fluid-attenuated inversion recovery (3D-FLAIR) MRI showed that the gadodiamide successfully penetrated the round window membrane, entering the perilymphatic space and delineating the gadodiamide-enhanced perilymphatic and gadodiamide-negative endolymphatic spaces of the inner ear. All the patients with MD showed a reduced gadodiamide-enhanced area representing the perilymphatic space, and the quantitative ratio was 0.15 to 0.85. Furthermore, endolymphatic hydrops was also demonstrated in the patient with atypical MD who had fluctuating low frequency sensorineural hearing loss without vertigo.

Endolymphatic hydrops and therapeutic effects are visualized in ‘atypical’ Meniere's disease

A 53-year-old male with fluctuating low frequency sensorineural hearing loss and tinnitus, but without vertigo, was evaluated by MRI obtained by intratympanic injection of a gadolinium-based contrast agent (GBCA) before and after the administration of isosorbide. The endolymphatic hydrops was semi-quantitatively evaluated by a 3.0-T MR scanner. For quantification, the affected side/contralateral side ratios were calculated. A gadodiamide (a kind of GBCA)-enhanced space surrounding the endolymph in the affected side with a 0.50 ratio (which may have represented endolymphatic hydrops) improved after isosorbide therapy to a 0.98 ratio. Thus, endolymphatic hydrops was demonstrated in a patient with ‘atypical’ Menieres disease (MD), suggesting that at least some atypical MD may share similar etiology with, and therefore be a continuum of, MD. Also, therapeutic effects could be visualized by using MRI. Therefore, MRI-based diagnosis of MD-related disease will be a powerful tool not only because of its precision but also its usefulness for therapeutic evaluation.

Ethnic-Specific Spectrum of GJB2 and SLC26A4 Mutations: Their Origin and a Literature Review

Objective: The mutation spectrum of the GJB2 and SLC26A4 genes, the 2 most common genes causing deafness, are known to be ethnic specific. In this study, the spectrum of the reported GJB2 and SLC26A4 mutations in different populations are reviewed and considered from a human migration perspective. Methods: Fifty-two and 17 articles on GJB2 and SLC26A4 mutations, respectively, were reviewed through the PubMed database from April 1996 to September 2014. The 4 most prevalent mutations were selected and compared. A cluster analysis was subsequently performed for these selected mutations. Results: The present review of frequent mutations shows the ethnic-specific GJB2 and SLC26A4 gene mutation spectrum. A cluster analysis of the GJB2 and SLC26A4 genes revealed similarities between ethnic populations. Conclusion: The mutation spectrum reviewed in this study clearly indicated that the frequent mutations in the GJB2 and SLC26A4 genes are consistent with the founder mutation hypothesis. A comparison with the Y-chromosome phylogenetic tree indicated that these mutations may have occurred during human migration.

Hearing preservation and clinical outcome of 32 consecutive electric acoustic stimulation (EAS) surgeries

Abstract Conclusions: Our results indicated that electric acoustic stimulation (EAS) is beneficial for Japanese-speaking patients, including those with less residual hearing at lower frequencies. Comparable outcomes for the patients with less residual hearing indicated that current audiological criteria for EAS could be expanded. Successful hearing preservation results, together with the progressive nature of loss of residual hearing in these patients, mean that minimally invasive full insertion of medium/long electrodes in cochlear implantation (CI) surgery is a desirable solution. The minimally invasive concepts that have been obtained through EAS surgery are, in fact, crucial for all CI patients. Objectives: This study was conducted to evaluate hearing preservation results and speech discrimination outcomes of hearing preservation surgeries using medium/long electrodes. Methods: A total of 32 consecutive minimally invasive hearing preservation CIs (using a round window approach with deep insertion of a flexible electrode) were performed in 30 Japanese patients (two were bilateral cases), including patients with less residual hearing. Hearing preservation rates as well as speech discrimination/perception scores were investigated on a multicenter basis. Results: Postoperative evaluation after full insertion of the flexible electrodes (24 mm, 31.5 mm) showed that residual hearing was well preserved in all 32 ears. In all patients, speech discrimination and perception scores were improved postoperatively.

Gene Expression Profiles of the Cochlea and Vestibular Endorgans: Localization and Function of Genes Causing Deafness

Objectives: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. Methods: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. Results: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. Conclusions: The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

The Patients Associated With TMPRSS3 Mutations Are Good Candidates for Electric Acoustic Stimulation

Objectives: To clarify the frequency of TMPRSS3 mutations in the hearing loss population, genetic analysis was performed, and detailed clinical characteristics were collected. Optical intervention for patients with TMPRSS3 mutations was also discussed. Methods: Massively parallel DNA sequencing (MPS) was applied for the target exon-sequencing of 63 deafness genes in a population of 1120 Japanese hearing loss patients. Results: Hearing loss in 5 patients was found to be caused by compound heterozygous TMPRSS3 mutations, and their detailed clinical features were collected and analyzed. Typically, all of the patients showed ski slope type audiograms and progressive hearing loss. Three of the 5 patients received electric acoustic stimulation (EAS), which showed good results. Further, the onset age was found to vary, and there were some correlations between genotype and phenotype (onset age). Conclusions: MPS is a powerful tool for the identification of rare causative deafness genes, such as TMPRSS3. The present clinical characteristics not only confirmed the findings from previous studies but also provided clinical evidence that EAS is beneficial for patients possessing TMPRSS3 mutations.

Effects of EAS cochlear implantation surgery on vestibular function

Abstract Conclusions: The patients who received electric acoustic stimulation (EAS) cochlear implantation had relatively good vestibular function compared with the patients who did not have residual hearing. The vestibular function was well preserved after atraumatic EAS surgery. The round window approach and soft electrode are preferred to decrease the risk of impairing vestibular function. Objectives: The aim of this study was to examine the characteristic features of vestibular functions before and after implantations in patients undergoing EAS. Methods: Vestibular functions in patients who underwent EAS implantation were examined by caloric testing and vestibular evoked myogenic potential (VEMP) in 11 patients before and in 13 patients after implantation. Results: Preoperative evaluation showed that of the 11 patients, most (73%) had good vestibular function. One of 11 patients (9%) had decreased response in postoperative VEMP but all of the patients had unchanged results in postoperative caloric testing.