New Genetic Variants in CYP2B6 and SLC6A Support the Role of Oxidative Stress in Familial Ménière's Disease.

The objective was to study the genetic etiology of Ménière's disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of CYP2B6 and SLC6A could predispose to MD via the oxidative stress pathway. Identification of ASPM and KNTC1 as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.

The impact of cardiovascular diseases on hearing deterioration: a 13-year follow-up study.

OBJECTIVE: To study the impact of cardiovascular diseases (CVDs) on hearing deterioration among ageing adults in a longitudinal setting. Furthermore, to describe the pure tone threshold changes at the 0.125-8 kHz frequency range over 13 years. DESIGN: A population-based follow-up study. STUDY SAMPLE: A random sample of 850 adults, of whom 559 participated in the follow-up study. Otological examination, a structured interview, and pure tone audiometry were conducted. Multivariate regression models were used to estimate the effect of CVD (participants had at least one cardiovascular condition) on hearing deterioration of the better ear hearing level (BEHL), defined as a change in the pure-tone average (PTA) of the frequencies 0.5, 1, 2, and 4 kHz and separately at the lower (0.125, 0.25, and 0.5 kHz) and higher (4, 6, and 8 kHz) frequencies. RESULTS: In the multivariable-adjusted analysis, the BEHL change at 13 years was 0.7 dB greater among participants with CVD (p = 0.3). The mean BEHL change during the 13-year follow-up was 12.0 dB (95% CI 11.4-12.6) among all participants. CONCLUSIONS: No significant association between CVD and hearing threshold changes was found.

Prevalence and incidence of hearing impairment among adults: a 13-year follow-up study.

OBJECTIVE: The aim of this study was to investigate the prevalence and incidence of hearing impairment (HI) in a longitudinal setting among adults. DESIGN: An unscreened, population-based epidemiological 13-year follow-up study. Study sample: 850 randomly sampled 54 to 66-year-old baseline participants, of whom 559 participated in the follow-up study at the age of 68 to 79 years. A questionnaire-based interview, an otological examination and pure-tone audiometry were performed. RESULTS: The overall prevalence of HI was 70.3%, defined by better ear hearing level (BEHL) ≥ 20 dB in the 0.5-4 kHz frequency range. The prevalence was higher among men (78.6%) than among women (63.7%). The overall incidence rate for HI was 45.8 per 1000 person years and the 13-year cumulative incidence was 60.9%. The incidence was higher among men and older participants. CONCLUSION: HI is highly prevalent and incident among older adults in Northern Finland.

Whole-exome sequencing suggests multiallelic inheritance for childhood-onset Ménière's disease.

The genetic background of Ménière's disease (MD) was studied in one patient with childhood-onset MD and his grandfather affected with middle age-onset MD. Whole-exome sequencing was performed and the data were compared to 76 exomes from unrelated subjects without MD. Thirteen rare inner ear expressed variants with pathogenic estimations were observed in the case of childhood-onset MD. These variants were in genes involved in the formation of cell membranes or the cytoskeleton and in genes participating in cell death or gene-regulation pathways. His grandfather shared two of the variants: p.Y273N in HMX2 and p.L229F in TMEM55B. HMX2 p.Y273N was considered the more likely candidate for MD, as the gene is known to affect both hearing and vestibular function. The variant in the HMX2 gene may affect inner ear development and structural integrity and thus might predispose to the onset of MD. As there was a significant difference in onset between the patients, an accumulation of defects in several pathways is probably responsible for the exceptionally early onset of the disease, and the genetic etiology of childhood-onset MD is most likely multifactorial. This is the first molecular genetic study of childhood-onset MD.

Concomitant diseases and their effect on disease prognosis in Meniere's disease: diabetes mellitus identified as a negative prognostic factor.

OBJECTIVE: To study comorbidities and their effect on the disease progression in Meniere's disease (MD). METHODS: Retrospective study on 350 definite MD patients diagnosed according to AAO-HNS 1995 criteria using hospital records and postal questionnaire. RESULTS: The prevalence of migraine, hypothyroidism, allergies, coronary heart disease and autoimmune diseases was more common in MD patients than reported in the general population of Finland. Diabetes mellitus was associated with both more severe hearing impairment (p = .033) and more frequent vertigo (p = .028) in MD patients. The number of concomitant diseases was associated with more frequent vertigo (p = .021). CONCLUSIONS: A patient's concomitant diseases, especially diabetes, should be treated effectively because they might affect the progression of MD. Further studies on the effects of concomitant diseases on MD prognosis are needed.

Hearing impairment is common among Saami adults in Northern Finland.

The Saami are the only indigenous population in Europe and their traditional living area is northern Scandinavia. Hearing impairment (HI) among Saami has not been studied before. The objective was to investigate the presence and type of HI among Saami adults, aged 49-77 years (median age 61 years), living in northern Finland. In addition, the presence of self-reported hearing difficulties, difficulties to hear in background noise and tinnitus were studied. An epidemiological, cross-sectional study encompassing a structured interview, otological examination and audiometry was performed. Bilateral HI was present in 42.9% of men and 29.4% of women, when HI was defined as a pure tone average (PTA) of at least 20 dB hearing level (HL) or more at the frequencies of 0.5, 1, 2 and 4 kHz. In one or both ears (worse ear hearing level, WEHL0.5,1,2,4≥20 dB HL) HI was present in 61.8% of men and 42.2% of women. Sensorineural high frequency hearing impairment was found to be most common. Nearly half (46.9%) of the study subjects reported hearing problems and more than half (55.6%) reported difficulties in following conversation in background noise. Measured HI and subjective hearing difficulties are common among the Saami adults. The healthcare personnel working in this area should be aware of the hearing problems of the Saami population. ABBREVIATIONS: ARHI, Age-related hearing impairment; PTA, Pure tone average; HI, Hearing impairment; HL, Hearing level; BEHL, Better ear hearing level; WEHL, Worse ear hearing level; CI, Confidence interval.

A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment.

Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938-1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.

Mutations in the two ribosomal RNA genes in mitochondrial DNA among Finnish children with hearing impairment.

BACKGROUND: Mutations in the two MT-RNR genes in mitochondrial DNA can cause hearing impairment that presents with variable severity and age of onset. In order to study the prevalence of mutations in MT-RNR1 and MT-RNR2 genes among Finnish children, we studied a ten-year cohort of hearing impaired children born in Northern Finland. METHODS: We studied children, who had been born in Northern Finland in 1993-2002 and who had been ascertained to have hearing impairment by 31 December 2007. Samples from 103 children were sequenced in order to find mutations in the MT-RNR1 and MT-RNR2 genes. RESULTS: One child harboured the pathogenic m.1555A > G mutation in MT-RNR1 suggesting a frequency of 4.4/100,000 in the Finnish paediatric population. In addition, eight rare variants and 13 polymorphisms were found in MT-RNR1 and MT-RNR2 genes. Five of the rare variants were deemed to be haplogroup-specific polymorphisms rather than putative pathogenic mutations, while the remaining three variants have been reported in various haplogroups. Among them m.990 T > C occurs at a conserved site. CONCLUSIONS: The presence of m.990 T > C variant in various haplogroups and the rather high degree of conservation at this site suggest that this transition is a pathogenic rather than homoplasic neutral variant. Identification of further patients with m.990 T > C and segregation analysis in their families should help in determining the pathogenic potential of this variant.

Hearing impairment among adults: the impact of cardiovascular diseases and cardiovascular risk factors.

OBJECTIVE: To investigate the influence of cardiovascular diseases on hearing impairment (HI) among adults. Furthermore, to seek other potential risk factors for HI, such as smoking, obesity, and socioeconomic class. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Cardiovascular diseases did not increase the risk for HI in a propensity-score adjusted logistic regression model: OR 1.24, 95% CI 0.79 to 1.96 for HI defined by better ear hearing level (BEHL), and OR 1.48, 95% CI 0.96 to 2.28 for HI defined by worse ear hearing level (WEHL), in the 0.5-4 kHz frequency range. Heavy smoking is a risk factor for HI among men (BEHL: OR 1.96, WEHL: OR 1.88) and women (WEHL: OR 2.4). Among men, obesity (BEHL, OR 1.85) and lower socioeconomic class (BEHL: OR 2.79, WEHL: OR 2.28) are also risk factors for HI. CONCLUSION: No significant association between cardiovascular disease and HI was found.

Childhood hearing impairment in northern Finland, etiology and additional disabilities.

OBJECTIVES: The purpose of this study was to determine the prevalence and etiology of hearing impairment (HI) in Finnish children and to evaluate the frequency and type of additional disabilities among children with HI. METHODS: Subjects consisted of 214 children with mild to profound HI ascertained until the age of 10 years. They belonged to the birth cohort spanning the years 1993-2002 in northern Finland. The clinical data were collected from the electronic patient records of the Oulu University Hospital. Age at ascertainment, degree and type of HI and audiogram configuration were determined. Risk factors and etiology of HI and co-existing disabilities were recorded. RESULTS: The prevalence of childhood HI was 2.3/1000 live births (95% CI; 2.0, 2.7). The etiology of HI was genetic in 47.2%, acquired in 16.4% and unknown in 36.4% children. Among the 214 children with HI, 101 (47.2%) had other minor or major disabilities. The frequency of additional disabilities did not differ between children with mild HI and those with moderate or severe HI (p=0.78). Additional disabilities were more common (65.7%) in children with acquired HI than in children with genetic or unknown HI (43.6%) (p=0.035). CONCLUSION: The prevalence of childhood HI has remained unchanged in northern Finland as compared to previous studies. Genetic causes were the most common (47%) etiology of childhood HI. Among acquired causes of HI, perinatal risk factors were more common than previously. The frequency of additional disabilities was similar among children with different degrees of HI. Because almost 40% of children had one or more additional disabilities affecting development or learning, it is important to take them into consideration in rehabilitation.

WFS1 mutations in hearing-impaired children.

OBJECTIVE: Mutations in the WFS1 gene can cause Wolfram syndrome or nonsyndromic hearing impairment (HI). The objective of this study was to ascertain the presence of mutations in WFS1 among children with HI from unknown causes. DESIGN: We screened 105 Finnish children with HI for mutations in exon 8 in WFS1. STUDY SAMPLE: Children were born in a defined area in Northern Finland and they had sensorineural, mild to profound, syndromic, or nonsyndromic HI. They were negative for GJB2 mutations and for the m.1555A> G and m.3243A> G mutations in mitochondrial DNA. RESULTS: We found three rare variants and the novel p.Gly831Ser variant in WFS1. Segregation analysis suggested that the novel variant had arisen de novo. The p.Gly831Ser variant may be a new member to the group of heterozygous WFS1 mutations that lead to HI, while the pathogenicity of the rare variant p.Gly674Arg remained unclear. The other two rare variants, p.Glu385Lys and p.Glu776Val, did not segregate with HI in the families. CONCLUSIONS: WFS1 gene mutations are a rare cause of HI among Finnish children with HI.

Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Ménière's disease: A clinical comparison of familial and sporadic Ménière's disease.

PURPOSE This study compared clinical features, predisposing factors, and concomitant diseases between sporadic and familial Ménière's disease (MD). METHOD Retrospective chart review and postal questionnaire were used. Participants were 250 definite patients with MD (sporadic, n =149; familial, n = 101) who fulfilled the American Academy of Otorhinolaryngology-Head and Neck Surgery (1995) criteria. RESULTS On average, familial patients were affected 5.6 years earlier than sporadic patients, and they suffered from significantly longer spells of vertigo (p = .007). The prevalence of rheumatoid arthritis (p = .002) and other autoimmune diseases (p = .046) was higher among the familial patients, who also had more migraine (p = .036) and hearing impairment (p = .002) in their families. CONCLUSION The clinical features of familial and sporadic MD are very similar in general, but some differences do exist. Familial MD patients are affected earlier and suffer from longer spells of vertigo.

Familial aggregation of pure tone hearing thresholds in an aging European population.

OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated. STUDY DESIGN: Multicenter survey in 8 European centers. SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study. RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies. DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects.

High incidence of Meniere-like symptoms in relatives of Meniere patients in the areas of Oulu University Hospital and Kainuu Central Hospital in Finland.

Objective of this study was to systematically investigate the family histories of a large set of patients affected with Meniere's disease to determine the prevalence of familial MD and Meniere-like symptoms in their families. All 640 patients treated at the Oulu University Hospital and Kainuu Central Hospitals during 2005-2010 for Meniere's disease were selected as the initial study population. A postal family history survey was sent to all subjects. Hospital records of all patients were studied to confirm diagnosis and sufficient differential diagnosis. All patients that revealed a positive family history of Meniere's disease or Meniere-like symptoms were phone interviewed and the probability of Meniere's disease in a relative was estimated on a three level scale: probable, possible or unlikely. Affected family members of the patients were recruited to the study if possible. Familial Meniere's disease could be confirmed in 9.3% of patients, but 32.7% patients reported Meniere-like symptoms in their family. It was not possible to confirm all cases, but a family history of Meniere's disease was convincing (confirmed or probable) in 23.4% of the patients. Genetic factors are significant in the development of Meniere's disease.

Audiological follow-up of children with the m.1555A>G mutation in mitochondrial DNA.

The age at onset and the severity of hearing impairment (HI) varies widely among subjects and within families with the m.1555A>G mutation in mitochondrial DNA. We examined prospectively the hearing of 19 children in three nuclear families of a pedigree with m.1555A>G during a period of 7.8 years. The children underwent an audiological examination annually. At the end of the follow-up, the children were 2-13 years old. The parents were asked about the exposure of the children to risk factors of HI. We found that the 19 children with m.1555A>G were born with normal hearing and that 10 of them had developed HI by the end of the follow-up. High frequencies were affected first. The median age at the onset of HI was 3.7 years. Both the severity of HI and the age of onset varied within and between families. Most commonly, audiograms revealed a sensorineural, progressive HI sloping towards high frequencies. We could not identify environmental factors which could modify the development of HI. In conclusion, we were able to pinpoint the time of onset of HI and to follow the progression of HI in childhood. Our results show that there are distinct phenotypes, but at present there are no means to predict which phenotype will develop. It is important to follow up the hearing of children in families with the m.1555A>G mutation, because these children generally pass the newborn hearing screening, and the age at onset or the phenotype of HI cannot be predicted.

Ear diseases and other risk factors for hearing impairment among adults: an epidemiological study.

OBJECTIVE: To investigate the prevalence of ear diseases, other otological risk factors potentially affecting hearing, and noise exposure among adults. Furthermore, subject-related factors possibly associated with hearing impairment (HI), i.e. handedness, eye color, and susceptibility to sunburn, were studied. DESIGN: A cross-sectional, unscreened, population-based, epidemiological study among adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: Chronic middle-ear disease (both active and inactive) was the most common ear disease with a prevalence of 5.3%, while the prevalence of otosclerosis was 1.3%, and that of Ménière's disease, 0.7%. Noise exposure was reported by 46% of the subjects, and it had no effect on hearing among those with no ear disease or other otological risk factors for HI. Dark eye color and non-susceptibility to sunburn were associated with HI among noise-exposed subjects. CONCLUSIONS: Common ear diseases and other otological risk factors constitute a major part of the etiologies of HI among adults. Contrary to previous studies, noise exposure turned out to have only marginal effect on hearing among those with no otological risk factors.

A replication study on proposed candidate genes in Ménière's disease, and a review of the current status of genetic studies.

OBJECTIVE: Multiple candidate genes have been presented for Ménière's disease (MD), but to date no positive replications have been reported. We review here all the previously proposed candidate genes for MD and report our results on the analysis of six such genes, AQP2, KCNE1, KCNE3, HCFC1, COCH, and ADD1. STUDY SAMPLE: A well-defined sample set of 38 sporadic and 21 familial Finnish MD patients. DESIGN: Mutation analysis, case-control study, and review of literature. RESULTS: A polymorphism rs1805127 in the potassium channel gene, KCNE1, was associated with MD in sporadic (p = 0.011), but not familial patients (p = 0.62). In addition, we identified four novel unique variations in the KCNE1 gene. PolyPhen and Mutation Taster analyses indicated that at least one of the variations c.259T > C; p.Trp87Arg is probably damaging to the coded protein. CONCLUSIONS: Our review of the reported candidate genes shows that the current understanding of the genetic factors contributing to the development of MD is limited, and that the study of its etiology would benefit greatly from more comprehensive genetic knowledge.

Self-reported hearing problems among older adults: prevalence and comparison to measured hearing impairment.

BACKGROUND: There are not many population-based epidemiological studies on the association between self-reported hearing problems and measured hearing thresholds in older adults. Previous studies have shown that the relationship between self-reported hearing difficulties and measured hearing thresholds is unclear and, according to our knowledge, there are no previous population-based studies reporting hearing thresholds among subjects with hyperacusis. PURPOSE: The aim was to investigate the prevalence of self-reported hearing problems, that is, hearing difficulties, difficulties in following a conversation in noise, tinnitus, and hyperacusis, and to compare the results with measured hearing thresholds in older adults. RESEARCH DESIGN: Cross-sectional, population-based, and unscreened. STUDY SAMPLE: Random sample of subjects (n=850) aged 54-66 yr living in the city of Oulu (Finland) and the surrounding areas. DATA COLLECTION AND ANALYSIS: Otological examination, pure tone audiometry, questionnaire survey RESULTS: The prevalence of self-reported hearing problems was 37.1% for hearing difficulties, 43.3% for difficulties in following a conversation in noise, 29.2% for tinnitus, and 17.2% for hyperacusis. More than half of the subjects had no hearing impairment, or HI (BEHL[better ear hearing level]0.5-4 kHz<20 dB HL) even though they reported hearing problems. Subjects with self-reported hearing problems, including tinnitus and hyperacusis, had significantly poorer hearing thresholds than those who did not report hearing problems. Self-reported hearing difficulties predicted hearing impairment in the pure-tone average at 4, 6, and 8 kHz, and at the single frequency of 4 kHz. CONCLUSIONS: The results indicate that self-reported hearing difficulties are more frequent than hearing impairment defined by audiometric measurement. Furthermore, self-reported hearing difficulties seem to predict hearing impairment at high frequencies (4-8 kHz) rather than at the frequencies of 0.5-4 kHz, which are commonly used to define the degree of hearing impairment in medical and legal issues.

Audiogram configurations among older adults: prevalence and relation to self-reported hearing problems.

OBJECTIVE: There are only a few population-based epidemiological studies on audiogram configurations among adults. The aim of this study was to investigate the prevalence of different audiogram configurations among older adults. In addition, audiogram configurations among subjects reporting hearing problems were examined. DESIGN: Cross-sectional, population-based, unscreened epidemiological study among older adults. STUDY SAMPLE: The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. RESULTS: The most prevalent audiogram configuration among men was high-frequency steeply sloping (65.3% left ear, 51.2% right ear) and among women, high-frequency gently sloping (33.0% left ear, 31.5% right ear). There were significantly more flat configurations among women than among men. Unclassified audiograms were common especially among women (17.5%). Subjects reporting hearing difficulties, difficulties in following conversation in noise, or tinnitus, more often had a high-frequency steeply sloping configuration than those not reporting. CONCLUSIONS: High-frequency sloping audiogram configurations were common among older adults, and a high-frequency steeply sloping configuration was common among those reporting hearing problems.