Involvement of T-cell receptor-beta alterations in the development of otosclerosis linked to OTSC2.

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-beta (TCR-beta) mRNA expression and percentage of blood circulating TCR-alphabeta(+) T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28(null) cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

Transient depression of inner ear function after stapedotomy: skeeter versus CO(2) laser technique.

Performing stapes surgery for otosclerosis is known to be potentially irreversibly harmful to the inner ear function in about 1% of the cases. An early postoperative transient depression of the bone conduction thresholds is frequently detected after stapes surgery. The purpose of this study was to compare the evolution of bone conduction thresholds after primary stapedotomy with two different techniques: skeeter versus CO(2) laser stapedotomy. Audiological data of 336 otosclerosis operations performed by 2 surgeons between 1997 and 2003 were subjected to analysis. The calibrated hole in the footplate was performed randomly either with the skeeter drill or with the CO(2) laser. Preoperative bone conduction thresholds were compared with the postoperative levels (day 2-3, week 2, week 6 and month 6) in all patients. Evolution of the bone conduction was compared for the two studied subgroups (laser versus skeeter).

Allograft tympanoplasty.

Tympano-ossicular allografts are human transplants of the tympanic membrane alone or with the ossicles included. The authors review its use in their department since the introduction of the technique 40 years ago by J. Marquet. The advantages of the technique (near normal anatomical and physiological reconstruction) are discussed, as well as its disadvantages (time consuming harvesting, risk of disease transmission). Some technical modifications for specific indications have been adapted in our department and are described in detail. The authors believe that the tympano-ossicular allograft is the material of choice in extensively diseased middle ears destroyed by chronic otitis media with or without cholesteatoma.

Results of 100 vestibular schwannoma operations.

Between 1991 and 2000, 154 cerebello-pontine angle (CPA) tumors were seen at the University ENT-department of the Sint-Augustinus Hospital, Antwerp. Amongst these, 127 were vestibular schwannomas detected by MR-imaging. Noteworthy is that in 5% of these, the ABR latencies were within normal limits. One hundred patients underwent tumor removal either by the translabyrinthine (66) or by the retrosigmoid (34) approach and all had a follow-up of at least two years. For large tumors (> 2 cm extension in the CPA) or in the case of poor hearing the translabyrinthine approach was used. For patients with tumor extension in the CPA ofless than 2 cm and with serviceable residual hearing on the affected side, (at least < 50 dB PTA, > 50% SSD) the retrosigmoid approach with endoscopic control was used. Most patients (96%) had a House-Brackmann grade 1 or 2 facial function before surgery. Although this group dropped to 76% 6 months after surgery it increased again to reach 84% within 2 years. Thus, 88% percent of patients with normal preoperative facial function achieved a Grade I or II after two years. The facial outcome is very much dependent on the size of the tumor. A good result (House-Brackmann Grade 1 or 2) is the rule (92%) for small tumors (< 10 mm extension in the CPA), still attainable (82%) for medium tumors (11-25 mm), but less apparent (56%) for large tumors (> 26 mm). It was possible to preserve hearing in 38% of the retrosigmoid interventions. Although unbalance and headache are rather frequent early postoperative symptoms (respectively 52% and 31%), these complaints decrease with time and are infrequent after two years (unbalance = 7%, headache = 4%). Our results were compared with three large multicentric studies. They are in line with data from the literature and compare favorably with the better results. Although good grading systems exist for facial nerve and hearing outcomes, the authors regret that a general consensus on tumor size measurement is still not yet available. It would facilitate data comparison between different centers and the choice between the therapeutical modalities.

Otosclerosis: a genetically heterogeneous disease involving at least three different genes.

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.

A second gene for otosclerosis, OTSC2, maps to chromosome 7q34-36.

Otosclerosis due to abnormal bone homeostasis of the otic capsule is a frequent cause of hearing loss in adults. Usually, the hearing loss is conductive, resulting from fixation of the stapedial footplate, which prevents normal ossicular vibration in response to sound. An additional type of sensorineural hearing loss may be caused by otosclerotic damage to the cochlea. The etiology of the disease is unknown, and both environmental and genetic factors have been implicated. Autosomal dominant inheritance with reduced penetrance has been proposed, but large families are extremely rare. To elucidate the pathogenesis of the disease, identification of the responsible genes is essential. In this study, we completed linkage analysis in a Belgian family in which otosclerosis segregates as an autosomal dominant disease. After excluding linkage to a known locus on chromosome 15 (OTSC1), we found linkage on chromosome 7q, with a multipoint LOD score of 3.54. Analysis of key recombinant individuals maps this otosclerosis locus (OTSC2) to a 16-cM interval on chromosome 7q34-36 between markers D7S495 and D7S2426.

Refined localization and two additional linked families for the DFNA10 locus for nonsyndromic hearing impairment.

DFNA10 originally was mapped to the long arm of chromosome 6 in a large American family segregating for autosomal dominant progressive nonsyndromic hearing impairment. By extending this American family, we have reduced the original DFNA10 candidate region from 13 cM to 3.7 cM. We also report a Belgian family with autosomal dominant nonsyndromic hearing impairment linked to DFNA10 and a Norwegian family with the same condition in which linkage is suggestive, although maximum lod scores are only 2.5. The hearing phenotype in all three DFNA10 families is similar, with losses beginning in the middle frequencies and involving the low and high frequencies later in life.

Audiometric analysis of a Belgian family linked to the DFNA10 locus.

OBJECTIVE: To report the otologic and audiometric characteristics of a nonsyndromic postlingual sensorineural hearing impairment in a Belgian family linked to DFNA10. STUDY DESIGN: Retrospective study of the otologic and audiometric data of 17 genetically affected persons. SETTING: Tertiary referral center. PATIENTS: All members of a Belgian kindred who carried the haplotype linked to the inherited hearing impairment of DFNA10. INTERVENTIONS: Diagnostic otologic and audiometric analysis. MAIN OUTCOME MEASURES: Pure-tone audiometry. RESULTS: To find the frequencies that were most affected by the genetic defect, the excess hearing loss of the 17 patients was calculated per frequency in comparison with the respective p50 and p95 thresholds of the normal population. CONCLUSIONS: The genetically affected persons of a Belgian family shared a progressive symmetric sensorineural hearing loss that started in the first to fourth decade. Thirty-five percent of the affected family members had tinnitus, and only one patient had very mild vestibular complaints. At onset, hearing losses were mainly situated at the midfrequencies. With increasing age, all frequencies became affected. The hearing loss was initially mild, with a spontaneous evolution to a moderate or severe hearing impairment. The progression of the hearing loss for the pure-tone average (between 0.5 and 4 kHz) was 1.08 dB/year for this family, compared with 0.50 dB/year and 0.35 dB/year at the 95th and 50th percentiles of the normal population, respectively.

Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.

We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.

Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene.

We studied a large Dutch family with maternally inherited, progressive, sensorineural hearing loss in 27 patients. Only in a single family member was the hearing loss accompanied by neurological symptoms including ataxia and dysarthria. DNA analysis of the mitochondrial genome revealed the insertion of a C at nucleotide position 7472 in the tRNASer(UCN) gene (7472insC mutation). We determined the percentage of mutant DNA (heteroplasmy) in blood from all family members, and found no correlation between hearing loss and leucocyte heteroplasmy. The 7472insC mutation was previously identified in a smaller family from Sicily with sensorineural hearing loss in 9 family members, six of them also presenting neurologically with ataxia and myoclonus. The presence of the 7472insC mutation in two different pedigrees strongly supports its pathogenicity. However, the interfamilial difference in penetrance of the neurologic abnormalities is most likely to be strongly influenced by secondary factors different from the 7472insC mutation, as heteroplasmy or age of the patients were similar in both families. This mutation should therefore be analysed in families with maternally inherited hearing loss, irrespective of whether the hearing loss is non-syndromic or accompanied by neurologic abnormalities.

A new autosomal-dominant locus (DFNA12) is responsible for a nonsyndromic, midfrequency, prelingual and nonprogressive sensorineural hearing loss.

OBJECTIVE: This study aimed to report on the audiologic findings of a nonsyndromic autosomal-dominant hearing loss of which the gene (DFNA 12) recently was found to map to chromosome 11q22-24. The study also aimed to propose and evaluate an algorithm based on the audiometric findings to discriminate between affected and unaffected family members before genetic linkage analysis. STUDY DESIGN: The study design was a retrospective analysis of the audiometric data of genetically affected and unaffected patients. SETTING: The study was conducted at a tertiary referral center. PATIENTS: A total of 17 genetically affected and 54 unaffected family members were studied. INTERVENTIONS: Pure-tone audiometry with air and bone conduction and construction and evaluation of an algorithm were performed. MAIN OUTCOME MEASURES: The type and degree of hearing loss as compared to age and gender-dependent values according to the International Organization for Standardization 7029 standard were measured. For this comparison, the variable "hearing standard deviations" (HSD) is introduced and is defined as the number of standard deviations that a hearing threshold is lying above the age and gender-related median at the given frequency. A description of the algorithm and an evaluation in terms of alpha- and beta-error also were measured. RESULTS: The hearing loss is nonsyndromic, sensorineural, moderate-to-moderately severe (pure-tone average, 51 dB at age 18 years), with an early onset (probably prelingual) and no progression. It affects all frequencies but mainly the midfrequencies (500, 1,000, and 2,000 Hz). The algorithm consists of an analysis of variance to determine the frequency that is most sensitive for the genetic trait under study and on the ranking of the family members according to their hearing loss (HSD) at this frequency. Individual persons are labeled as "affected" or "unaffected" according to this ranking.

Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.

The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major non-collagenous components of the tectorial membrane. Recently, the gene encoding mouse alpha-tectorin (Tecta) was mapped to a region of mouse chromosome 9, which shows evolutionary conservation with human chromosome 11q (ref. 3), where linkage was found in two families, one Belgian (DFNA12; ref. 4) and the other, Austrian (DFNA8; unpublished data), with autosomal dominant non-syndromic hearing impairment. We determined the complete sequence and the intron-exon structure of the human TECTA gene. In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA. These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment.

A Moroccan family with autosomal recessive sensorineural hearing loss caused by a mutation in the gap junction protein gene connexin 26 (GJB2).

We report a mutation in the connexin 26 gene (Cx26) in a consanguineous Moroccan family linked to the DFNA3/DFNB1 locus on human chromosome 13q11-q12. Affected subjects display congenital, bilateral, sensorineural hearing loss. We have previously identified Cx26 mutations in consanguineous Pakistani families. This current finding indicates that Cx26 mutations are not restricted to ethnically and geographically distinct populations. This is an important observation since it will help to determine the overall contribution of connexin 26 mutations to autosomal deafness in different populations.

A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24.

We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.

Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p.

Thus far, 13 genes for autosomal dominant hearing loss have been localized to specific chromosomal regions, but none of the genes has been cloned. Only a single family has been linked to each of these loci, with the exception of DFNA2. DFNA2 was originally mapped in two extended families originating from Indonesia and the United States. In this study we report linkage to DFNA2 in three additional large families with autosomal dominant hearing loss from Belgium and The Netherlands. These five DFNA2 families show a similar progressive sensorineural hearing loss, starting in the high frequencies and also affecting the middle and low frequencies later in life. Combining the information from all linked families, the candidate region that is most likely to contain the DFNA2 gene was reduced to a 1.25-Mb region between markers D1S432 and MYCL1. Different haplotypes segregating with the hearing loss were found in all five families, suggesting that different mutations are present in the same gene. These results indicate that DFNA2 is most likely an important gene for autosomal dominant hearing loss.

Selective vestibular neurectomy in Menière's disease: a review.

A review of the literature on selective vestibular neurectomy for Meniere's disease is presented. The procedure is placed in historical context and current refinements of the technique are highlighted. In particular, the different methods of evaluating results on vertigo, hearing, tinnitus, aural pressure and imbalance are summarised. The controversy over the indication, timing and outcome measures for selective vestibular neurectomy is discussed. In experienced hands there appears to be a low complication rate, emphasising the value of this procedure in relieving intractable vertigo when a destructive procedure is indicated.

Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea.

A gene for an autosomal dominant form of progressive sensorineural hearing loss (DFNA5) was previously assigned by us to a 15-cM region on chromosome 7p15. In this study, the DFNA5 candidate region was refined to less than 2 cM, and completely cloned in a YAC contig. The HOXA1 gene located in 7p15 was considered to be a good candidate gene for DFNA5 as it harbours mutations leading to developmental defects of the inner ear in mice. However, the refinement of the candidate region of DFNA5 excludes the HOXA1 gene as a candidate for DFNA5. We cloned a novel candidate gene (CG1, candidate gene 1), which is expressed in human fetal cochlea, from the DFNA5 candidate region. The complete cDNA sequence of CG1, encoding a 423 amino acid protein of unknown function, was determined. Mutation analysis of the CG1 gene in DFNA5 patients, however, could not reveal a disease-causing mutation.