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Biomedical subjects

Cor W R J Cremers

Publications and source records attributed to Cor W R J Cremers.

At least 19 recordsLinked to original sources
PubMed2006

Audiological evaluation of affected members from a Dutch DFNA8/12 (TECTA) family.

In DFNA8/12, an autosomal dominantly inherited type of nonsyndromic hearing impairment, the TECTA gene mutation causes a defect in the structure of the tectorial membrane in the inner ear. Because DFNA8/12 affects the tectorial membrane, patients with DFNA8/12 may show specific audiometric characteristics. In this study, five selected members of a Dutch DFNA8/12 family with a TECTA sensorineural hearing impairment were evaluated with pure-tone audiometry, loudness scaling, speech perception in quiet and noise, difference limen for frequency, acoustic reflexes, otoacoustic emissions, and gap detection. Four out of five subjects showed an elevation of pure-tone thresholds, acoustic reflex thresholds, and loudness discomfort levels. Loudness growth curves are parallel to those found in normal-hearing individuals. Suprathreshold measures such as difference limen for frequency modulated pure tones, gap detection, and particularly speech perception in noise are within the normal range. Distortion otoacoustic emissions are present at the higher stimulus level. These results are similar to those previously obtained from a Dutch DFNA13 family with midfrequency sensorineural hearing impairment. It seems that a defect in the tectorial membrane results primarily in an attenuation of sound, whereas suprathreshold measures, such as otoacoustic emissions and speech perception in noise, are preserved rather well. The main effect of the defects is a shift in the operation point of the outer hair cells with near intact functioning at high levels. As most test results reflect those found in middle-ear conductive loss in both families, the sensorineural hearing impairment may be characterized as a cochlear conductive hearing impairment.

Adult↗
PubMed2006

Reproducibility of sonotubometry as Eustachian tube ventilatory function test in healthy children.

OBJECTIVES: To devise a simple and reliable diagnostic procedure to test Eustachian tube function routinely in an ENT outpatient setting. One method to measure ET ventilatory function is sonotubometry. The reproducibility of a recently updated sonotubometry set-up was tested in healthy children. METHODS: The test population comprised 61 school children aged from 6 to 8 years. Only otologically healthy children were included. Health state was established by means of a 12-item questionnaire. To test reproducibility, sonotubometric testing took place in two sessions of 10 acts of swallowing each. Spearman's coefficient was used to test the correlation between the two sets of measurements. All testing took place at a primary school in a nearby village. RESULTS: Opening of the ET was recorded in at least one of the two measurement sessions in 82% of the children. The first and second sessions were highly correlated, with a Spearman's coefficient of 0.89. CONCLUSIONS: In otologically healthy children, opening of the ET was recorded frequently using the updated sonotubometry set-up. Measurement results had high reproducibility. Therefore, the test forms a useful method to assess ET ventilatory function in otologically healthy children. The performance of this updated version needs to be established in children with otological diseases.

Acoustic Impedance Tests↗
PubMed2006

Development of a genotyping microarray for Usher syndrome.

BACKGROUND: Usher syndrome, a combination of retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction, displays a high degree of clinical and genetic heterogeneity. Three clinical subtypes can be distinguished, based on the age of onset and severity of the hearing impairment, and the presence or absence of vestibular abnormalities. Thus far, eight genes have been implicated in the syndrome, together comprising 347 protein-coding exons. METHODS: To improve DNA diagnostics for patients with Usher syndrome, we developed a genotyping microarray based on the arrayed primer extension (APEX) method. Allele-specific oligonucleotides corresponding to all 298 Usher syndrome-associated sequence variants known to date, 76 of which are novel, were arrayed. RESULTS: Approximately half of these variants were validated using original patient DNAs, which yielded an accuracy of >98%. The efficiency of the Usher genotyping microarray was tested using DNAs from 370 unrelated European and American patients with Usher syndrome. Sequence variants were identified in 64/140 (46%) patients with Usher syndrome type I, 45/189 (24%) patients with Usher syndrome type II, 6/21 (29%) patients with Usher syndrome type III and 6/20 (30%) patients with atypical Usher syndrome. The chip also identified two novel sequence variants, c.400C>T (p.R134X) in PCDH15 and c.1606T>C (p.C536S) in USH2A. CONCLUSION: The Usher genotyping microarray is a versatile and affordable screening tool for Usher syndrome. Its efficiency will improve with the addition of novel sequence variants with minimal extra costs, making it a very useful first-pass screening tool.

DNA↗
PubMed2006

A novel TECTA mutation in a Dutch DFNA8/12 family confirms genotype-phenotype correlation.

A novel TECTA mutation, p.R1890C, was found in a Dutch family with nonsyndromic autosomal dominant sensorineural hearing impairment. In early life, presumably congenital, hearing impairment occurred in the midfrequency range, amounting to about 40 dB at 1 kHz. Speech recognition was good with all phoneme recognition scores exceeding 90%. An intact horizontal vestibuloocular reflex was found in four tested patients. The missense mutation is located in the zona pellucida (ZP) domain of alpha-tectorin. Mutations affecting the ZP domain of alpha-tectorin are significantly associated with midfrequency hearing impairment. Substitutions affecting other amino acid residues than cysteines show a significant association with hearing impairment without progression. Indeed, in the present family progression seemed to be absent. In addition, the presently identified mutation affecting the ZP domain resulted in a substantially lesser degree of hearing impairment than was previously reported for DFNA8/12 traits with mutations affecting the ZP domain of alpha-tectorin.

Adult↗
PubMed2006

Mutations in different components of FGF signaling in LADD syndrome.

Lacrimo-auriculo-dento-digital (LADD) syndrome is characterized by lacrimal duct aplasia, malformed ears and deafness, small teeth and digital anomalies. We identified heterozygous mutations in the tyrosine kinase domains of the genes encoding fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3) in LADD families, and in one further LADD family, we detected a mutation in the gene encoding fibroblast growth factor 10 (FGF10), a known FGFR ligand. These findings increase the spectrum of anomalies associated with abnormal FGF signaling.

Abnormalities, Multiple↗
PubMed2006

Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction.

Seven missense mutations and one in-frame deletion mutation have been reported in the coagulation factor C homology (COCH) gene, causing the adult-onset, progressive sensorineural hearing loss and vestibular disorder at the DFNA9 locus. Prevalence of COCH mutations worldwide is unknown, as there is no systematic screening effort for late-onset hearing disorders; however, to date, COCH mutations have been found on four continents and the possibility of COCH playing an important role in presbycusis and disorders of imbalance has been considered. Cochlin (encoded by COCH) has also been shown as a major target antigen for autoimmune sensorineural hearing loss. In this report, we present histopathology, immunohistochemistry and proteomic analyses of inner ear tissues from post-mortem DFNA9 temporal bone samples of an individual from a large Dutch kindred segregating the P51S mutation and adult human unaffected controls, and wild-type (+/+) and Coch null (-/-) knock-out mice. DFNA9 is an inner ear disorder with a unique histopathology showing loss of cellularity and aggregation of abundant homogeneous acellular eosinophilic deposits in the cochlear and vestibular labyrinths, similar to protein aggregation in well-known neurodegenerative disorders. By immunohistochemistry on the DFNA9 temporal bone sections, we have shown cochlin staining of the characteristic cochlear and vestibular deposits, indicating aggregation of cochlin in the same structures in which it is normally expressed. Proteomic analysis identified cochlin as the most abundant protein in mouse and human cochleae. The high-level expression and stability of cochlin in the inner ear, even in the absence and severe atrophy of the fibrocytes that normally express COCH, are shown through these studies and further elucidate the pathobiologic events occurring in DFNA9 leading to hearing loss and vestibular dysfunction.

Adult↗
PubMed2006

The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.

Mutations in the DFNB31 gene encoding the PDZ scaffold protein whirlin are causative for hearing loss in man and mouse. Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear, though its complete spatial and temporal expression patterns remained elusive. Here, we demonstrate that, in embryonic development, the gene is not only expressed in the inner ear, but also in the developing brain and the retina. Various isoforms of whirlin are widely and differentially expressed, and we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b, two proteins that we previously reported to be part of the Usher protein interactome. These proteins co-localize with whirlin at the synaptic regions of both photoreceptor cells and outer hair cells in the cochlea. These findings indicate that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of the pre- and/or postsynaptic side of photoreceptor and hair cell synapses. Whirlin might be involved in synaptic adhesion through interaction with USH2A and VLGR1b as well as in synaptic development as suggested by its spatial and temporal expression patterns. In addition, we demonstrate that whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear. Our data show that whirlin is connected to the dynamic Usher protein interactome and indicate that whirlin has a pleiotropic function in both the retina and the inner ear.

Animals↗
PubMed2006

Estimated cost-effectiveness of active middle-ear implantation in hearing-impaired patients with severe external otitis.

OBJECTIVE: To determine the cost-effectiveness of middle-ear implantations in hearing-impaired patients with severe external otitis in the Netherlands. DESIGN: Cost-effectiveness analysis, using single-subject repeated measures of quality of life and total cost determinations. SETTING: Hospital based. Patients Moderately to severely sensorineurally hearing-impaired patients (n = 21) with severe chronic external otitis, eligible to receive a middle-ear implant. Main Outcome Measure Cost per quality-adjusted life-year (QALY), based on scores of the Medical Outcomes Study Short-Form Health()Survey (SF-36) generic quality of life questionnaire. Only direct costs were included in cost calculation of middle-ear implantation. RESULTS: Mean health utility gain was 0.046 (0.012-0.079) (P = .01) measured at the mental component of the SF-36. With a mean profitable time of 19.4 years and an overall cost of euro 14,354, minimal cost-effectiveness of middle-ear implantation was euro 16,085/QALY. CONCLUSION: Based on the cost per QALY, middle-ear implantation proved to be a cost-effective and justified health care intervention in the Netherlands.

Adolescent↗
PubMed2006

Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss.

In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.

Amino Acid Sequence↗
PubMed2006

No evidence of hearing loss in pseudohypoaldosteronism type 1 patients.

CONCLUSIONS: The fact that pseudohypoaldosteronism type 1 (PHA-1) patients with a defect in the alpha subunit of epithelial sodium channels (ENaC) in the cochlea have normal hearing suggests compensation by alternative sodium transport mechanisms. Consequently, hearing loss due to defective cochlear transmembrane serine protease TMPRSS3 activity is likely to be related to its effect on proneurotrophin cleavage, indicating an action on neurological components of hearing. The normal hearing of PHA-1 patients with affected mineralocorticoid receptors, together with experimental results in animals, indicates that the mineralocorticoid aldosterone is not the most crucial regulator of sodium transport in the cochlea. OBJECTIVE: Profound hearing loss has been observed in patients with a defect in transmembrane serine protease TMPRSS3, the presumed activator of ENaCs. Renal ENaCs and their regulators, such as the mineralocorticoid receptors, are present in the cochlear structures involved in hearing. The aim of this study was to investigate whether PHA-1 patients with defects in these channels or regulators suffer from hearing impairment. MATERIAL AND METHODS: Pure-tone audiometry was performed in four cases with PHA-1 due to mutations in alphaENaC (n=2) or mineralocorticoid receptor (n=2). RESULTS: All examined cases had normal hearing at all tested frequencies.

Adult↗
PubMed2006

Fitting range of the BAHA Cordelle.

The performance of the most powerful Bone-Anchored Hearing Aid (BAHA) currently available, the BAHA Cordelle, was evaluated in 25 patients with severe to profound mixed hearing loss. Patients showed bone conduction thresholds at 500, 1000 and 2000 Hz, ranged between 30 and 70 dB HL, and an additional air-bone gap of about at least 30 dB. With the BAHA Cordelle, free-field thresholds improve relative to bone-conduction thresholds with 1.5, 5.0, 17.8, and 4.3 dB at 500, 1000, 2000, and 4000 Hz, respectively, with substantial inter-individual variability. The differences in unaided air conduction thresholds and aided free-field thresholds amount to 45.3, 45.8, 47.5, and 43.5 dB at 500, 1000, 2000, and 4000 Hz, respectively. Speech perception, measured both with monosyllables of the consonant-vowel-consonant type and with bisyllables, showed highly similar results. The fitting range of a (linear) hearing aid is determined by its gain characteristics. Requiring aided speech reception thresholds at or better than 65 dB SPL results in an upper limit of the fitting range of the BAHA Cordelle for bone-conduction thresholds of 51, 56, 67, and 58 dB HL at 500, 1000, 2000, and 4000 Hz, respectively. The dynamic range provided by the BAHA Cordelle was estimated from loudness growth functions at 500, 1500, and 3000 Hz employing 7-point categorical scaling. On average, aided loudness growth functions exhibit normal slopes but they level off at input levels of about 80, 70, 65 dB SPL for 500, 1500, and 3000 Hz stimuli, respectively. Measurements with a skull simulator demonstrated that the levelling-off reflects saturation of the output of the Cordelle. The relatively low saturation levels of the device suggest that increasing maximum output levels may be a worthwhile consideration for candidates with more profound sensorineural loss.

Acoustic Stimulation↗
PubMed2006

The phenotype of the first otosclerosis family linked to OTSC5.

OBJECTIVE: To report the audiometric and radiologic findings in the first otosclerosis family linked to OTSC5. STUDY DESIGN: A clinical investigation of a family linked to OTSC5, including analyses of audiometric data and of high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members. SETTING: Tertiary referral center. PATIENTS: Family members from a four-generation pedigree with otosclerosis segregating as an autosomal dominant trait. MAIN OUTCOME MEASURE(S): Pre-surgery pure tone audiometric data. Classification of otosclerotic foci on high-resolution spiral CT images of the temporal bones of genetically affected individuals. RESULTS: Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not disclose any clear age dependence of threshold-related data. Systematic differences between mean parameter values relating to the thresholds in the best or the worst ear were found. High-resolution CT images revealed a fenestral otosclerotic focus in seven of nine (78%) clinically affected individuals and cochlear foci in one of these seven patients. CONCLUSION: The phenotype of OTSC5 seems to be variable. Additional long-term audiometric data are needed to construct age-related typical audiograms, which may also facilitate the comparison between phenotypes of the different otosclerosis loci. The detection rate of otospongiotic foci in our study group is similar or lower compared with previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.

Adult↗
PubMed2006

Cochleovestibular and ocular features in a Dutch DFNA11 family.

OBJECTIVES: To report hearing impairment and vestibular and ocular features in a Dutch DFNA11 family and to compare these results to reported data on three other DFNA11 families. STUDY DESIGN: Family study. METHODS: Regression analysis was performed in relation to age to outline the development of hearing thresholds and speech recognition scores. Vestibular and ocular functions were examined. RESULTS: First symptoms of hearing impairment started between the ages of 4 and 43 years. Most of the audiograms were symmetric and flat or downsloping. The annual threshold deterioration increased from 0.2 to 2.6 dB per year at 0.25 to 8 kHz in the longitudinal analyses and in the cross-sectional analysis from 0.3 to 0.9 dB per year. The speech recognition score was quite good, deteriorating by 0.9% per year from a 90% score at the age of 36 years onward. Remarkably, extensive ocular examination including corrected visual acuity and refraction measurements, slit-lamp examination, ophthalmoscopy, Goldmann perimetry, electroretinography and electro-oculography revealed signs of subclinical retinal dysfunction. None of the patients showed the classic triad of retinitis pigmentosa. Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the mutation carriers were fairly similar to previously described DFNA11 families. CONCLUSION: Even though the diverse mutations are located in different regions of the myosin VIIa gene, the cochleovestibular phenotype is fairly similar in all DFNA11 families. Surprisingly, only in this family was subclinical retinal dysfunction detected.

Adult↗
PubMed2006

Rehabilitation of patients with conductive hearing loss and moderate mental retardation by means of a bone-anchored hearing aid.

OBJECTIVE: To evaluate whether the bone-anchored hearing aid (BAHA) can be applied successfully to patients with conductive hearing loss and moderate mental retardation. STUDY DESIGN: Retrospective clinical evaluation. SETTING: Tertiary referral center. PATIENTS: Twenty-two patients with congenital moderate mental retardation and conductive or mixed hearing loss were selected to receive a BAHA at the University Medical Centre Nijmegen, the Netherlands. Four of them were fitted despite a limited air-bone gap. INTERVENTION: Rehabilitative BAHA application. MAIN OUTCOME MEASURES: Implantation results, skin reactions, and audiological data were evaluated during a mean follow-up of 36 months. RESULTS: All the patients were still using the BAHA 7 days a week and for more than 8 hours a day after a follow-up period between 5 and 96 months. Two implants (9%) were lost due to insufficient integration but were reimplanted successfully. With the BAHA, mean free-field thresholds showed a clear mean improvement of 9 dB compared with the previous hearing aid. Considerable improvements in daily activities were seen in at least five patients. CONCLUSION: Moderate mental retardation should no longer be considered as a contraindication for BAHA application. Although implant loss was low, extra attention may be required from the personal care providers to maintain the percutaneous implant. The BAHA was well-accepted by the patients with moderate mental retardation and was being used for most of the day. Implementation of the BAHA as hearing aid treatment in patients with moderate mental retardation proved to be sufficiently effective and may have strongly positive effects on activities at school or at work.

Adolescent↗
PubMed2006

Progressive sensorineural hearing impairment in maternally inherited diabetes mellitus and deafness (MIDD).

OBJECTIVE: To study the progression of hearing impairment (HI) and audiological features in patients with the mitochondrial A to G mutation in the tRNA(LEU(RUU)) gene at position 3,243 associated with maternally inherited diabetes and deafness. DESIGN: Retrospective phenotype genotype family study. SETTING: Tertiary referral center. PATIENTS: Six adult family members with the mitochondrial tRNA(LEU(RUU)) gene mutation at location 3,243. Data were obtained on medical history, otological examination, and pure tone and speech audiometry. Peripheral leukocytes were analyzed for the presence of the mutation, and heteroplasmy levels were determined. Selected patients underwent vestibular testing, brainstem-evoked response audiometry and neurological examination. RESULTS: One patient showed relatively normal hearing, whereas in the others, HI had started at 27 to 79 years of age. All the patients showed progression in HI of approximately 1.4 dB/yr on average at 0.25 and 8 kHz. In the frequency range 0.5 to 2 kHz, progression was approximately 2 dB/yr; at 4 kHz, progression was 2.4 dB/yr. Vestibular and brainstem-evoked response audiometry test results were normal. All the patients achieved the maximum speech recognition score, as was expected based on their pure-tone average at 1, 2, and 4 kHz. CONCLUSION: Our six adult patients with the mitochondrial tRNA(LEU(RUU)) gene mutation at location 3,243 showed almost normal to severe HI which was progressive beyond presbyacusis. Data from the literature and our findings suggest a cochlear localization of the HI.

Adult↗
PubMed2006

Audiologic performance and benefit of cochlear implantation in Usher syndrome type I.

OBJECTIVE: The objective of this retrospective study was to evaluate the benefit and performance of cochlear implantation in patients with Usher syndrome type 1 (USH1). METHODS: Fourteen patients with a clinical diagnosis of USH1 were included. Mutation analysis of USH1 genes was performed in all of them. All patients filled in the G(C)BI questionnaire, which measures the benefit of implantation. In addition, equivalent hearing level scores (EHL) were calculated to measure performance. Correlations between the mentioned parameters were studied. RESULTS: One or two pathogenic mutations were identified in seven of the 14 examined patients. Similar to previous studies, it was demonstrated that implantation at an earlier age results in better performance than implantation at higher age. Cochlear implantation performed within the first 2 decades of life was beneficial to 13 of 14 (93%) of the patients with USH1. Finally, the EHL score and the G(C)BI score showed a significant correlation; the benefit of implantation increases with a decreasing EHL score. CONCLUSIONS: Cochlear implantation in patients with USH1 improves the audiologic performance when patients are implanted at an earlier age and is beneficial according to the G(C)BI when performed within the first 2 decades of life.

Adolescent↗
PubMed2006

Visual impairment in Finnish Usher syndrome type III.

PURPOSE: To evaluate visual impairment in Finnish Usher syndrome type 3 (USH3) and compare this with visual impairment in Usher syndrome types 1b (USH1b) and 2a (USH2a). METHODS: We carried out a retrospective study of 28 Finnish USH3 patients, 24 Dutch USH2a patients and 17 Dutch USH1b patients. Cross-sectional regression analyses of the functional acuity score (FAS), functional field score (FFS*) and functional vision score (FVS*) related to age were performed for all patients. The FFS* and FVS* were calculated using the isoptre V-4 test target instead of the usual III-4 target. Statistical tests relating to regression lines and Student's t-test were used to compare between USH3 patients and the other genetic subtypes of Usher syndrome. RESULTS: Cross-sectional analyses revealed significant deterioration in the FAS (1.3% per year), FFS* (1.4% per year) and FVS* (1.8% per year) with advancing age in the USH3 patient group. At a given age the USH3 patients showed significantly poorer visual field function than the USH2a patients. CONCLUSIONS: The rate of deterioration in visual function in Finnish USH3 patients was fairly similar to that in Dutch USH1b or USH2a patients. At a given age, visual field impairment in USH3 patients was similar to that in USH1b patients but poorer than in USH2a patients.

Adolescent↗