Cause Of Congenital Deafness Research Articles

Preservation of developmental spontaneous activity enables early auditory system maturation in deaf mice.

Intrinsically generated neural activity propagates through the developing auditory system to promote maturation and refinement of sound processing circuits prior to hearing onset. This early patterned activity is induced by non-sensory supporting cells in the organ of Corti, which are highly interconnected through gap junctions containing connexin 26 (Gjb2). Although loss of function mutations in Gjb2 impair cochlear development and are the most common cause of congenital deafness, it is not known if these variants disrupt spontaneous activity and the developmental trajectory of sound processing circuits in the brain. Here, we show in a new mouse model of Gjb2-mediated congenital deafness that cochlear supporting cells adjacent to inner hair cells (IHCs) unexpectedly retain intercellular coupling and the capacity to generate spontaneous activity, exhibiting only modest deficits prior to hearing onset. Supporting cells lacking Gjb2 elicited coordinated activation of IHCs, leading to coincident bursts of activity in central auditory neurons that will later process similar frequencies of sound. Despite alterations in the structure of the sensory epithelium, hair cells within the cochlea of Gjb2-deficient mice were intact and central auditory neurons could be activated within appropriate tonotopic domains by loud sounds at hearing onset, indicating that early maturation and refinement of auditory circuits was preserved. Only after cessation of spontaneous activity following hearing onset did progressive hair cell degeneration and enhanced auditory neuron excitability manifest. This preservation of cochlear spontaneous neural activity in the absence of connexin 26 may increase the effectiveness of early therapeutic interventions to restore hearing.

Способ кохлеарной имплантации у пациентов с цитомегаловирусной инфекцией

At the present stage of medical development, cochlear implantation is the optimal method of auditory and speech rehabilitation for patients with binaural deafness. Congenital cytomegalovirus infection, according to Russian and international scientific literature, is one of the two most common causes of congenital deafness. At the same time, its relevance in cochlear implantation is due not only to its high incidence among patients, but also to the influence on surgical procedure and the final results of hearing and speech rehabilitation. The surgery stage of cochlear implantation in patients with cytomegalovirus infection, due to a number of circumstances, requires individual technical procedure. The most significant thing in this context is the phenomenon of frequent preservation of natural hearing residues at low frequencies, requiring careful and accurate preservation. Moreover, due to the pathogenetic effect of an infectious agent, such patients have a high risk of intraoperative bleeding. Therefore, the most important goal is to prevent the penetration of blood cells into the lumen of the cochlear spiral canal in order to prevent damage to the cochlear sensory structures. However, to date, all the proposed methods of performing surgery in such patients have a number of limitations and do not in all cases meet all the requirements of efficacy and safety. In this regard, on the basis of the St. Petersburg Research Institute of Ear, Throat, Nose and Speech, an original surgical technique was developed for cochlear implantation in patients with cytomegalovirus infection. This technique most significantly meets the requirements of hearing-safe surgical techniques when performing cochlear implantation.

Goiter and Sensorineural Hearing Loss: Pendred Syndrome Should Be Suspected: A Case Report

BACKGROUND: Pendred syndrome (PS) is an autosomal recessive disorder, caused by biallelic mutations in the SLC26A4 gene which codes for the pendrin protein. It is characterized by sensorineural hearing loss associated with dyshormonogenic goiter. Which is a common cause of congenital deafness. CASE PRESENTATION: Hereby we describe a case of a 21- year-old women who presented to the ORL department with an anterior cervical mass that gradually increased in volume over 3 years associated with severe hearing loss since birth for which the patient was provided with hearing aids. Pendred syndrome is suspected because of the present of goiter and congenital hearing loss. CONCLUSIONS: Clinical presentation is very variable. However, the association of goiter and progressive deafness suggests the diagnosis of Pendred syndrome.

Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children.

The p.V37I (c.109G>A) mutation in the GJB2 gene is the common frequent cause of congenital deafness; however, its pathogenicity is debated. The present study investigated the prevalence of p.V37I in Chinese infants and young children and associated clinical characteristics. The subjects of the present study were screened for mutations in GJB2 (235delC, 299delAT, 176dell6, 35delG), SLC26A4 (IVS7-2A>G, 2168A>G), GJB3 (538C>T), and in the mitochondrial 12S rRNA gene (1555A>G, 1494C>T). Subjects with p.V37I underwent an audiological evaluation. GJB2 exon sequencing revealed that 20 subjects had p.V37I compound heterozygous mutations, one of whom had a family history; the mutations included c.235delC/p.V37I (n = 12), c.299AT/p.V37I (n = 7), and c.176del16/p.V37I (n = 1). Of the 20 subjects, 12 were referred for Universal Newborn Hearing Screening (UNHS). Nine of the 20 subjects had mild hearing loss in the better ear and 5 had moderate hearing loss in the better ear while 4 had normal hearing. Among subjects with the c.235delC/p.V37I mutation, 5 had mild hearing loss and 2 had moderate hearing loss while 3 had normal hearing. Among subjects with the c.299AT/p.V37I mutation, 3 had mld hearing loss and 3 had moderate hearing loss while 1 had normal hearing. One subject with the c.176del16/p.V37I mutation had mild hearing loss. Few studies have reported on the clinical characteristics of Chinese infants with p.V37I compound heterozygous mutations identified via screening for deafness genes and GJB2 sequencing. The c.235delC/p.V37I mutation was the most prevalent mutation found in subjects. The degree of hearing loss associated with p.V37I compound heterozygous mutations was mainly mild to moderate.

ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi Arabian population

Hearing impairment is the common human sensorineural disorder and is a genetically heterogeneous phenotype for which more than 100 genomic loci have been mapped so far. ILDR1 located on chromosome 3q13.33, encodes a putative transmembrane receptor containing an immunoglobulin-like domain. We used a combination of autozygosity mapping and candidate gene sequencing to identify a novel mutation in ILDR1, as a causative gene for autosomal-recessive non-syndromic hearing loss (arNSHL) in a consanguineous Saudi family with three affected children. Autozygosity mapping identified a shared region between the affected individuals encompassing ILDR1 on chromosome 3q13.12-3q22.1. Sequencing revealed homozygous 9 base pair duplication, resulting in an in-frame duplication of three amino acids p.(Asn109_Pro111dup). The mutation was segregating with the disease phenotype and is predicted to be pathogenic by SIFT and PROVEAN. The identified mutation is located in the immunoglobulin-type domain of the ILDR1 protein. In silico analysis using I-TASSER server and PyMOL offers the first predictions on the structural and functional consequences of this mutation. To our knowledge, this is the first ILDR1 mutation identified in a Saudi family. Identification of ILDR1 mutation in only one of 100 Saudi familial and sporadic individuals with hearing loss suggests that this mutation is unique to this family and that ILDR1 should be considered as a rare cause of congenital deafness among Saudi Arabian population. Our data also confirms the evidence for ILDR1 allelic heterogeneity and expands the number of familial arNSHL-associated ILDR1 gene mutations.

Outcomes of cochlear implantation in children with CHARGE syndrome

Conclusion: Regardless of the extent of inner ear anomalies and intellectual faculties, cochlear implantation (CI) with careful treatment planning can be a highly effective option for hearing rehabilitation in children with sensorineural hearing loss and CHARGE syndrome. Objective: CHARGE is a mnemonic term for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. CHARGE syndrome is one of the leading causes of congenital deafness and blindness in children. We evaluated the language performance of six pediatric patients with CHARGE syndrome. Methods: Six patients with CHARGE syndrome underwent CI at the Asan Medical Center in Seoul between 2002 and 2012. The mean age of these CI patients was 4.9 years (range 2–9.8 years). All six patients had inner ear malformations; five children had an auricle anomaly and otitis media with effusion; three of these cases showed ossicle anomalies and four patients had downward displacement of the facial nerve (FN) toward the promontory; five patients showed delayed development; four of these children had cardiovascular malformations; three patients had cryptorchidism; two had choanal atresia; and there was one case of coloboma. Results: In the initial operations, two patients each were implanted with a CI512, CI24R, or CI24RE device. One patient initially received a CI512 device in the right ear, followed by a CI24RE device in the left ear. Another patient (case 1) first received a CI24R and then CI24RST device in the right ear due to poor performance, but this was eventually removed due to exposure of the electrode from adhesive otitis media and continuing poor performance. Assessment of the meaningful auditory integration scale (MAIS) showed that four patients reached a score above 95% and one patient achieved 60%. The categories of auditory performance (CAP) score showed that one patient reached CAP 7 at 2 years postoperatively and two cases showed CAP 5.5 at 1 year after implantation, while the remaining two patients had CAP scores of 3 at 12 months and 4.5 at 4 years, respectively. The speech intelligibility rating (SIR) score at 18 months post-surgery was 4.5 in two patients, 2.5 in two patients, and 1.5 in one case. The remaining patient (case 1) who was explanted showed no meaningful speech improvement.

Impact of human papillomavirus vaccination depends on effective vaccination strategy

Impact of human papillomavirus vaccination depends on effective vaccination strategy

Comparison of MRI findings with traditional criteria in diagnosis of Pendred syndrome

Pendred syndrome, defined as the constellation of goiter, sensori-neural hearing loss, and positive perchlorate discharge test, is the most frequent cause of congenital deafness. Newly introduced diagnostic approaches to the disease are rather expensive and complicated, therefore we evaluated the value of MRI as the sole, or adjunctive diagnostic approach, and compared it with the traditional ones. Presuming the classic triad as the gold standard, we compared MRI findings in six such defined patients with six cases having goiter, hearing loss, and normal perchlorate discharge test. Our results indicated that MRI was 83.6% sensitive and 66.7% specific in patients fulfilling all three criteria (complete), while in the ‘partial’ group the sensitivity and specificity were 66.7% and 100% respectively. In conclusion, MRI, although impressive as an adjunctive diagnostic tool, may not replace the holistic approach, and the latter may be more convenient, cheaper, and still more accurate. However in ‘partial’ cases with equivocal findings, and in relatives of the patients, MRI may be a valuable diagnostic adjunct.

Frequency of the 35delG mutation in the GJB2 gene in samples of European, Asian, and African Brazilians.

Mutations in the GJB2 gene are a major cause of congenital deafness. One specific mutation, the 35delG mutation, has accounted for most of the GJB2 mutations detected in European populations and is one of the most frequent disease mutations identified so far. We evaluated the frequency of the 35delG mutation in DNA samples from Brazilians of European, Asian, and African ancestry. All DNA samples were screened for the 35delG mutation using an allele-specific PCR. This study shows that the frequency of a common mutation (35delG) is significantly lower in non-European populations.

Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome.

Pendred syndrome is a major cause of congenital deafness, goiter and defective iodide organification. Mutations in the transmembrane protein, pendrin, cause diminished export of iodide from thyroid follicular cells to the colloid and are associated with the syndrome. We used green fluorescent protein (GFP) chimeras of wild-type (WT) pendrin and three common natural mutants (L236P, T416P and G384) to study their intracellular trafficking in living cells. Time-lapse imaging, dual color labeling and fluorescent recovery after photobleaching (FRAP) studies demonstrated that GFP-WT pendrin targets to the plasma membrane. In contrast, all three mutant pendrins were retained in the endoplasmic reticulum (ER) in co-localization studies with ER and Golgi markers. The ER retention of L236P appeared to be selective as this mutant did not prevent a viral membrane protein, VSVGtsO45 or wild-type pendrin from targeting the plasma membrane. These findings suggest that ER retention and defective plasma membrane targeting of pendrin mutants play a key role in the pathogenesis of Pendred syndrome.

Performance of cochlear implant recipients with GJB2-related deafness.

Congenital profound hearing loss affects 0.05-0.1% of children and has many causes, some of which are associated with cognitive delay. For prelingually-deafened cochlear implant recipients, the etiology of deafness is usually unknown. Mutations in GJB2 have been established as the most common cause of heritable deafness in the United States. In this report, we identify cochlear implant recipients with GJB2-related deafness and examine the performance of these individuals. Cochlear implant recipients received a battery of perceptive, cognitive, and reading tests. Neither subjects nor examiners knew the etiology of deafness in these individuals. The implant recipients were then examined for mutations in GJB2 using an allele-specific polymerase chain reaction assay, single-strand conformation polymorphism analysis, and direct sequencing. GJB2 mutations were the leading cause of congenital deafness among the cochlear implant recipients screened. Cochlear implant recipients with GJB2-related deafness read within one standard deviation of hearing controls better than other congenitally deaf cochlear implant recipients and non-cochlear implant recipients. Individuals with congenital deafness should be offered GJB2 screening. Positive results establish an etiologic diagnosis and provide prognostic, genetic, and therapeutic information. Effective rehabilitation for profoundly deaf individuals with GJB2-related deafness is possible through cochlear implantation.

Pendrin does not increase sulfate uptake in mammalian COS-7 cells.

Pendred's syndrome is characterized by goiter, sensorineural deafness and impaired iodide organification. It is one of the most frequent causes of congenital deafness accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, which was postulated to be a sulfate transporter, because of its homology with other genes. We tested sulfate transport in mammalian COS-7 cells that were transiently transfected with PDS cDNA. 35SO4 uptake increased in a time-dependent manner, but this phenomenon was similar in cells transfected with PDS and in mock-transfected cells (450 and 360 cpm/beta-gal units at 10 min, respectively; 38,250 and 31,000 cpm/beta-gal units, at 12 h, respectively). There was no significant increase in 35SO4 uptake using increasing amounts of PDS-containing plasmid (up to 12 microg per dish). These data indicate that pendrin is not a sulfate transporter. Additional functional studies on this protein are warranted to clarify its role in thyroid pathophysiology and inner ear development.

A novel mutation in the pendrin gene associated with Pendred's syndrome.

Pendred's syndrome is an autosomal recessive disorder characterized by goitre, sensorineural deafness and iodide organification defect. It is one of the most frequent causes of congenital deafness, accounting for about 10% of hereditary hearing loss. It is caused by mutations in the pendrin (PDS) gene, a 21 exon gene located on chromosome 7. The aim of this study was to examine an Italian family affected with Pendred's syndrome at the molecular level. Thirteen subjects belonging to a family from Southern Italy were evaluated for the clinical and genetic features of Pendred's syndrome. Exons 2-21 of the PDS gene were amplified from peripheral leucocytes by the polymerase chain reaction; mutation analysis was performed by single strand conformation polymorphism, direct sequencing and restriction analysis. The index patient had the classical triad of the syndrome and harboured two mutations in the PDS gene in the form of compound heterozygosity. He was found to be heterozygous for a cytosine to adenosine mutation at nucleotide 1523 in exon 13 and for a IVS 1001 + 1G --> A mutation. The former is a novel mutation which results in a change of 508 threonine to asparagine in the putative eleventh transmembrane domain. The latter mutation in the donor splice site has already been described in other patients and is thought to lead to aberrant splicing and premature protein truncation. Three subjects who were heterozygous for one mutation had normal phenotypes. Two subjects had sensorineural deafness and were heterozygous for a single mutation. Goitre was found only in patients with Pendred's syndrome and was absent in all other individuals, albeit residing in an iodine-deficient area. We have identified a novel mutation in the pendrin gene causing Pendred's syndrome, and confirm that molecular analysis is a useful tool for a definitive diagnosis. This is particularly relevant in cases such as in the subjects of our family in which the clinical features might be misleading and other genetics factors might be responsible for deafness.

Concepts and management of deafness in the Yoruba medical system: A case study of traditional healers in Ile-Ife, Nigeria

This paper examines the concept and management of deafness among 98 randomly selected healers in Ile-Ife. We are concerned with deafness because in an earlier study mothers of deaf children reported that they had consulted these practitioners. All of the healers distinguished congenital and non-congenital deafness, and in their efforts to cure patients they were guided by experience and specialist knowledge. A higher proportion of the herbalists associated congenital deafness with natural causes than did the other type of healers. The babalawos and indigenous faith healers who mentioned a natural cause of congenital deafness believed that the primary causative agents were supernatural. Half of the indigenous faith healers and more than half of the babalawos we interviewed attributed non-congenital deafness to malevolent forces, while only 12.5% of the herbalists made this attribution. Treatment procedures and preventive techniques were based on conceptions of causality. While the majority of the herbalists prescribed a herbal ear drop, a majority of the babalawos and the indigenous faith healers prescribed sacrifices to appease the aggrieved parties. Some interesting points that emanated from the study include the healers' explanation that a person's essence is transmitted to his personal effects, which are used with incantation to inflict the deaf person. Closely associated with this is the healers' warning that patients need to maintain good-neighbourliness to avoid further harm. The paper further highlights the adherence to pregnancy taboos to avoid congenital deafness.

CYTOMEGALOVIRUS (CMV) INFECTIONS: INFANT DEVELOPMENT VS. DAY CARE CENTERS

CMV causes congenital infection in 0.5-2% of births and may be the leading cause of congenital deafness in the U.S. Personnel in centers for developmentally delayed infants and toddlers are concerned that admission of children known to have CMV may increase the transmission of CMV to pregnant staff and the risk of subsequent congenital infection. Despite lack of data to warrant this assumption, children are denied services because they shed CMV. We studied CMV shedding in urine and saliva in children 0-3 yrs. in day care (DCC) and infant development centers (IDC) and the CMV immunity of the staff (58 staff in 6 DCC and 72 staff in 10 IDC). 59% of DCC and 42% of IDC staff were seropositive. Among staff, seropositivity did not differ by center type, age, or socioeconomic status (SES). There was no positive correlation between seropositivity and length of employment. Among 100 children in 4 DCC and 62 children in 7 IDC, 21% and 22% respectively had CMV urinary shedding. There were no significant differences by age, center type, ambulatory status, or center SES. Thus, CMV urinary shedding is common in these settings. Since 48% of the staff under 35 are seronegative, rates of shedding among the children are of concern. Seroconversion rates among staff working with young children need to be established and more learned about transmission of CMV. Nevertheless, we found no difference between DCC and IDC; thus, staff in IDC are no more likely to have acquired CMV than DCC staff, and there is no indication for excluding known CMV shedders from IDC.

Review of Environmental Factors Affecting Hearing

The major nongenetic causes of sensorineural hearing loss are exposure to noise, aging, ototoxic drugs, viral and bacterial infections, and interactions between these factors. Regarding exposure to continuous noise, the data base from laboratory and field studies indicates that a risk of hearing loss is present when noise levels exceed 75-80 dBA. As noise level, duration and number of exposures increase so does risk. The data base for other forms of noise (intermittent, impact) is not as established. Risk of hearing loss due to impulse noise increases as the peak SPL exceeds 145-155 dB and as the duration of the impulse, the number of impulses and the number of exposures increase. High-level acoustic impulses can cause severe, permanent hearing loss. Interaction between some steady-state noises and some acoustic impulses can be synergistic, producing extensive injuries to the organ of Corti. Noise can also interact synergistically with some aminoglycoside antibiotics to produce severe injuries in the inner ear. These antibiotics are also capable of producing hearing loss and indeed may do so in up to 55% of the one million persons who receive aminoglycoside antibiotics during the course of treatment for tuberculosis or severe gram-negative infections. Bacterial and viral infections may also produce mild to severe hearing loss. With the development of rubella vaccine and Rhogam, cytomegalovirus may have become the most common cause of congenital deafness. Aging is also a major cause of hearing loss. Exposure to occupational and environmental noise, certain diseases and life styles (diet, stress, drugs) may interact with the specific effects of aging. The result is moderate to severe hearing loss in a majority of older persons.

Review of environmental factors affecting hearing.

The major nongenetic causes of sensorineural hearing loss are exposure to noise, aging, ototoxic drugs, viral and bacterial infections, and interactions between these factors. Regarding exposure to continuous noise, the data base from laboratory and field studies indicates that a risk of hearing loss is present when noise levels exceed 75-80 dBA. As noise level, duration and number of exposures increase so does risk. The data base for other forms of noise (intermittent, impact) is not as established. Risk of hearing loss due to impulse noise increases as the peak SPL exceeds 145-155 dB and as the duration of the impulse, the number of impulses and the number of exposures increase. High-level acoustic impulses can cause severe, permanent hearing loss. Interaction between some steady-state noises and some acoustic impulses can be synergistic, producing extensive injuries to the organ of Corti. Noise can also interact synergistically with some aminoglycoside antibiotics to produce severe injuries in the inner ear. These antibiotics are also capable of producing hearing loss and indeed may do so in up to 55% of the one million persons who receive aminoglycoside antibiotics during the course of treatment for tuberculosis or severe gram-negative infections. Bacterial and viral infections may also produce mild to severe hearing loss. With the development of rubella vaccine and Rhogam, cytomegalovirus may have become the most common cause of congenital deafness. Aging is also a major cause of hearing loss. Exposure to occupational and environmental noise, certain diseases and life styles (diet, stress, drugs) may interact with the specific effects of aging. The result is moderate to severe hearing loss in a majority of older persons.

Causes of Congenital Deafness

Summary 677 cases of congenital deafness were analysed in order to find out the proportion of various causes of congenital deafness. Criteria for diagnosing deafness as congenital are discussed and the sample for the study was selected according to this criteria. The results showed that 36% of congenital deafness was of genetic origin. In 30·5% the cause was unknown. In 13·4% the cause was neonatal anoxia and in 12·2% haemolytic disease of the newborn and 5·9% rubella. In cases of children examined in 1964, 1965 and 1966, the proportion of maternal rubella cases was 33·7%. It is thought that although a considerable proportion within the “unknown” group is probably of genetic origin in a large number of cases, within this group deafness was caused by so far completely unsuspected aetiological influences.

Causes of congenital deafness

677 cases of congenital deafness were analysed in order to find out the proportion of various causes of congenital deafness. Criteria for diagnosing deafness as congenital are discussed and the sample for the study was selected according to this criteria. The results showed that 36% of congenital deafness was of genetic origin. In 30·5% the cause was unknown. In 13·4% the cause was neonatal anoxia and in 12·2% haemolytic disease of the newborn and 5·9% rubella. In cases of children examined in 1964, 1965 and 1966, the proportion of maternal rubella cases was 33·7%. It is thought that although a considerable proportion within the “unknown” group is probably of genetic origin in a large number of cases, within this group deafness was caused by so far completely unsuspected aetiological influences.

RUBELLA AS A CAUSE OF CONGENITAL DEAFNESS IN ENGLAND

RUBELLA AS A CAUSE OF CONGENITAL DEAFNESS IN ENGLAND