Connexin 26 (GJB2) gene-related deafness and speech intelligibility after cochlear implantation.

HYPOTHESIS: Speech intelligibility in children after cochlear implantation may depend on their deafness cause, including connexin 26 (GJB2) gene-related deafness. BACKGROUND: There is significant variability in the degree of intelligibility, or clarity, of children's speech after cochlear implantation. GJB2 gene-related deafness may be a factor, as preliminary data suggest that pathologic changes do not affect the spiral ganglion cells, which are the neural elements stimulated by the implant, thus favoring better results. METHODS: In an observational retrospective cohort study of pediatric cochlear implantees, 38 patients with nonsyndromic deafness of unknown cause and 1 with keratitisichthyosis-deafness syndrome underwent GJB2 mutation analysis using polymerase chain reaction amplification and direct sequencing. The primary outcome measure assessed was Speech Intelligibility Rating score from postoperative Year 1 (n = 39) to Year 5 (n = 17). Educational setting was considered as a secondary outcome measure. Statistical analysis was double-blinded, with patients and assessors of outcome unaware of GJB2 status. RESULTS: Fourteen patients had GJB2-related deafness and 25 had GJB2-unrelated deafness. Comparisons at Year 3 (n = 31) revealed intelligible speech achieved by 9 of 11 with GJB2-related deafness, compared with only 6 of 20 with GJB2-unrelated deafness (p = 0.017). Ordinal logistic regression analysis on Speech Intelligibility Rating scores found statistically significantly better scores in children with GJB2-related deafness (p < 0.05) both before and after adjustment for confounding variables. A larger proportion with GJB2-related deafness also attended mainstream school (p = 0.01). CONCLUSION: In pediatric cochlear implantees, GJB2-related deafness is a predictor of good speech intelligibility.     

Electrocochleography (ecog) in sensorineural deafness.

We examined 340 normal ears and cases of sensorineural deafness with electrocochleography using click stimuli (duration: 0.5 standard deviation of a population; repetition rate: plus or minus 10/sec; N=1 000, alternately positive and negative; analysis time: 31 standard deviation of a population). The latency of N-1 is a function of the sound pressure level and of the age of the subject. The intensity of N-1 (in mu-v) is a function of hearing level and is influenced by the presence of recruitment. The pure-tone audiogram is a function of the ECOG threshold and of the shape of the reaction obtained at maximal stimulation intensity.     

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.     

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive sensorineural deafness

Mutations in the Connexin 26 (Cx26) gene (GJB2) are a common cause of hereditary hearing impairment. We report the identification of a novel point mutation in the Cx26 gene, Leu205Pro(L205P), linked to familial, autosomal recessive sensorineural hearing loss. This missense mutation, causing amino acid leucine at position 205 to be substituted by proline, is located in the highly conserved sequence of the fourth transmembrane domain (TM4) of Cx26. Hearing loss with this mutation occurred in a Georgian Jewish family, was congenital, moderate to profound and nonprogressive. We have shown that the new mutation L205P in Cx26 is strongly associated with congenital NSHL. Multiple-sample screening for this mutation can be easily performed with a mismatch PCR that creates a restriction site.     

Lack of association between inherited thrombophilic risk factors and idiopathic sudden sensorineural hearing loss in Italian patients

OBJECTIVES: We investigated the presence of congenital thrombophilic risk factors in a population of consecutive Italian patients affected by idiopathic sudden sensorineural hearing loss (SSNHL). METHODS: We investigated 48 patients with idiopathic SSNHL for the presence of congenital thrombophilic risk factors. The factor V Leiden G1691A, the prothrombin G20210A allele, and methylenetetrahydrofolate reductase (MTHFR) C677T genotypes were investigated. Allele frequencies and genotype distribution of all factors found in patients were compared to those of 48 healthy subjects of the same ethnic background by Chi2 and odds-ratio analysis. Odds ratios and 95% confidence intervals were calculated for allele and genotype frequencies of all thrombophilia variants. Statistical significance was accepted with a p value of less than .05. We also performed the following blood tests: hemacytometric analysis including platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, erythrocyte sedimentation rate, C-reactive protein, protein S, protein C, antithrombin III, and activated protein C resistance. RESULTS: In our series, we did not find an association between SSNHL and abnormal levels of antithrombin III, protein C, protein S, D-dimer, or fibrinogen; activated protein C resistance; or factor V G1691A, prothrombin G20210A, or MTHFR C677T mutations. CONCLUSIONS: At present, the few studies regarding genetic polymorphisms of congenital thrombophilic factors in SSNHL are not conclusive. According to our data, factor V G1691A, prothrombin G20210A, and MTHFR C677T variants should be not considered risk factors for SSNHL. Further large prospective studies are needed to provide currently lacking information and to improve our knowledge in the field before we recommend the determination of genetic polymorphism in SSNHL as routine practice.     

内耳Connexin缝隙连接的功能与耳聋机理

缝隙连接对于维持正常听觉功能有着重要的作用，编码组成缝隙连接蛋白的Connexin基因突变可引起严重的听力损失．占整个新生儿耳聋病例的70—80％。此类基因病理变化仅发生于耳蜗内，虽听觉毛细胞上并无缝隙连接或Connexin基因表达，但其支持细胞借助于缝隙连接的耦合作用在内耳联结成一个特殊的网络。本文总结了近年来内耳缝隙连接生物物理学特性方面的研究进展，阐述了耳蜗缝隙连接对于听觉功能的重要性；同时也展望了阐明其功能对治疗因Connexin基因突变所致的遗传性耳聋的前景。     

GJB3在携带GJB2单等位基因突变的中国耳聋人群中的突变分析

目的 在GJB2病理性单等位基因突变携带者中进行GJB3基因编码区序列分析,探讨GJB2与GJB3双基因模式遗传致聋的可能性.方法 对从全国24个省市自治区3323例重度-极重度感音神经性耳聋患者中筛查出的108例携带GJB2病理性单等位基因突变的耳聋患者进行GJB3基因编码区全序列测序,分析测得序列,对所发现突变或变异编码氨基酸的物种进化保守性进行分析,结合听力正常对照人群中GJB3基因编码区测序结果,对考虑为携带GJB3突变及GJB2病理性单等位基因突变的耳聋患者进行家系分析.结果 108例携带GJB2病理性单等位基因突变的耳聋患者中共检测到7种GJB3基因变异类型,其中错义突变3种,静止变异4种.5例携带GJB3基因的错义变异(V84I,A194T,N166S),结合对照组检测结果,V84I为中国人群GJB3基因的多态改变,GJB3基因N166S和A194T可能为导致常染色体隐性非综合征性耳聋的的病理性突变.结论 GJB3与GJB2可能以双基因模式遗传导致耳聋,其致病机制还待进一步阐明.     

The novel c.247_249delTTC (p.F83del) GJB2 mutation in a family with prelingual sensorineural deafness

Non-syndromic hearing loss is one of the most common hereditary determined diseases in human, and the disease is a genetically heterogeneous disorder. Mutations in the GJB2 gene, encoding connexin 26 (Cx26), are a major cause of non-syndromic recessive hearing impairment in many countries and are largely dependent on ethnic groups. Due to the high frequency of the c.35delG GJB2 mutation in the Greek population, we have previously suggested that Greek patients with sensorineural, non-syndromic deafness should be tested for the c.35delG mutation and the coding region of the GJB2 gene should be sequenced in c.35delG heterozygotes. Here we present on the clinical and molecular genetic evaluation of a family suffering from prelingual, sensorineural, non-syndromic deafness. A novel c.247_249delTTC (p.F83del) GJB2 mutation was detected in compound heterozygosity with the c.35delG GJB2 mutation in the proband and was later confirmed in the father, while the mother was homozygous for the c.35delG GJB2 mutation. We conclude that compound heterozygosity of the novel c.247_249delTTC (p.F83del) and the c.35delG mutations in the GJB2 gene was the cause of deafness in the proband and his father.     

GJB6基因突变与遗传性耳聋

连接蛋白(connexins,Cxs)组成缝隙连接通道,使相邻细胞离子、代谢物质和分子量小于1～1.5kDa的信使分子直接转运.缝隙连接是细胞间通讯的结构基础,对胚胎发育、形态建成、增殖分化以及细胞群的协调活动具有重要意义.     

Prevalence of the GJB2 mutations and the del(GJB6-D13S1830) mutation in Brazilian patients with deafness

Mutations in the GJB2 gene are the most common cause of sensorineural non-syndromic deafness in different populations. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in many countries. The aim of this study was to determine the prevalence of GJB2 mutations and the del(GJB6-D13S1830) mutation in non-syndromic deaf Brazilians. The 33 unrelated probands were examined by clinical evaluation to exclude syndromic forms of deafness. Mutation analysis in the GJB2 gene and the testing for the del(GJB6-D13S1830) were performed in both the patients and their family members. The 35delG mutation was found in nine of the probands or in 14 of the mutated alleles. The V37I mutation and the del(GJB6-D13S1830) mutation were also found in two patients, both are compound heterozygote with 35delG mutation. These findings strengthen the importance of genetic diagnosis, providing early treatment, and genetic counseling of deaf patients.     

Aetiology of bilateral sensorineural deafness in children

The study was carried out in children born during the four year period 1981-1984 in the Greater Manchester County. The children were investigated for possible congenital infections. Perinatal assessment was carried out for adverse aetiological factors. Family histories were obtained and parents and siblings were examined for any hearing impairment. A total of 164 cases were investigated. Various aetiological groups were formed which showed the following distribution: cause unknown 36.5 per cent; genetic group 20.1 per cent; adverse perinatal factors 14.6 per cent; congenital infections 9.8 per cent; meningitis 6.1 per cent; chromosomal abnormalities 3.7 per cent; syndromal group 3.7 per cent; and miscellaneous 5.5 per cent. The findings are discussed in the light of previous studies.     

中青年突发性聋患者与全身性低血压的相关性研究

目的：综合评估中青年突发性聋（SSHL）患者与全身低血压的关系。方法：选择28例确诊为SSHL未经治疗的中青年（50岁以下）患者为实验组,均行听力学、即时血压、心率、24h动态血压连续监测、脂质代谢参数等检查。同时选择30例年龄、性别相匹配的正常血压非SSHL者为对照组进行同等处理。结果：实验组平均的即时和动态血压（SBP、DBP）都显著低于对照组。两组在心血管疾病高危因子的统计差异不显著。实验组的低血压患病率显著高于对照组。结论：全身性低血压的存在可引起耳蜗微循环的低灌注,而耳蜗缺血很可能是中青年SSHL患者的发病机制之一,尤其是耳蜗末梢顶转的血供会直接影响到低频听力。对此类患者的血压动态监测和限制使用血管扩张药是很有必要的。     

Diagnostic significance of summating potential in sensorineural deafness

The polarity of the summating potential wave induced by electrocochleographical examination has an important bearing upon the pathophysiology or the prognostic evaluation of sensorineural deafness. Electrocochleographical examination was performed on cases of sudden deafness, Ménière's disease, progressive sensorineural deafness, sensorineural deafness due to barotrauma, etc. When the polarity of the summating potential showed an increased negative wave, physiological blockage in sensorineural structures was revealed. In other words, under such conditions sensorineural structures have a potential for activity although hearing acuity was damaged. On the other hand, when the summating potential has an increased positive polarity wave, gradual decrease of the hearing acuity was revealed.     

Screening for monogenetic del(GJB6-D13S1830) and digenic del(GJB6-D13S1830)/GJB2 patterns of inheritance in deaf individuals from Eastern Austria

Genetically caused congenital deafness is a common trait affecting 1 in 2000 newborn children and is predominantly inherited in an autosomal recessive fashion. Genes such as the gap junction protein beta 2 (GJB2) encoding for Connexin (Cx26) and GJB6 (Cx30) are known to cause sensorineural deafness. Autosomal recessive deafness has been linked both to the monogenetic occurrence of mutated GJB2 or the GJB6 deletion del(GJB6-D13S1830) and digenic GJB2/del(GJB6-D13S1830) inheritance. Monogenetic GJB2 alterations are responsible for 25.5% of deafness in the eastern Austrian population. An additional 9.8% are heterozygous carriers of a single GJB2 mutation which is not responsible for deafness alone. Del(GJB6-D13S1830) and GJB2/del(GJB6-D13S1830) mutations have been shown to be the second most frequent cause of deafness in different populations. To address the question of the relevance of mutations in GJB6 either as a monogenetic or a digenic GJB2/del(GJB6-D13S1830) cause of deafness in this population, 76 unrelated individuals (33 families and 43 sporadic cases) were screened using PCR strategies. Similar to studies in other hard of hearing populations with similar or lower carrier frequencies of single GJB2 mutations, the presence of del(GJB6-D13S1830) was not detected in any individual within the patient group. Data therefore exclude a digenetic association of del(GJB6-D13S1830) with heterozygous GJB2 mutations as a cause of deafness in a representative sample of the population from Eastern Austria.