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Speech Recognition Scores Related to Age and Degree of Hearing Impairment in DFNA2/KCNQ4and DFNA9/COCH

Speech Recognition Scores Related to Age and Degree of Hearing Impairment in DFNA2/KCNQ4and... ObjectiveTo analyze the relationship between pure-tone hearing threshold and speech recognition performance in DFNA2/KCNQ4and DFNA9/COCH, 2 types of high-frequency nonsyndromic hearing impairment.DesignCase series with cross-sectional analysis of phoneme recognition scores related to age and hearing level.SettingUniversity hospital.PatientsForty-five members of 4 separate families, all carrying 1 of 3 different mutations in the KCNQ4gene at the DFNA2 locus (1p34); 42 members of 7 separate families, all carrying the same Pro51Ser mutation in the COCHgene at the DFNA9 locus (14q12-q13).ResultsThe deterioration of speech recognition dropped to a 90% score at a higher level of hearing impairment (pure-tone-average at 1, 2, and 4 kHz) in DFNA2-affected patients (65 dB) than in DFNA9-affected patients (46 dB).ConclusionAt similar levels of hearing impairment, DFNA2/KCNQ4-affected patients showed better speech recognition performance than DFNA9/COCH-affected patients.AUTOSOMAL dominant nonsyndromic types of hereditary sensorineural hearing impairment can be identified by genetic linkage and mutation analysis. The corresponding chromosomal loci are genetically designated DFNA, followed by a number in order of discovery (DFN = deafness, A = autosomal dominant inheritance).One locus may harbor 1 or more disease-causing genes. The discovery of such genes and their function may enhance our understanding of the pathophysiology of the inner ear. Concurrently, clinical studies are necessary to relate the latter to the resulting phenotype.Clinical studies on DFNA2/KCNQ4-affected families and DFNA9/COCH-affected families have demonstrated fairly similar high-frequency sensorineural hearing impairment and progression (S.J.H.B., unpublished data, 2000)In addition to sensorineural hearing loss, DFNA9-affected patients also develop vestibular failure.The DFNA9-affected families studied in the Netherlands and Flanders all have the same mutation in the COCHgene, corresponding to a P51S substitution in the expressed protein, cochlin.The function of cochlin is still unknown. In the 4 Dutch DFNA2-affected families, 3 different mutations (W276S, G321S, L274W) of the KCNQ4gene were found.KCNQ4encodes a potassium (K+) channel that is predominantly expressed in the basolateral membrane of cochlear hair cells.The present study focuses on the relationship between speech recognition performance on the one hand and age and pure-tone hearing threshold on the other hand in 2 different types of nonsyndromic, autosomal dominant, sensorineural hearing impairment. The 2, DFNA2/KCNQ4and DFNA9/COCH, are both characterized by progressive, predominantly high-frequency hearing impairment.PATIENTS AND METHODSThis study compared speech recognition data between patients with DFNA2/KCNQ4-affected patients and DFNA9/COCH-affected patients. Speech recognition data for patients with DFNA2 were obtained from 45 carriers of a mutation in the KCNQ4gene. There were 30 patients from 2 families with a W276S mutation (G.V.C., unpublished data, 2000),10 patients with a G321S mutation,and 5 patients with a L274W mutation.Speech recognition data for patients with DFNA9 were obtained from 42 carriers of the P51S mutation in the COCHgene, from 6 Dutchfamilies and 1 Flemish family (S.J.H.B., unpublished data, 2000).Audiometry was performed according to common clinical standards. For speech recognition, standard monosyllabic Dutch word lists were presented at either ear.Performance-intensity curves relating to the phoneme recognition score were analyzed for the right ear only. The last-visit speech reception threshold (SRT) (in decibels sound pressure level [dB SPL] for 50% phoneme score) and the maximum phoneme recognition score (percentage correct), at which the pure-tone-threshold at 1, 2, and 4 kHz could be measured, were used.Plots of SRT vs pure-tone-average at 1, 2, and 4 kHz (PTA1,2,4 kHz) were used with linear regression analysis to check for the reliability of the phoneme recognition scores. The Chauvenet criterionand the residual SD were used to identify and exclude outlying values.Because a comparison of speech recognition scores between the patient groups may be complicated by underlying differences in sensorineural hearing threshold, the thresholds at each frequency for "modal-age" patients between the groups were compared, using the ttest. These patients were selected from each group by requiring their age to be within the limits of the percentiles P37.5and P62.5of the corresponding age distribution.Nonlinear regression analysis of the maximum phoneme recognition score on log(age) and on log(PTA1,2,4 kHz) was performed using the Prism PC version 3.02 program (GraphPad, San Diego, Calif). Cross-sectional and individual longitudinal performance-age (percentage recognition vs age) and performance-impairment plots (percentage recognition vs PTA1,2,4 kHz) were fitted with a sigmoidal dose-response function with a variable slope: Y= {100%/[1 + 10(logX90− logX)×HillSlope−log9]}, where Yis the phoneme score, Xis either age or PTA1,2,4 kHz, X90is the value of Xwhere Y= 90%, and HillSlopeis the slope factor on a log scale of X. The fitted values of X90and HillSlopewere used to test between curves relating to the patient groups, using the ttest (with the Welch correction if the Bartlett test detected unequal variances).To simplify the results and allow for additional testing, "local average" slope (ie, on a linear scale) for X>X90was obtained by using a linear regression line as an approximation of the corresponding part of the fitted sigmoidal curve. Slope was the deterioration rate in the performance-age plot, whereas it was the deterioration gradient in the performance-impairment plot. X.90was the onset age for the performance-age plot and onset level for the performance-impairment plot. Regression lines were compared between the groups using analysis of covariance (ANCOVA) to find out whether slopes and intercepts were significantly different. Again, Chauvenet's criterionwas used in combination with the residual SD to detect outlying values.Individual longitudinal data were available in 18 DFNA2/KCNQ4-affected patients and 23 DFNA9/COCH-affected patients. Analyses constituted plotting of serial phoneme recognition scores against age and PTA1,2,4 kHz, and comparing these to the curves fitted to the corresponding cross-sectional data. A 5% lower normal limit established at the Nijmegen Otorhinolaryngology department (P.L.M.H., unpublished data, 2000) was used to see whether there were scores that raised suspicion of retrocochlear dysfunction.The phenotype of the DFNA2/KCNQ4-affected patients may be influenced by the nature of the mutation that is present in the family. In addition, even for patients carrying the same mutation, differences in other genes (genetic background) may also influence the phenotype. It was, therefore, checked whether there were significant differences in score behavior between either the different DFNA2/KCNQ4-affected families or the different DFNA9/COCH-affected families.RESULTSIn each group, the SRT showed an excellent correlation with the corresponding PTA1,2,4 kHz(n = 33-44 after exclusion of 3 outlying values; r= 0.8-0.9, residual SD = 9-13 dB). This corresponds fairly well with the residual SD found by Bosman and Smoorenburg.Mean pure-tone thresholds for a representative, "modal-age" selection from each group, that is, cases with P37.5<age<P62.5(percentiles in the frequency distribution of age), generally did not differ significantly at any frequency.Figure 1shows cross-sectional performance vs age plots (A-B) and combined performance-impairment plots (C). Onset age was 34 years in DFNA2/KCNQ4-affected patients and 43 years in DFNA9/COCH-affected patients. The local average deterioration rate in DFNA2-affected patients was 0.3% per year, while in DFNA9-affected patients, it was 1.8% per year (Figure 1A-B). There was no significant difference in HillSlopebetween the plotted curves in Figure 1C. However, the local average deterioration gradients were significantly different (0.5% per decibel vs 1.2% per decibel). The latter finding is related to the significant difference in onset level that can be detected (65 vs 46 dB), as well as the observation that there is a clear separation between the data points (Figure 1C). In other words, at a given level of impairment, DFNA2/KCNQ4-affected patients showed higher scores than DFNA9/COCH-affected patients.Speech recognition score against age (A [DFNA2-affected patients] and B [DFNA9-affected patients]) and pure-tone average (PTA) at 1, 2, and 4 kHz expressed in decibels hearing level (dB HL) (C [DFNA2 vs DFNA9]) in DFNA2/KCNQ4-affected patients (circles) and DFNA9/COCH-affected patients (triangles). Smaller symbols indicate outlying values.Individual longitudinal analyses produced fairly similar results to the cross-sectional analysis (data not shown). Four of the DFNA9/COCH-affected patients had scores below the normal limit that would have been suggestive of retrocochlear dysfunction. Some of these scores renormalized during follow-up. None of the DFNA2/KCNQ4-affected patients had any scores suggestive of retrocochlear dysfunction. No significant differences in score behavior between either the different DFNA2/KCNQ4-affected families or the different DFNA9/COCH-affected families were found (data not shown).COMMENTThe marked difference in speech recognition performance as related to sensorineural hearing level between DFNA2/KCNQ4and DFNA9/COCH, both characterized by predominantly high-frequency sensorineural hearing impairment, is an appealing finding in this study. Better recognition scores in the DFNA2-affected patients are remarkable, especially in light of recent findings that the mouse homologue of KCNQ4is abundantly expressed in the central auditory pathways.KCNQ4is thought to play a role in the K+recycling pathway of the inner ear.Three of the 4 studied families with DFNA2/KCNQ4-affected patients had different mutations, but fairly similar speech recognition. The L274W and W276S mutations produce changes in the pore region of the expressed K+channel protein, whereas the G321S mutation exerts an effect just outside the pore region, however, apparently to a similar phenotypic effect.On the other hand, the DFNA9/COCH-affected patients had poorer speech recognition scores compared with age and sensorineural hearing level (Figure 1C). The American DFNA9-affected patients, with a V66G mutation within the COCHgene,however, showed an even greater drop in recognition scores.The latter had earlier onset (at age 20 years) and anacusis at around age 45 years. Combined speech performance-impairment plots of the recognition scores (not shown) are suggestive of poorer scores in the American V66G carriers. However, our longitudinal analyses also disclosed the existence of temporarily poor scores in some of our DFNA9/COCH-affected patients. Such poor scores may have been related to Ménière-like paroxysms.Histopathologic findings reported for 1 American COCH/V66G–mutation carrier comprised general destruction of the cochlear and vestibular sensory elements, including hair cells and dendrites (cochlea, crista, and macula), as well as accumulation of an acellular substance (glycosaminoglycan) throughout the labyrinth.These findings were similar to those reported previously in DFNA9/COCH-affected patients.In chicken, COCHexpression was found in fairly similar places where the deposits were found in human patients.It has been postulated that "strangulation" of cochlear and vestibular nerve endings occurs.Alternatively, the possibility was suggested that normal fibrillogenesis is disrupted by an excess in microfibrillar substance, which results in degradation of collagens and extracellular matrix components.It is also possible that cochlin, which is expressed in the stroma underlying the sensory structures of the inner ear,has a role in ion homeostasis, for example, recycling of K+ions from the hair cells to the endolymph.In the present study, DFNA2/KCNQ4-affected patients seemed to have better speech recognition scores than DFNA9/COCH-affected patients (Figure 1C); the difference could not be explained by underlying differences in pure-tone thresholds. Cochlear KCNQ4expression was initially thought to be confined to the outer hair cells.However, recent findings in the rat have shown that it is also expressed in inner hair cells and the spiral ganglion.The strongest KCNQ4expression, that is, in normally hearing animals, was found in inner hair cells in the lower cochlear turns and in outer hair cells in the upper turns. Thus DFNA2/KCNQ4-related high-frequency sensorineural hearing impairment, which is associated with primary dysfunction of the lower cochlear turns, might be attributed to a lack of expression of K+channels, especially in inner hair cells. Relative sparing of function of outer hair cells in the lower turns, thus preserving their function as "cochlear preamplifier" in fine tuning mechanisms,might account for the better speech recognition in DFNA2/KCNQ4-affected patients. On the other hand, the poor recognition scores in DFNA9/COCH-affected patients might be explained by the generalized, histopathologic, vestibulocochlear changes,already mentioned earlier, and, in part, by its Ménièriform features.GVan CampRJHSmithHereditary Hearing Loss Homepage.Available at: http://dnalab-www.uia.ac.be/dnalab/hhh/index.html. Accessed December 2000.HMarresMvan EwijkPHuygenInherited nonsyndromic hearing loss: an audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2.Arch Otolaryngol Head Neck Surg.1997;123:573-577.HKunstHMarresPHuygenNonsyndromic autosomal dominant progressive sensorineural hearing loss: audiologic analysis of a pedigree linked to DFNA2.Laryngoscope.1998;108:74-80.RJHEnsinkPLMHuygenPVan HauwePCouckeCWRJCremersGVan CampAnother family with progressive sensorineural hearing impairment linked to the DFNA2 region.Eur Arch Otorhinolaryngol.2000;257:62-67.EMRDe LeenheerPLMHuygenPJCouckeRJCAdmiraalGVan CampCWRJCremersLongitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4family.Ann Otol Rhinol Laryngol.In press.SJHBomMHKempermanYJMDe KokProgressive cochleovestibular impairment caused by a point mutation in the COCHgene at DFNA9.Laryngoscope.1999;109:1525-1530.WIMVerhagenPLMHuygenEMGJoostenFamilial progressive vestibulocochlear dysfunction.Arch Neurol.1988;45:766-768.WIMVerhagenPLMHuygenEJJMTheunissenEMGJoostenHereditary vestibulo-cochlear dysfunction and vascular disorders.J Neurol Sci.1989;92:55-63.WIMVerhagenPLMHuygenEMGJoostenFamilial progressive vestibulocochlear dysfunction [letter].Arch Neurol.1991;48:262.WIMVerhagenPLMHuygenWBlesA new autosomal dominant syndrome of idiopathic progressive vestibulo-cochlear dysfunction with middle-age onset.Acta Otolaryngol (Stockh).1992;112:899-906.WIMVerhagenSJHBomPLMHuygenEFransenGVan CampCWRJCremersFamilial progressive vestibulocochlear dysfunction caused by a COCHmutation (DFNA9).Arch Neurol.2000;57:1045-1047.EFransenMVerstrekenWIMVerhagenHigh prevalence of symptoms of Menière's disease in three families with a mutation in the COCHgene.Hum Mol Genet.1999;8:1425-1429.FXLemaireLFeenstraPLHuygenProgressive late-onset sensorineural hearing loss and vestibular impairment with vertigo.Otol Neurotol.In press.CHalpinUKhetarpalMMcKennaAutosomal-dominant progressive sensorineural hearing loss in a large North American family.Am J Audiol.March 1996;5:105-111.UKhetarpalDFNA9is a progressive audiovestibular dysfunction with a microfibrillar deposit in the inner ear.Laryngoscope.2000;110:1379-1384.UKhetarpalHFSchuknechtRRGacekLBHolmesAutosomal dominant sensorineural hearing loss: pedigrees, audiologic findings, and temporal bone findings in two kindreds [review].Arch Otolaryngol Head Neck Surg.1991;117:1032-1042.YJMde KokSJHBomTMBruntA Pro51Ser mutation in the COCHgene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects.Hum Mol Genet.1999;8:361-366.EFransenMVerstrekenSJHBomA common ancestor for COCH-related cochleovestibular (DFNA9) patients in Belgium and the Netherlands, all bearing the P51S mutation.J Med Genet.2001;38:61-64.PJCouckePVan HauwePMKelleyMutations in the KCNQ4gene are responsible for autosomal dominant deafness in four DFNA2 families.Hum Mol Genet.1999;8:1321-1328.PVan HauwePJCouckeRJEnsinkPHuygenCWCremersGVan CampMutations in the KCNQ4K+channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.Am J Med Genet.2000;93:184-187.CKubischBCSchroederTFriedrichKCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.Cell.1999;96:437-446.KWBeiselNCNelsonDCDelimontBFritzschLongitudinal gradients of KCNQ4expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2.Brain Res Mol Brain Res.2000;82:137-149.AJBosmanGFSmoorenburgIntelligibility of Dutch CVC syllabes and sentences for listeners with normal hearing and with three types of hearing impairment.Audiology.1995;34:260-284.Documenta GeigyScientific Tables.5th ed. Basel, Switzerland: S Karger AG; 1959:47.TKharkovetsJHardelinSSafieddineKCNQ4, a K+channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.Proc Natl Acad Sci U S A.2000;97:4333-4338.PVan HauwePCouckeGVan CampThe DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear.Br J Audiol.1999;33:285-289.ENManolisNYandaviJBNadol JrA gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13.Hum Mol Genet.1996;5:1047-1050.NGRobertsonLLuSHellerMutations in a novel cochlear gene cause DFNA9, a human nonsyndromic sensorineural deafness with vestibular dysfunction.Nat Genet.1998;20:299-303.UKhetarpalAutosomal dominant sensorineural hearing loss: further temporal bone findings.Arch Otolaryngol Head Neck Surg.1993;119:106-108.RNobiliFMammanoJAshmoreHow well do we understand the cochlea [review]?Trends Neurosci.1998;21:159-167.Accepted for publication February 7, 2001.This study was supported in part by the Heinsius Houbolt Foundation, Wassenaar, the Netherlands, and the Nijmegen KNO-Research Foundation (Dr Cor Cremers).We thank the family members who participated in this study.Drs Bom and De Leenheer contributed equally to this work.Corresponding author: Steven J. H. Bom, MD, Department of Otorhinolaryngology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands (e-mail: S.Bom@kno.azn.nl). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Otolaryngology–Head & Neck Surgery American Medical Association

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References (31)

Publisher
American Medical Association
Copyright
Copyright 2001 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
ISSN
2168-6181
eISSN
2168-619X
DOI
10.1001/archotol.127.9.1045
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See Article on Publisher Site

Abstract

ObjectiveTo analyze the relationship between pure-tone hearing threshold and speech recognition performance in DFNA2/KCNQ4and DFNA9/COCH, 2 types of high-frequency nonsyndromic hearing impairment.DesignCase series with cross-sectional analysis of phoneme recognition scores related to age and hearing level.SettingUniversity hospital.PatientsForty-five members of 4 separate families, all carrying 1 of 3 different mutations in the KCNQ4gene at the DFNA2 locus (1p34); 42 members of 7 separate families, all carrying the same Pro51Ser mutation in the COCHgene at the DFNA9 locus (14q12-q13).ResultsThe deterioration of speech recognition dropped to a 90% score at a higher level of hearing impairment (pure-tone-average at 1, 2, and 4 kHz) in DFNA2-affected patients (65 dB) than in DFNA9-affected patients (46 dB).ConclusionAt similar levels of hearing impairment, DFNA2/KCNQ4-affected patients showed better speech recognition performance than DFNA9/COCH-affected patients.AUTOSOMAL dominant nonsyndromic types of hereditary sensorineural hearing impairment can be identified by genetic linkage and mutation analysis. The corresponding chromosomal loci are genetically designated DFNA, followed by a number in order of discovery (DFN = deafness, A = autosomal dominant inheritance).One locus may harbor 1 or more disease-causing genes. The discovery of such genes and their function may enhance our understanding of the pathophysiology of the inner ear. Concurrently, clinical studies are necessary to relate the latter to the resulting phenotype.Clinical studies on DFNA2/KCNQ4-affected families and DFNA9/COCH-affected families have demonstrated fairly similar high-frequency sensorineural hearing impairment and progression (S.J.H.B., unpublished data, 2000)In addition to sensorineural hearing loss, DFNA9-affected patients also develop vestibular failure.The DFNA9-affected families studied in the Netherlands and Flanders all have the same mutation in the COCHgene, corresponding to a P51S substitution in the expressed protein, cochlin.The function of cochlin is still unknown. In the 4 Dutch DFNA2-affected families, 3 different mutations (W276S, G321S, L274W) of the KCNQ4gene were found.KCNQ4encodes a potassium (K+) channel that is predominantly expressed in the basolateral membrane of cochlear hair cells.The present study focuses on the relationship between speech recognition performance on the one hand and age and pure-tone hearing threshold on the other hand in 2 different types of nonsyndromic, autosomal dominant, sensorineural hearing impairment. The 2, DFNA2/KCNQ4and DFNA9/COCH, are both characterized by progressive, predominantly high-frequency hearing impairment.PATIENTS AND METHODSThis study compared speech recognition data between patients with DFNA2/KCNQ4-affected patients and DFNA9/COCH-affected patients. Speech recognition data for patients with DFNA2 were obtained from 45 carriers of a mutation in the KCNQ4gene. There were 30 patients from 2 families with a W276S mutation (G.V.C., unpublished data, 2000),10 patients with a G321S mutation,and 5 patients with a L274W mutation.Speech recognition data for patients with DFNA9 were obtained from 42 carriers of the P51S mutation in the COCHgene, from 6 Dutchfamilies and 1 Flemish family (S.J.H.B., unpublished data, 2000).Audiometry was performed according to common clinical standards. For speech recognition, standard monosyllabic Dutch word lists were presented at either ear.Performance-intensity curves relating to the phoneme recognition score were analyzed for the right ear only. The last-visit speech reception threshold (SRT) (in decibels sound pressure level [dB SPL] for 50% phoneme score) and the maximum phoneme recognition score (percentage correct), at which the pure-tone-threshold at 1, 2, and 4 kHz could be measured, were used.Plots of SRT vs pure-tone-average at 1, 2, and 4 kHz (PTA1,2,4 kHz) were used with linear regression analysis to check for the reliability of the phoneme recognition scores. The Chauvenet criterionand the residual SD were used to identify and exclude outlying values.Because a comparison of speech recognition scores between the patient groups may be complicated by underlying differences in sensorineural hearing threshold, the thresholds at each frequency for "modal-age" patients between the groups were compared, using the ttest. These patients were selected from each group by requiring their age to be within the limits of the percentiles P37.5and P62.5of the corresponding age distribution.Nonlinear regression analysis of the maximum phoneme recognition score on log(age) and on log(PTA1,2,4 kHz) was performed using the Prism PC version 3.02 program (GraphPad, San Diego, Calif). Cross-sectional and individual longitudinal performance-age (percentage recognition vs age) and performance-impairment plots (percentage recognition vs PTA1,2,4 kHz) were fitted with a sigmoidal dose-response function with a variable slope: Y= {100%/[1 + 10(logX90− logX)×HillSlope−log9]}, where Yis the phoneme score, Xis either age or PTA1,2,4 kHz, X90is the value of Xwhere Y= 90%, and HillSlopeis the slope factor on a log scale of X. The fitted values of X90and HillSlopewere used to test between curves relating to the patient groups, using the ttest (with the Welch correction if the Bartlett test detected unequal variances).To simplify the results and allow for additional testing, "local average" slope (ie, on a linear scale) for X>X90was obtained by using a linear regression line as an approximation of the corresponding part of the fitted sigmoidal curve. Slope was the deterioration rate in the performance-age plot, whereas it was the deterioration gradient in the performance-impairment plot. X.90was the onset age for the performance-age plot and onset level for the performance-impairment plot. Regression lines were compared between the groups using analysis of covariance (ANCOVA) to find out whether slopes and intercepts were significantly different. Again, Chauvenet's criterionwas used in combination with the residual SD to detect outlying values.Individual longitudinal data were available in 18 DFNA2/KCNQ4-affected patients and 23 DFNA9/COCH-affected patients. Analyses constituted plotting of serial phoneme recognition scores against age and PTA1,2,4 kHz, and comparing these to the curves fitted to the corresponding cross-sectional data. A 5% lower normal limit established at the Nijmegen Otorhinolaryngology department (P.L.M.H., unpublished data, 2000) was used to see whether there were scores that raised suspicion of retrocochlear dysfunction.The phenotype of the DFNA2/KCNQ4-affected patients may be influenced by the nature of the mutation that is present in the family. In addition, even for patients carrying the same mutation, differences in other genes (genetic background) may also influence the phenotype. It was, therefore, checked whether there were significant differences in score behavior between either the different DFNA2/KCNQ4-affected families or the different DFNA9/COCH-affected families.RESULTSIn each group, the SRT showed an excellent correlation with the corresponding PTA1,2,4 kHz(n = 33-44 after exclusion of 3 outlying values; r= 0.8-0.9, residual SD = 9-13 dB). This corresponds fairly well with the residual SD found by Bosman and Smoorenburg.Mean pure-tone thresholds for a representative, "modal-age" selection from each group, that is, cases with P37.5<age<P62.5(percentiles in the frequency distribution of age), generally did not differ significantly at any frequency.Figure 1shows cross-sectional performance vs age plots (A-B) and combined performance-impairment plots (C). Onset age was 34 years in DFNA2/KCNQ4-affected patients and 43 years in DFNA9/COCH-affected patients. The local average deterioration rate in DFNA2-affected patients was 0.3% per year, while in DFNA9-affected patients, it was 1.8% per year (Figure 1A-B). There was no significant difference in HillSlopebetween the plotted curves in Figure 1C. However, the local average deterioration gradients were significantly different (0.5% per decibel vs 1.2% per decibel). The latter finding is related to the significant difference in onset level that can be detected (65 vs 46 dB), as well as the observation that there is a clear separation between the data points (Figure 1C). In other words, at a given level of impairment, DFNA2/KCNQ4-affected patients showed higher scores than DFNA9/COCH-affected patients.Speech recognition score against age (A [DFNA2-affected patients] and B [DFNA9-affected patients]) and pure-tone average (PTA) at 1, 2, and 4 kHz expressed in decibels hearing level (dB HL) (C [DFNA2 vs DFNA9]) in DFNA2/KCNQ4-affected patients (circles) and DFNA9/COCH-affected patients (triangles). Smaller symbols indicate outlying values.Individual longitudinal analyses produced fairly similar results to the cross-sectional analysis (data not shown). Four of the DFNA9/COCH-affected patients had scores below the normal limit that would have been suggestive of retrocochlear dysfunction. Some of these scores renormalized during follow-up. None of the DFNA2/KCNQ4-affected patients had any scores suggestive of retrocochlear dysfunction. No significant differences in score behavior between either the different DFNA2/KCNQ4-affected families or the different DFNA9/COCH-affected families were found (data not shown).COMMENTThe marked difference in speech recognition performance as related to sensorineural hearing level between DFNA2/KCNQ4and DFNA9/COCH, both characterized by predominantly high-frequency sensorineural hearing impairment, is an appealing finding in this study. Better recognition scores in the DFNA2-affected patients are remarkable, especially in light of recent findings that the mouse homologue of KCNQ4is abundantly expressed in the central auditory pathways.KCNQ4is thought to play a role in the K+recycling pathway of the inner ear.Three of the 4 studied families with DFNA2/KCNQ4-affected patients had different mutations, but fairly similar speech recognition. The L274W and W276S mutations produce changes in the pore region of the expressed K+channel protein, whereas the G321S mutation exerts an effect just outside the pore region, however, apparently to a similar phenotypic effect.On the other hand, the DFNA9/COCH-affected patients had poorer speech recognition scores compared with age and sensorineural hearing level (Figure 1C). The American DFNA9-affected patients, with a V66G mutation within the COCHgene,however, showed an even greater drop in recognition scores.The latter had earlier onset (at age 20 years) and anacusis at around age 45 years. Combined speech performance-impairment plots of the recognition scores (not shown) are suggestive of poorer scores in the American V66G carriers. However, our longitudinal analyses also disclosed the existence of temporarily poor scores in some of our DFNA9/COCH-affected patients. Such poor scores may have been related to Ménière-like paroxysms.Histopathologic findings reported for 1 American COCH/V66G–mutation carrier comprised general destruction of the cochlear and vestibular sensory elements, including hair cells and dendrites (cochlea, crista, and macula), as well as accumulation of an acellular substance (glycosaminoglycan) throughout the labyrinth.These findings were similar to those reported previously in DFNA9/COCH-affected patients.In chicken, COCHexpression was found in fairly similar places where the deposits were found in human patients.It has been postulated that "strangulation" of cochlear and vestibular nerve endings occurs.Alternatively, the possibility was suggested that normal fibrillogenesis is disrupted by an excess in microfibrillar substance, which results in degradation of collagens and extracellular matrix components.It is also possible that cochlin, which is expressed in the stroma underlying the sensory structures of the inner ear,has a role in ion homeostasis, for example, recycling of K+ions from the hair cells to the endolymph.In the present study, DFNA2/KCNQ4-affected patients seemed to have better speech recognition scores than DFNA9/COCH-affected patients (Figure 1C); the difference could not be explained by underlying differences in pure-tone thresholds. Cochlear KCNQ4expression was initially thought to be confined to the outer hair cells.However, recent findings in the rat have shown that it is also expressed in inner hair cells and the spiral ganglion.The strongest KCNQ4expression, that is, in normally hearing animals, was found in inner hair cells in the lower cochlear turns and in outer hair cells in the upper turns. Thus DFNA2/KCNQ4-related high-frequency sensorineural hearing impairment, which is associated with primary dysfunction of the lower cochlear turns, might be attributed to a lack of expression of K+channels, especially in inner hair cells. Relative sparing of function of outer hair cells in the lower turns, thus preserving their function as "cochlear preamplifier" in fine tuning mechanisms,might account for the better speech recognition in DFNA2/KCNQ4-affected patients. On the other hand, the poor recognition scores in DFNA9/COCH-affected patients might be explained by the generalized, histopathologic, vestibulocochlear changes,already mentioned earlier, and, in part, by its Ménièriform features.GVan CampRJHSmithHereditary Hearing Loss Homepage.Available at: http://dnalab-www.uia.ac.be/dnalab/hhh/index.html. Accessed December 2000.HMarresMvan EwijkPHuygenInherited nonsyndromic hearing loss: an audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2.Arch Otolaryngol Head Neck Surg.1997;123:573-577.HKunstHMarresPHuygenNonsyndromic autosomal dominant progressive sensorineural hearing loss: audiologic analysis of a pedigree linked to DFNA2.Laryngoscope.1998;108:74-80.RJHEnsinkPLMHuygenPVan HauwePCouckeCWRJCremersGVan CampAnother family with progressive sensorineural hearing impairment linked to the DFNA2 region.Eur Arch Otorhinolaryngol.2000;257:62-67.EMRDe LeenheerPLMHuygenPJCouckeRJCAdmiraalGVan CampCWRJCremersLongitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4family.Ann Otol Rhinol Laryngol.In press.SJHBomMHKempermanYJMDe KokProgressive cochleovestibular impairment caused by a point mutation in the COCHgene at DFNA9.Laryngoscope.1999;109:1525-1530.WIMVerhagenPLMHuygenEMGJoostenFamilial progressive vestibulocochlear dysfunction.Arch Neurol.1988;45:766-768.WIMVerhagenPLMHuygenEJJMTheunissenEMGJoostenHereditary vestibulo-cochlear dysfunction and vascular disorders.J Neurol Sci.1989;92:55-63.WIMVerhagenPLMHuygenEMGJoostenFamilial progressive vestibulocochlear dysfunction [letter].Arch Neurol.1991;48:262.WIMVerhagenPLMHuygenWBlesA new autosomal dominant syndrome of idiopathic progressive vestibulo-cochlear dysfunction with middle-age onset.Acta Otolaryngol (Stockh).1992;112:899-906.WIMVerhagenSJHBomPLMHuygenEFransenGVan CampCWRJCremersFamilial progressive vestibulocochlear dysfunction caused by a COCHmutation (DFNA9).Arch Neurol.2000;57:1045-1047.EFransenMVerstrekenWIMVerhagenHigh prevalence of symptoms of Menière's disease in three families with a mutation in the COCHgene.Hum Mol Genet.1999;8:1425-1429.FXLemaireLFeenstraPLHuygenProgressive late-onset sensorineural hearing loss and vestibular impairment with vertigo.Otol Neurotol.In press.CHalpinUKhetarpalMMcKennaAutosomal-dominant progressive sensorineural hearing loss in a large North American family.Am J Audiol.March 1996;5:105-111.UKhetarpalDFNA9is a progressive audiovestibular dysfunction with a microfibrillar deposit in the inner ear.Laryngoscope.2000;110:1379-1384.UKhetarpalHFSchuknechtRRGacekLBHolmesAutosomal dominant sensorineural hearing loss: pedigrees, audiologic findings, and temporal bone findings in two kindreds [review].Arch Otolaryngol Head Neck Surg.1991;117:1032-1042.YJMde KokSJHBomTMBruntA Pro51Ser mutation in the COCHgene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects.Hum Mol Genet.1999;8:361-366.EFransenMVerstrekenSJHBomA common ancestor for COCH-related cochleovestibular (DFNA9) patients in Belgium and the Netherlands, all bearing the P51S mutation.J Med Genet.2001;38:61-64.PJCouckePVan HauwePMKelleyMutations in the KCNQ4gene are responsible for autosomal dominant deafness in four DFNA2 families.Hum Mol Genet.1999;8:1321-1328.PVan HauwePJCouckeRJEnsinkPHuygenCWCremersGVan CampMutations in the KCNQ4K+channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.Am J Med Genet.2000;93:184-187.CKubischBCSchroederTFriedrichKCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.Cell.1999;96:437-446.KWBeiselNCNelsonDCDelimontBFritzschLongitudinal gradients of KCNQ4expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2.Brain Res Mol Brain Res.2000;82:137-149.AJBosmanGFSmoorenburgIntelligibility of Dutch CVC syllabes and sentences for listeners with normal hearing and with three types of hearing impairment.Audiology.1995;34:260-284.Documenta GeigyScientific Tables.5th ed. Basel, Switzerland: S Karger AG; 1959:47.TKharkovetsJHardelinSSafieddineKCNQ4, a K+channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway.Proc Natl Acad Sci U S A.2000;97:4333-4338.PVan HauwePCouckeGVan CampThe DFNA2 locus for hearing impairment: two genes regulating K+ ion recycling in the inner ear.Br J Audiol.1999;33:285-289.ENManolisNYandaviJBNadol JrA gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13.Hum Mol Genet.1996;5:1047-1050.NGRobertsonLLuSHellerMutations in a novel cochlear gene cause DFNA9, a human nonsyndromic sensorineural deafness with vestibular dysfunction.Nat Genet.1998;20:299-303.UKhetarpalAutosomal dominant sensorineural hearing loss: further temporal bone findings.Arch Otolaryngol Head Neck Surg.1993;119:106-108.RNobiliFMammanoJAshmoreHow well do we understand the cochlea [review]?Trends Neurosci.1998;21:159-167.Accepted for publication February 7, 2001.This study was supported in part by the Heinsius Houbolt Foundation, Wassenaar, the Netherlands, and the Nijmegen KNO-Research Foundation (Dr Cor Cremers).We thank the family members who participated in this study.Drs Bom and De Leenheer contributed equally to this work.Corresponding author: Steven J. H. Bom, MD, Department of Otorhinolaryngology, University Medical Centre St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands (e-mail: S.Bom@kno.azn.nl).

Journal

JAMA Otolaryngology–Head & Neck SurgeryAmerican Medical Association

Published: Sep 1, 2001

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