Agnete Parving

GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment.

The prevalence of Usher syndrome and other retinal dystrophy-hearing impairment associations

The study was undertaken to procure population‐based prevalence data on the various types of Usher syndrome and other retinal dystrophy‐hearing impairment associations. The medical files on 646 patients with a panretinal pigmentary dystrophy aged 20–49 years derived from the Danish Retinitis Pigmentosa (RP) register were scrutinised. The data were supplemented by a prior investigation on hearing ability in a part of the study population. After exclusion of patients with possibly extrinsic causes of hearing impairments, 118 patients, including 89 cases of Usher syndrome were allocated to one of five clinically defined groups. We calculated the following prevalence rates: Usher syndrome type I: 1.5/100000, Usher syndrome type II: 2.2/100000, and Usher syndrome type III: 0.1/100000 corresponding to a 2:3 ratio between Usher syndrome type I and II. The overall prevalence rate of Usher syndrome was estimated to 5/100000 in the Danish population, devoid of genetic isolates. The material comprised 11 cases with retinal dystrophy, hearing impairment, and additional syndromic features. Finally, 18 subjects with various retinal dystrophy‐hearing impairment associations without syndromic features were identified, corresponding to a prevalence rate of 0.8/100000. This group had a significant overrepresentation of X‐linked RP, including two persons harboring a mutation in the retinitis pigmentosa GTP‐ase regulator (RPGR) gene.

GRM7 variants confer susceptibility to age-related hearing impairment

Age-related hearing impairment (ARHI), or presbycusis, is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. Here we describe the results of the first whole genome association study for ARHI. The study was performed using 846 cases and 846 controls selected from 3434 individuals collected by eight centers in six European countries. DNA pools for cases and controls were allelotyped on the Affymetrix 500K GeneChip for each center separately. The 252 top-ranked single nucleotide polymorphisms (SNPs) identified in a non-Finnish European sample group (1332 samples) and the 177 top-ranked SNPs from a Finnish sample group (360 samples) were confirmed using individual genotyping. Subsequently, the 23 most interesting SNPs were individually genotyped in an independent European replication group (138 samples). This resulted in the identification of a highly significant and replicated SNP located in GRM7, the gene encoding metabotropic glutamate receptor type 7. Also in the Finnish sample group, two GRM7 SNPs were significant, albeit in a different region of the gene. As the Finnish are genetically distinct from the rest of the European population, this may be due to allelic heterogeneity. We performed histochemical studies in human and mouse and showed that mGluR7 is expressed in hair cells and in spiral ganglion cells of the inner ear. Together these data indicate that common alleles of GRM7 contribute to an individuals risk of developing ARHI, possibly through a mechanism of altered susceptibility to glutamate excitotoxicity.

Potential Language and Attentional Networks Revealed through Factor Analysis of rCBF Data Measured with SPECT

We used changes in regional cerebral blood flow (rCBF) to disclose regions involved in central auditory and language processing in the normal brain. rCBF was quantified with a fast-rotating, single-photon emission computerized tomograph (SPECT) and inhalation of 133Xe. rCBF data were obtained simultaneously from parallel, transverse slices of the brain. The lower slice was positioned to include both Brocas and Wernickes areas. The upper slice included regions generally regarded by neurobehaviorists as less related to primary auditory or linguistic functions. We presented three types of auditory stimuli to ten healthy, young volunteers: (a) diotically presented Danish speech, (b) dichotic word stimulation, and (c) white noise. Wilcoxons signed ranks sum test revealed increased rCBF in language-related areas of cortex, viz., Wernickes area and its right-sided homologous area as well as in Brocas area (left hemisphere), when subjects listened to narrative speech, compared to white noise (baseline). No significant rCBF differences were detected with this test during dichotic stimulation vs. white noise. A more sophisticated statistical method (factor analysis) disclosed patterns of functionally intercorrelated regions. The factor analysis reduced the highly intercorrelated rCBF measures from 28 regions of interest to a set of three independent factors. These factors accounted for 77% of the total variation in rCBF values. These three factors appeared to represent statistical analogues of independent brain networks involved in (I) auditory/linguistic, (II) attentional, and (III) visual imaging activity.

Congenital hearing disability — epidemiology and identification: a comparison between two health authority districts

The objective of the present study was to describe some epidemiological aspects of congenital/early acquired (i.e. in the neonatal period) hearing disability (CEHD) in children born between 1980 and 1990, living in two separate health authority districts, i.e. the Copenhagen City/County; in addition, to evaluate the age at identification of the children, the persons raising suspicion of the hearing loss and the pattern of referral; finally, to compare some epidemiological aspects and the age at identification of similarly defined cohorts of children, born 1970-80. Thus the evaluation can be considered as an audit of the primary health care sector concerning children with CEHD. An identical prevalence rate of CEHD was demonstrated, i.e. 1.5/1000 with a better ear hearing level average at 0.5-4 kHz > or = 25 dB (BEHL 0.5-4 kHz) in both regions and unchanged from 1970-80. The median age at identification in the total cohort was 16/18 months in the City/County, respectively, demonstrating a significantly earlier identification of at-risk children in the County with the opposite pattern in the City. The parents were the first to raise suspicion of their childs hearing disability in 50%/57% in the City/County and only minor differences in the pattern of referral was found in the two regions. The frequency of at-risk children among parents/professionals who first suspected the CEHD showed no significant differences; however, the BEHL 0.5-4 kHz in the children was poorer in the group of parents who first raised the suspicion when compared with the group of professionals. Thus the BEHL 0.5-4 kHz is of significance for the age at identification and for the person raising the suspicion of CEHD. Although an improvement in the early identification of CEHD has taken place, when comparing the 1970-80 cohort and 1980-90 cohort, it is concluded that children with CEHD are identified with a substantial delay and that the line of information both concerning high-risk criteria and general information should be continued and intensified towards both parents and professionals.

Middle components of the auditory evoked response in bilateral temporal lobe lesions. Report on a patient with auditory agnosia.

An investigation of the middle components of the auditory evoked response (10--50 msec post-stimulus) in a patient with auditory agnosia is reported. Bilateral temporal lobe infarctions were proved by means of brain scintigraphy, CAT scanning, and regional cerebral blood flow measurements. The middle components were found to be normal regarding latency (pa approximately 30 msec) and configuration of the recordings, when evaluated relative to the peripheral hearing loss in the patient and to the corresponding normative template. Based upon the combined procedures, it is concluded that the middle components cannot be generated exclusively, if at all, in the primary auditory cortex, located in the temporal lobe. Furthermore, the responses are found to be of neurogenic origin according to the methodological procedure applied.

Longitudinal study of hearing

Our knowledge of the progression and aetiology of hearing impairments is mainly inferred from cross-sectional studies of populations or individual case studies of relatively rare conditions. Longitudinal studies of carefully stratified samples enable scientific analysis of these two aspects of the ageing auditory system and also provide much needed incidence data on the basis of which to plan comprehensive hearing services. This preliminary paper using data from two studies over relatively short periods (between 2-4.5 years in Great Britain (GB) and up to 8 years in Denmark (DK] confirms (a) that deterioration of hearing impairment appears to be continuous and gradual for the majority (up to 97% on a 2-year assessment) with a median of about 5-6 dB/decade, and (b) that for mid-frequency average hearing levels applied to the samples of average age 55 (range 40-65) the incidence of hearing impairment is predicted accurately by interpolation of the relevant prevalence figures, and runs at about 1.8% per annum for 25+ dBHL bilateral hearing impairments. However, the actual rate of deterioration does seem to be influenced by age, those over 55 showing a high rate of up to 9 dB/decade against 3 dB/decade for those under 55. This implies that study over a much longer time is required to find a more exact form for the relationship between age and the rate of deterioration of hearing impairments.

Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment

Background: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4. Methods: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Zlow and Zhigh, representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene–environment and gene–gene interactions. Results: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data. Conclusion: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

A Five-Year Longitudinal Study of Hearing in a Danish Rural Population Aged 31–50 Years

Abstract This paper aims to report changes in hearing sensitivity over five years in a rural population aged 31–50 years and to identify risk factors associated with hearing deterioration. The study is prospective and based on data from pure tone audiometry and questionnaires in the Ebeltoft Health Promotion Project in Denmark. A representative sample of 705 subjects had a complete follow-up, including audiometry. The median hearing deterioration was 2.5 dB at 3–4 kHz and 0 dB at 0.5–2 kHz. There was a high degree of individual variability in deterioration. The overall deterioration of hearing sensitivity of the population was largely predicted from the cross-sectional findings reported previously. In the analysis of risk factors, hearing deterioration was defined as an average deterioration 10 dB/5 years at 3–4 kHz in at least one ear. Deterioration was present in 23.5% of the sample. The 41–50-year-olds had a relative risk of deterioration of 1.32 (95% CI 1.01–1.73) compared with the 31–40-year-olds. Males had a relative risk of 1.35 (1.03–1.76) compared with females. The risk was not significantly elevated for a range of other possible risk factors confirmed by logistic regression analysis. In conclusion, deterioration in hearing sensitivity on population level can be predicted on the basis of cross-sectional findings. Hearing sensitivity deteriorated mainly at 3–4 kHz. The deterioration increased with age and was higher in males than in females. Other risk factors were not found. The present study does not support the hypothesis that hypertension or tobacco smoking is associated with deterioration in hearing.