Congenital Profound Sensorineural Hearing Loss Research Articles

A Novel Mutation of POU3F4 Causes Congenital Profound Sensorineural Hearing Loss in a Large Chinese Family

It is known that approximately 5% of congenital profound hearing impaired cases are inherited in X-linked inheritance. This study aimed at identifying its underlying molecular determinant(s) using a large, five-generation Chinese family with multiple familial cases. Model-based linkage analysis and positional cloning. Model-based genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine disease locus. Mutation screening was performed within the family and unrelated population-based controls to establish molecular evidence as to what caused the specific X-linked inheritance pattern in the family. Clinical investigations of the pedigree demonstrated the extremely high penetrance in the male members but no penetrance in the female members. Linkage analyses mapped the disease to the chromosomal region Xq13.I-Xq23 (maximum X-linkage logarithm of odds score = 3.27). Mutation screening of the candidate genes in the linkage region by direct sequencing revealed a de novo missense substitution (925T>C) in the well-known deaf gene. POU3F4. Direct sequencing on 240 unrelated controls did not detect any mutation. Multiple analysis approaches demonstrated that these disorders in the family were caused by a founder mutation in the POU3F4 gene. Our findings provided confirmatory molecular evidence to support that development of congenital profound sensorineural hearing loss in the Chinese population results from a novel mutation in the same gene.

Quantitative Study Of The Vestibular Sensory Epithelium In Cochleosaccular Dysplasia

Cochleosaccular dysplasia is the most common pathologic finding seen in children with profound congenital sensorineural hearing loss. There has been no quantitative study on the peripheral vestibular system in cochleosaccular dysplasia. To investigate quantitatively the extent of pathologic changes of the vestibular sensory epithelium in cochleosaccular dysplasia. Thirteen temporal bones with congenital deafness from 10 individuals were selected for this study from the temporal bone collection of University of Minnesota that showed suitable pathologic findings for the histopathologic criteria of cochleosaccular dysplasia. Age-matched normal control temporal bones were also selected. The vestibular hair cells including types I and II hair cells were counted separately in the saccular macula, utricular macula, and three cristae of the semicircular canals using Nomarski microscopy. The hair cell densities of types I and II hair cells in the macula of the saccule in cochleosaccular dysplasia were significantly decreased compared with the data of normal subjects. Both types I and II hair cells in the utricular macula and the cristae of the three semicircular canals in cochleosaccular dysplasia were well preserved, and no significant difference was observed between findings of cochleosaccular dysplasia and normal controls in the utricle and the three semicircular canals. In cases with cochleosaccular dysplasia, the neurosensorial hair cells of the saccule were affected; however, the osseous labyrinth, the membranous utricle, and the semicircular canals were normal. Further studies should be performed to establish the pathogenesis of cochleosaccular dysplasia in humans.

Refining the DFNB17 interval in consanguineous Indian families.

We previously mapped the DFNB17 locus to a 3-4 cM interval on human chromosome 7q31 in a large consanguineous Indian family with congenital profound sensorineural hearing loss. To further refine this interval, 30 new highly polymorphic markers and 8 SNPs were analyzed against the pedigree. Re-analysis in the original DFNB 17 family and additional data from a second unrelated consanguineous family with congenital deafness found to map to the interval, limited the area of shared homozygosity-by-descent (HBD) to approximately 4 megabase (Mb) between markers D7S2453 and D7S525. Nineteen known genes and over 20 other cDNAs have been identified in the refined DFNB 17 interval, including the SLC26A4 gene. We have analyzed 4 other cochlear-expressed genes that map to the DFNB17 interval as candidate genes. Analysis of coding and splice site regions of these cochlear expressed genes did not reveal any disease causing mutations. Further study of other candidate genes is currently underway.

Clinical and genetic linkage analysis of a large Venezuelan kindred with Usher syndrome

Objective: To undertake a comprehensive investigation into the very high incidence of congenital deafness on the Macano peninsula of Margarita Island, Venezuela. Methods: Numerous visits were made to the isolated island community over a 4-year-period. During these visits, it became apparent that a significant number of individuals complained of problems with hearing and vision. Socioeconomic assessments, family pedigrees and clinical histories were recorded on standard questionnaires. All individuals underwent thorough otolaryngologic and ophthalmologic examinations. Twenty milliliters of peripheral venous blood was obtained from each participant. A Genome-wide linkage analysis study was performed. Polymorphic microsatellite markers were amplified by polymerase chain reaction and separated on polyacrylamide gels. An ABI 377XL sequencer was used to separate fragments and LOD scores were calculated by using published software. Results: Twenty-four families were identified, comprising 329 individuals, age range 1–80 years, including 184 children. All families were categorized in the lower two (least affluent) socioeconomic categories. A high incidence of consanguinity was detected. Fifteen individuals (11 adults, 4 children) had profound congenital sensorineural hearing loss, vestibular areflexia and retinitis pigmentosa. A maximum LOD score of 6.76 (Linkage >3.0), between markers D11s4186 and D11s911, confirmed linkage to chromosome 11q13.5. The gene myosin VIIA ( MYO7A) was confirmed in the interval. Clinical and genetic findings are consistent with a diagnosis of Usher syndrome 1B for those with hearing and vision problems. Conclusions: We report 15 Usher syndrome 1B individuals from a newly detected Latin American socio-demographic origin, with a very high prevalence of 76 per 100,000 population.

Refinement of the locus for non-syndromic sensorineural deafness (DFN2).

Non-syndromic X-linked deafness is a rare form of genetic deafness in humans accounting for a small proportion of all hereditary hearing loss. Different clinical forms of non-syndromic X-linked deafness have been described, and most of these have been mapped. Here, we report a Chinese family affected by a congenital profound sensorineural hearing loss. All phenotypes of this family are clinically compatible with non-syndromic sensorineural deafness (DFN2). A maximum two-point Lod score of 2.32 was obtained at marker DXS6797 (theta = 0.00). Recombinants define a region of 4.3 cM flanked by markers DXS6799 and GATA172D05. This region overlaps the previously reported DFN2 region by 2.0 cM.

Cochlear implant in Jervell and Lange‐Nielsen syndrome

The Jervell and Lange‐Nielsen syndrome is one of the best known and most extensively studied deafness syndromes inherited as an autosomal recessive trait. Its hallmarks are congenital profound bilateral sensorineural hearing loss associated with electrocardiograph anomalies. In this case study we report on a child affected with the Jervell and Lange‐Nielsen syndrome and suffering from congenital profound bilateral sensorineural hearing loss who had a cochlear implantation at age three. No surgical or cardiological complications were encountered and excellent post‐operative functional hearing and communicative outcomes were achieved. It is concluded that cochlear implantation could be safely performed in these patients, with the achievement of a very good outcome in functional hearing and communication.

Vestibular-Evoked Myogenic Potentials as a Test of Otolith Function

Objectives: To evaluate the use of 75 auditory clicks rather than the usual 100–256 for production of the vestibular-evoked myogenic potential (VEMP) response and to assess if the VEMP correlates with measures of cochlear function such as hearing loss (decibels on pure-tone testing) or auditory brainstem response (ABR). Subjects and Methods: Testing of the VEMP was carried out on 24 subjects: 7 normal individuals and 13 hard-of-hearing patients, 2 patients with known vestibular lesions, 1 with profound sensorineural hearing loss and 1 patient with unilateral acoustic neuroma prior to resection. The recording was performed using a conventional ABR machine. Using 75 refraction clicks as auditory stimuli, VEMP responses were measured from a surface electrode applied to the sternocleidomastoid muscle. The 75 responses were averaged. Results: A consistent unilateral biphasic response, the first negative and the second positive (nI, pII), was elicited from 39 of 40 ears (7 normal and 13 hard-of-hearing subjects with no known vestibular dysfunction). No statistical difference was found between the right and left ear responses for nI or pII wave latencies. Two patients with loss of peripheral vestibular function showed no VEMP responses on the affected side. The responses, however, were elicited bilaterally in a patient with congenital profound sensorineural hearing loss. In addition, ABR latencies did not correlate with VEMP latencies. Conclusion: Clear VEMP responses were elicited by using only 75 auditory clicks. This shortens the testing time and facilitates the procedure for the tested subject. Our data also indicate that the VEMP is generated secondary to auditory stimulation of the vestibular end organs (specifically the saccule) and does not correlate with cochlear function.

Vestibular Evoked Myogenic Potentials: Preliminary Report

Vestibular evoked myogenic potentials (VEMPs) are short-latency electromyograms evoked by high-level acoustic stimuli recorded from surface electrodes over the tonically contracted sternocleidomastoid (SCM) muscle. These responses are presumed to originate in the saccule. The purpose of this preliminary report is to provide an overview of our initial experience with the VEMP by describing the responses obtained in five subjects. Click-evoked VEMPs were present at short latencies in two normal-hearing subjects, one patient with profound congenital sensorineural hearing loss, and one patient with a severe sensorineural hearing loss due to Meniere's disease. Additionally, VEMPs were absent in a patient with profound sensorineural hearing loss following removal of a cerebellopontine angle tumor. The amplitude of the VEMP was influenced by the amount of background activity of the SCM muscle, stimulus level, and stimulus frequency. Tone-burst evoked responses showed an inverse relationship between stimulus frequency and response latency. VEMPs may prove to be a reliable technique in the clinical assessment of vestibular function.

Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity.

Usher syndrome is a heterogeneous autosomal recessive trait and the most common cause of hereditary deaf-blindness. Usher syndrome type I (USH1) is characterised by profound congenital sensorineural hearing loss, vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. Of the at least six different loci for USH1, USH1B maps on chromosome 11q13, and the MYO7A gene has been shown to be defective in USH1B. MYO7A encodes myosin VIIA, an unconventional myosin, and it consists of 48 coding exons. In this study, MYO7A was analysed in 34 unrelated Usher type I patients by single-strand conformation polymorphism analysis and direct sequencing. We identified a total of 12 novel and unique mutations, all single base changes. In addition, we found a previously reported nonsense mutation (C31X) on nine alleles of a total of six patients from Denmark.

Mapping of DFN2 to Xq22.

Non-syndromic X-linked deafness is a rare form of genetic deafness accounting for a small proportion of all hereditary hearing loss. It is both clinically and genetically heterogeneous and five loci have been described to date but only two of these have been mapped. DFN2 represents a locus for congenital profound sensorineural hearing loss that has yet to be mapped. We describe a four generation family with this phenotype in which female carriers have a mild/moderate hearing loss affecting the high frequencies. The mutant gene has been mapped to Xq22 using polymorphic microsatellite markers. A maximum two point lod score of 2.91 at theta = 0 was observed with a fully informative dinucleotide repeat at COL4A5, and flanking recombinations were observed at DXS990 and DXS1001.

Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22.

We report here, the localization of a new recessive non-syndromal deafness gene (DFNB12) to 10q21-22 by linkage analysis, of a Sunni family. Affected individuals suffer from congenital profound sensorineural hearing loss. A maximum LOD score of 6.40 (theta = 0.00) was obtained with locus D10S535. Analysis of patients carrying recombinations mapped the gene distal to D10S529 and proximal to D10S532, delineating an interval between 11 and 15 cM. Three deaf mouse mutants Jackson circler (jc), Waltzer (v) and Ames waltzer (av) have been localized to the homologous murine region on chromosome 10. Each of these mouse mutants is a candidate mouse model for the DFNB12-associated hearing impairment.

Defective myosin VIIA gene responsible for Usher syndrome type 1B.

Usher syndrome represents the association of a hearing impairment with retinitis pigmentosa and is the most frequent cause of deaf-blindness in humans. It is inherited as an autosomal recessive trait which is clinically and genetically heterogeneous. Some patients show abnormal organization of microtubules in the axoneme of their photoreceptors cells (connecting cilium), nasal ciliar cells and sperm cells, as well as widespread degeneration of the organ of Corti. Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Of three different genes responsible for USH1. USH1B maps to 11q13.5 (ref. 10) and accounts for about 75% of USH1 patients. The mouse deafness shaker-1 (sh1) mutation has been localized to the homologous murine region. Taking into account the cytoskeletal abnormalities in USH patients, the identification of a gene encoding an unconventional myosin as a candidate for shaker-1 (ref. 14) led us to consider the human homologue as a good candidate for the gene that is defective in USH1B. Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B. Two different premature stop codons, a six-base-pair deletion and two different missense mutations were detected in five unrelated families. In one of these families, the mutations were identified in both alleles. These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein. Thus USH1B appears as a primary cytoskeletal protein defect. These results implicate the genes encoding other unconventional myosins and their interacting proteins as candidates for other genetic forms of Usher syndrome.