Endolymphatic deafness: a particular variety of cochlear disorder

Experimental and clinical data made us consider some types of perceptive hearing loss secondary to an alteration of the secretory structures of the cochlea including stria vascularis, spiral ligament and supporting cells. These structures are responsible for the secretion of endolymph, a fluid characterized by a high potassium concentration (150-180 mM), a low sodium concentration (<1 mM) and a positive potential (80-100 mV). This intracellular-like fluid fills the endolymphatic compartment and is essential in the transduction process which takes place in the organ of Corti. Experimental studies have shown that drugs such as loop diuretics induced marked histological lesions in the stria vascularis and profound alterations in the electrochemical features of endolymph. Histopathological data have demonstrated that several entities such as prebyacusis, sudden deafness, and congenital or acquired progressive hearing loss could be related to strial abnormalities. Recent genetic studies have shown that a mutation of genes encoding connexins, a gap junction protein present in the secretory structures, was involved in some dominant or recessive forms of congenital deafness. Finally, the evaluation of labyrinthine fluids in humans has evidenced a decreased endocochlear potential in two cases of progressive flat hearing loss. All these arguments suggest that among the various types of so-called 'sensorineural' deafness, several entities including strial presbyacusis, diuretic-induced ototoxic deafness, some forms of congenital hearing loss and sudden deafness should be classified as endolymphatic deafness. Such an identification seems necessary since these entities result from different pathogenetic mechanisms, do not have the same evolution nor will they probably benefit from the same therapeutic management.     

标准聋病分子诊断实验室的结构及功能

听力学和聋病的分子生物学方面的一些最新进展已经从实验室研究转化到临床领域并改进了对病人的治疗和护理,医师、听力学家以及患者及其家属对于耳聋分子病因基础的了解是非常重要的,聋病分子诊断实验室为耳科医师、听力学家及患者方提供了了解聋病分子病因的工具.本文介绍了现代标准聋病分子诊断实验室结构及其功能,解放军总医院聋病分子诊断中心的建立提供了聋病密切相关的GJB2、PDS、线粒体等基因的常规检测方法和场所,能够提供所有与聋病有关的已知基因的序列分析,可以开展未知耳聋基因的定位和克隆工作,帮助在全国建立聋病的基因诊断网络,以推动我国聋病的诊断和防治工作更上一个台阶.     

Hereditary hearing loss: from human mutation to mechanism

The genetic heterogeneity of hereditary hearing loss is thus far represented by hundreds of genes encoding a large variety of proteins. Mutations in these genes have been discovered for patients with different modes of inheritance and types of hearing loss, ranging from syndromic to non-syndromic and mild to profound. In many cases, the mechanisms whereby the mutations lead to hearing loss have been partly elucidated using cell culture systems and mouse and other animal models. The discovery of the genes has completely changed the practice of genetic counseling in this area, providing potential diagnosis in many cases that can be coupled with clinical phenotypes and offer predictive information for families. In this review we provide three examples of gene discovery in families with hereditary hearing loss, all associated with elucidation of some of the mechanisms leading to hair cell degeneration and pathology of deafness.     

Cochlear implantation in common forms of genetic deafness

Genetic factors are among the main etiologies of severe to profound hearing loss and may play an important role in cochlear implantation (CI) outcomes. While genes for common forms of deafness have been cloned, efforts to correlate the functional outcome of CIs with a genetic form of deafness carried by the patient have been largely anecdotal to date. It has been suggested that the differences in auditory performance may be explained by differences in the number of surviving spiral ganglion cells, etiology of hearing loss, and other factors. Knowledge of the specific loci and mutations involved in patients who receive cochlear implants may elucidate other factors related to CI performance. In this review article, current knowledge of cochlear implants for hereditary hearing loss will be discussed with an emphasis on relevant clinical genotype-phenotype correlations.     

耳聋遗传咨询从业人员继续教育模式的探讨

遗传性耳聋主要由单基因突变引起,个别也有双基因突变致聋的报道。已明确的致聋基因达121个,耳聋具有极高的遗传异质性且表型多样,这些特点为临床耳聋遗传咨询带来挑战。目前国内耳聋遗传咨询工作由耳鼻喉科、妇幼保健机构及医学遗传科的医生兼职完成,尚存在医务人员的遗传学知识不够系统、对遗传性耳聋认识不够深入、遗传咨询内涵和原则把握不准等问题。结合本单位举办共13届全国耳聋基因诊断学习班的经验及对英国曼彻斯特大学临床遗传咨询研究生班课程的系统学习的经历,我们从基础知识培训、研究进展文献检索与交流培训、情景教学及案例总结讨论三个模块对从业人员进行渗透式、交互式教学,取得了理想效果。基础渗透配合情景交互式教学模式适合耳聋遗传咨询人才培养,值得在单基因遗传病遗传咨询教学中推广。     

Cochlear implants in genetic deafness

Genetic defects are one of the most important etiologies of severe to profound sensorineural hearing loss and play an important role in determining cochlear implantation outcomes. While the pathogenic mutation types of a number of deafness genes have been cloned, the pathogenesis mechanisms and their relationship to the outcomes of cochlear implantation remain a hot research area. The auditory performance is considered to be affected by the etiology of hearing loss and the number of surviving spiral ganglion cells, as well as others. Current research advances in cochlear implantation for hereditary deafness, especially the relationship among clinic-types, genotypes and outcomes of cochlear implantation, will be discussed in this review.     

Genetic testing for deafness--GJB2 and SLC26A4 as causes of deafness

Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge will enhance patient care by making the diagnosis of hereditary deafness easier; however physicians and audiologists must clearly identify that subset of the deaf and hearing populations best served by this knowledge. It is also essential for physicians and audiologists to understand the limitations of genetic testing for deafness, and it is imperative that these limitations be appropriately explained to patients and their families. Learning outcomes: The reader will be introduced to the concept of genetic testing for deafness. Two genes that make appreciable contributions to the autosomal recessive non-syndromic deafness (ARNSD) genetic load will be reviewed, GJB2 and SLC26A4. In addition, the unique aspects of genetic counseling for deafness and recurrence chance estimates are explained.     

毛细胞退化相关耳聋基因及其病理机制探讨

遗传性聋的遗传异质性是由几百个蛋白编码基因决定的.无论耳聋程度的轻还是重,不同遗传背景的耳聋患者中均发现相关基因突变.在许多文献报道中,利用细胞培养技术以及小鼠等动物模型可部分解释基因突变致聋的分子机制.这些基因的发现不仅为一些可能伴有临床症状的耳聋病例提供诊断依据,也为耳聋家庭提供生育指导.其中,与毛细胞的退化(尤其是外毛细胞)相关的基因突变可直接导致耳聋的发生.本文选取DFNB28、DFNA51、DFNA50等与毛细胞退化相关的耳聋基因来阐述其病理机制及研究进展.     

Survival of spiral ganglion cells in profound sensorineural hearing loss: implications for cochlear implantation

Ninety-three temporal bones from 66 patients who were profoundly deaf during life were reconstructed by analysis of serial light microscopic sections. The correlations of total and segmental spiral ganglion cell counts with age, duration of hearing loss and profound deafness, and cause of hearing loss were evaluated. Bivariate analysis demonstrated that total spiral ganglion cell count tended to be lower in older than in younger deaf individuals and lower with longer duration of hearing loss and total deafness. However, multiple regression analysis demonstrated that the cause of hearing loss was the single most significant determinant of total spiral ganglion cell count. Patients with deafness due to aminoglycoside toxicity or sudden idiopathic deafness had the highest residual spiral ganglion cell count and patients with deafness due to presumptive postnatal viral labyrinthitis, bacterial labyrinthitis, and congenital or genetic causes had the lowest numbers of residual spiral ganglion cells.     

Correlation between GJB2 mutations and audiological deficits: personal experience

Mutations in GJB2 gene are the most common cause of genetic deafness. More than 100 mutations have been described. The aim of this work is to describe the personal experience in genetic hearing loss, investigating the audiological and genetical characteristics of Cx26 deafness and correlating genotype and phenotype. We performed audiological and genetical evaluation in 154 patients affected by non-syndromic deafness of different degree. All patients showed a bilateral symmetrical sensorineural hearing loss. From the genetical analysis 127 probands resulted as negatives while 27 as positives (51.8% homozygous for 35 delG, 14.8% compound heterozygosis and 33.3% single mutation); 7.5% of patients had a mild deafness, 37% moderate, 33.3% severe and 22.2% profound. The c.35 delG mutation was detected in 66.6% of patients. Three mutations were found in compound heterozygosis with 35 delG, six different single mutations already described, and a new mutation S138G were also found. Correlation between genotype and phenotype confirmed the high variability of hearing loss.     

Genes in the ear: what have we learned over the last years?

In developed countries 50% of childhood hearing impairment is attributable to genetic causes. In a limited number of cases, the hearing impairment is part of a syndrome, and several genes for syndromic deafness have been identified over the last 10 years. In the majority of cases, the hearing impairment occurs without additional clinical abnormalities (non-syndromic). Progressive hearing loss is very frequent in adults. By the age of 80 approximately 50% of the population is affected by age-related hearing loss, which is due partly to genetic factors. Before 1994, little was known about the genes responsible for non-syndromic hearing impairment, although epidemiological studies have suggested that more than 100 genes might be involved. Over the last 6 years, extremely rapid progress was realized in the field of the molecular genetics of hearing and deafness. More than 70 genes for non-syndromic hearing impairment have been localized to the human genome, and 18 of these have been identified.     

Etiological diagnosis of bilateral, sensorineural hearing impairment in a pediatric Greek population

Early diagnosis, evaluation and treatment of childhood deafness are essential for a child's normal growth. Etiological diagnosis of hearing loss makes prevention, family scheduling and more effective therapy feasible goals. Etiological assessment of sensorineural deafness still remains difficult although recently with the progress of genetics it has become more efficient. In this retrospective study, the etiology of bilateral, sensorineural hearing loss with indication for hearing aids has been studied in 153 hearing impaired children. Etiological diagnosis was based on family and patient record, physical, audiological and laboratory examinations. Among the 94 children who completed the diagnostic protocol etiological groups revealed the following distribution: non-hereditary acquired hearing impairment was present in 36 children (38%) and hereditary was present in 44 (47%) children. The etiology remained unknown in 14 (15%) children. Non-syndromic autosomal dominant type accounted for 13 (29% of hereditary hearing loss) children, non-syndromic autosomal recessive type for 21 (48%) children and syndromic deafness for 10 (23%) children. Modern diagnostic methods, such as genetic testing, help diminish the number of cases with hearing impairment of unknown etiology, for the benefit of children who receive early and appropriate medical, audiologic, genetic and educational counseling based on the etiology of their hearing loss.     

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 population's spectrum may be appropriate and effective for detecting deafness genes, facilitating precise clinical diagnosis, appropriate counseling, and proper management.     

Epidemiology of congenital hearing loss

This paper deals with congenital hearing loss (genetic, intrauterine and unfavourable perinatal influences). Data on prevalence vary. Confusion concerning terminology and inadequate facilities for diagnosis makes comparisons difficult.

The prevalence of profound deafness in most European and North American countries is about 1:2 000. When partial deafness is included, the prevalence is considerably higher. Few dependable data are available regarding the distribution of types and degrees of hearing loss and these vary from country to country. Information is better known within the congenitally hearing impaired population. The relation between aetiology and the type of hearing loss helps this knowledge. Sex distribution has been studied recently by the author and data are given. The relative distribution of causes is fairly well known and described in the paper.

The natural history of many types of congenital hearing loss has been inadequately studied. The pathology has been described but the processes leading to hearing loss are little understood. Progress has been made which will enable us to prevent several types of congenital hearing loss.

Certain rehabilitative measures enhance the propagation of the genetic type. Integration into the normal society should decrease this. Genetic counselling should help prevention. Probably unsuspected mutagenic agencies anhance the propagation of genetic hearing loss.

Social conditions influence many aspects of the condition. Movements of populations expose to infection those unprotected immunologically. They change the genetic composition of populations. Migrant populations create difficulties in rehabilitation because of different language backgrouds.

A disabled child always means a disabled family. The basic sociopolitical aspects of rehabilitation depend largely on the attitudes of society to the disability. Deafness still rates low in the hierarchy of disabilities in the estimation of society.

Population studies conducted at an acceptable standard are long overdue. International agreement on terminology and on identification is called for.     

Audiological features of GJB2 (connexin 26) deafness

OBJECTIVE: The aim of the present study was to characterize audiological profiles in patients with GJB2 deafness DESIGN: We screened DNA from 399 individuals with nonsyndromic deafness for mutations in the connexin 26 gene (GJB2) by sequence analysis. A total of 77 (19%) of these deaf individuals were biallelic GJB2 mutations (either homozygous or compound heterozygous mutations) (GJB2 deafness). Using the audiological classification criteria of genetic deafness proposed by the European Workshop on Genetic Hearing Loss, we analyzed audiograms of these patients to characterize audiological features of the GJB2 deafness. In addition, we reviewed audiological data of 411 deafness cases from the literature providing details of audiological data (including 157 with GJB2 deafness). RESULTS: All categories of hearing loss severity were found, with significant differences in the findings from GJB2 cases: 1 (4.5%) of 22 individuals with mild hearing loss, 10 (13.3%) of 75 with moderate loss, 14 (14.9%) of 94 with severe loss, and 52 (25%) of 208 with profound deafness (Chi-square test, 3 df, p = 0.016). 81.6% of patients with GJB2 mutations had severe to profound loss, 18.4% with mild to moderate loss (Chi-square test, p = 0.014). The 235delC mutation was always associated with profound deafness. The main audiogram shapes found were residual/sloping (72.7%) and flat (23.4%). There were no differences in the severity and audiogram shapes of the hearing impairment between homozygous and compound heterozygous GJB2 deafness (Chi-square test, p > 0.05). CONCLUSIONS: Our study shows that the probability of finding biallelic GJB2 mutations increases with the severity of hearing loss. Audiograms associated with GJB2 deafness were usually nonspecific. Patients with unknown causes of severe or profound hearing loss should be routinely tested for GJB2 mutations, but due to the variability in hearing loss, individuals with lesser degrees of hearing loss should not be precluded from testing.     

Electrophysiology and genetic testing in the precision medicine of congenital deafness: A review

Background:Congenital hearing loss is remarkably heterogeneous,with over 130 deafness genes and thousands of variants,making for innumerable genotype/phenotype combinations.Understanding both the pathophysiology of hearing loss and molecular site of lesion along the auditory pathway permits for significantly individualized counseling.Electrophysiologic techniques such as electrocochleography(ECochG)and electrically-evoked compound action potentials(eCAP)are being studied to localize pathology and estimate residual cochlear vs.neural health.This review describes the expanding roles of genetic and electrophysiologic evaluation in the precision medicine of congenital hearing loss.The basics of genetic mutations in hearing loss and electrophysiologic testing(ECochG and eCAP)are reviewed,and how they complement each other in the diagnostics and prognostication of hearing outcomes.Used together,these measures improve the understanding of insults to the auditory system,allowing for individualized counseling for CI candidacy/outcomes or other habilitation strategies.Conclusion:Despite tremendous discovery in deafness genes,the effects of individual genes on neural function remain poorly understood.Bridging the understanding between molecular genotype and neural and functional phenotype is paramount to interpreting genetic results in clinical practice.The future hearing healthcare provider must consolidate an ever-increasing amount of genetic and phenotypic information in the precision medicine of hearing loss.     

The genetic load for hereditary hearing impairment in Chinese population and its clinical implication

Objective To understand the genetic load in the Chinese population for improvement in diagnosis, prevention and rehabilitation of deafness. Methods DNA samples, immortalized cell lines as well as detailed clinical and audiometric data were collected through a national genetic resources collecting network. Two conventional genetic approaches were used in the studies. Linkage analysis in X chromosome and autosomes with microsatellite markers were performed in large families for gene mapping and positional cloning of novel genes. Candidate gene approach was used for screening the mtDNA 12SrRNA, GJB2 and SLC26A4 mutations in population-based samples. Results A total of 2,572 Chinese hearing loss families or sporadic cases were characterized in the reported studies, including seven X-linked, one Y-linked, 28 large and multiplex autosomal dominant heating loss families, 607 simplex autosomal recessive hereditary hearing loss families, 100 mitochondrial inheritance families, 147 GJB2 induced heating loss cases, 230 cases with enlarged vestibular aqueduct(EVA) syndrome, 169 sporadic cases with auditory neuropathy, and 1,283 sporadic sensorineural hearing loss cases. Through linkage analysis or sequence analysis, two X-linked families were found transmitting two novel mutations in the POU3F4 gene, while another X-linked family was mapped onto a novel locus, nominated as A UNX1 (auditory neuropathy, X-linked locus 1). The only Y-linked family was mapped onto the DFNY1 locus(Y-linked locus 1, DFNY1). Eight of the 28 autosomal dominant families were linked to various autosomal loci. In population genetics studies, 2,567 familial cases and sporadic patients were subjected to mutation screening for three common hearing loss genes: mtDNA 12S rRNA 1555G, GJB2 and SLC26A4. The auditory neuropathy cases in our samples were screened for OTOF gene mutations. Conclusions These data show that the Chinese population has a genetic load on hereditary heating loss. Establishing personalized surveillance and prevention models for hearing loss based on genetic research will provide the opportunity to decrease the prevalence of deafness in the Chinese population.     

Deafness in the genomics era

Our understanding of hereditary hearing loss has greatly improved since the discovery of the first human deafness gene. These discoveries have only accelerated due to the great strides in DNA sequencing technology since the completion of the human genome project. Here, we review the immense impact that these developments have had in both deafness research and clinical arenas. We review commonly used genomic technologies as well as the application of these technologies to the genetic diagnosis of hereditary hearing loss and to the discovery of novel deafness genes.     

SLC26A4基因突变与听力表型的关系

SLC26A4是导致前庭导水管扩大的主要责任基因。该基因突变引起的听力损失多为感音神经性聋,也可为传导性或混合性聋,听力损失程度多为重度或极重度,听力曲线类型主要表现为高频下降型,也可表现为上升型、平坦型、W型及岛型。本文将SLC26A4基因突变与听力表型的关系进行文献综述,可为临床耳聋基因诊断和遗传咨询提供参考。     

Sodium, potassium, chloride and calcium concentrations measured in pigeon perilymph and endolymph

The mouse is the model organism for the study of hearing loss in mammals. In recent years, the identification of five different mutated genes in the mouse (Pax3, Mitf, Myo7a, Pou4f3, and Myo15) has led directly to the identification of mutations in families with either congenital sensorineural deafness or progressive sensorineural hearing loss. Each of these cases is reviewed here. In addition to providing a powerful gateway to the identification of human hearing loss genes, the study of mouse deafness mutants can lead to the discovery of critical components of the auditory system. Given the availability of several mouse mutants that affect possible homologues of other human deafness genes, it is likely that the mouse will play a key role in identifying other human hearing loss genes in the years to come.