Congenital chloride diarrhea and Pendred syndrome: case report of siblings with two rare recessive disorders of SLC26 family genes.

BACKGROUND: Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION: We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS: Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.

Correction to: The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

The following information was inadvertently omitted in the original publication.

The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

Headphone listening habits, hearing thresholds and listening levels in Swedish adolescents with severe to profound HL and adolescents with normal hearing.

OBJECTIVE: Research has minimally focussed on the music listening habits and preferred sound volumes among adolescents with severe to profound congenital HL. Listening to music played at loud sound volumes and for a long duration of time could imply risks of worsening the HL. Therefore, it is important to investigate the listening habits in adolescents with HL. The aim of the present study was to describe the use of personal music devices, subjective estimated sound levels, measured sound levels, listening habits, and hearing symptoms in adolescents with severe to profound hearing loss compared with adolescents with normal hearing. DESIGN: The study was conducted in two steps. First, a questionnaire was given to students with or without hearing loss. In step two, hearing and sound level measurements were made in a subsample from both groups. STUDY SAMPLE: The study sample were based on 112 seventeen-year-old students with severe to profound hearing loss and 279 adolescents with normal hearing. Hearing thresholds and listening levels was measured on two subsamples based on 29 adolescents with severe to profound hearing loss and 50 adolescents from the group with normal hearing. RESULTS: The results showed that adolescents with severe to profound hearing loss listened to significantly louder sound levels for longer periods. For both groups, those listening at louder sound levels had poorer hearing thresholds. This finding is especially alarming for subjects with hearing loss. Among those listening above 85 dB per occasion, the sound level ranged between 85.8 dB up to 109 dB for those with hearing loss, whereas the sound level ranged between 85.5 dB and 100 dB for those with normal hearing. CONCLUSIONS: Adolescents with congenital hearing loss used portable music devices in the same manner as adolescents with normal hearing. However, adolescents with hearing loss listened to louder sound volumes most likely to compensate for their hearing loss, which significantly increases the risk of further damage to their hearing. From a hearing rehabilitation perspective it could be concluded that aspect of music listening habits should be focussed in order to prevent noise induced hearing loss among individuals with congenital hearing loss.

Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC.

ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid pathways, its precise functional role(s) leading to PHARC disease had not previously been characterized. Cell and zebrafish models were designed to demonstrate the causal link between an identified new missense mutation p.T253R, characterized in ABHD12 from a young patient, the previously characterized p.T202I and p.R352* mutations, and the associated PHARC. Measuring ABHD12 monoacylglycerol lipase activity in transfected HEK293 cells demonstrated inhibition with mutated isoforms. Both the expression pattern of zebrafish abhd12 and the phenotype of specific antisense morpholino oligonucleotide gene knockdown morphants were consistent with human PHARC hallmarks. High abhd12 transcript levels were found in the optic tectum and tract, colocalized with myelin basic protein, and in the spinal cord. Morphants have myelination defects and concomitant functional deficits, characterized by progressive ataxia and motor skill impairment. A disruption of retina architecture and retinotectal projections was observed, together with an inhibition of lens clarification and a low number of mechanosensory hair cells in the inner ear and lateral line system. The severe phenotypes in abhd12 knockdown morphants were rescued by introducing wild-type human ABHD12 mRNA, but not by mutation-harboring mRNAs. Zebrafish may provide a suitable vertebrate model for ABHD12 insufficiency and the study of functional impairment and potential therapeutic rescue of this rare, neurodegenerative disease.

Physical functioning in older persons with dizziness: a population-based study.

BACKGROUND: Dizziness is one of the most prevalent symptoms in old age and tends to increase with age. AIMS: To report physical functioning, health-related aspects and gender differences in elderly persons with and without dizziness in a population-based sample of 75-year-olds. METHODS: A cross-sectional sample of 75-year-olds from Gothenburg, Sweden (n = 675, 398 women and 277 men) was examined by means of questionnaires and functional tests. The questions concerned dizziness/imbalance, physical activity level, walking habits, falls efficacy, number of falls, subjective health or general fatigue and medication. The tests included were self-selected and maximum gait speed, stair climbing capacity, one leg stance and grip strength. RESULTS: More women than men reported dizziness/imbalance (40 vs 30 %, p < 0.001). Persons with dizziness, compared to those without dizziness, less often regularly exercised at a moderate intensity level (summer: 62 vs 74 %, p < 0.001; winter: 41 vs 51 %, p < 0.001), less often took a daily walk (p < 0.05), had lower scores on the FES(S) (p < 0.001), more often reported general fatigue (p < 0.001), more often had fallen in the previous year (40 vs 23 %, p < 0.001) and had a higher intake of medical drugs (4.6 vs 3.3, p < 0.001). They also performed worse regarding gait speed, stair climbing and one leg stance (p < 0.001), but there was no difference in grip strength. CONCLUSION: Older persons with dizziness are less physically active, have worse lower extremity function, are more often fallers and report lower self-rated health than persons without dizziness.

Headphone listening habits and hearing thresholds in swedish adolescents.

INTRODUCTION: The aim of this study was to investigate self-reported hearing and portable music listening habits, measured hearing function and music exposure levels in Swedish adolescents. The study was divided into two parts. MATERIALS AND METHODS: The first part included 280 adolescents, who were 17 years of age and focused on self-reported data on subjective hearing problems and listening habits regarding portable music players. From this group, 50 adolescents volunteered to participate in Part II of the study, which focused on audiological measurements and measured listening volume. RESULTS: The results indicated that longer lifetime exposure in years and increased listening frequency were associated with poorer hearing thresholds and more self-reported hearing problems. A tendency was found for listening to louder volumes and poorer hearing thresholds. Women reported more subjective hearing problems compared with men but exhibited better hearing thresholds. In contrast, men reported more use of personal music devices, and they listen at higher volumes. DISCUSSION: Additionally, the study shows that adolescents listening for ≥3 h at every occasion more likely had tinnitus. Those listening at ≥85 dB LAeq, FF and listening every day exhibited poorer mean hearing thresholds, reported more subjective hearing problems and listened more frequently in school and while sleeping. CONCLUSION: Although the vast majority listened at moderate sound levels and for shorter periods of time, the study also indicates that there is a subgroup (10%) that listens between 90 and 100 dB for longer periods of time, even during sleep. This group might be at risk for developing future noise-induced hearing impairments.

Hearing thresholds, tinnitus, and headphone listening habits in nine-year-old children.

OBJECTIVE: Investigate hearing function and headphone listening habits in nine-year-old Swedish children. DESIGN: A cross-sectional study was conducted and included otoscopy, tympanometry, pure-tone audiometry, and spontaneous otoacoustic emissions (SOAE). A questionnaire was used to evaluate headphone listening habits, tinnitus, and hyperacusis. STUDY SAMPLE: A total of 415 children aged nine years. RESULTS: The prevalence of a hearing threshold ≥20 dB HL at one or several frequencies was 53%, and the hearing thresholds at 6 and 8 kHz were higher than those at the low and mid frequencies. SOAEs were observed in 35% of the children, and the prevalence of tinnitus was 5.3%. No significant relationship between SOAE and tinnitus was found. Pure-tone audiometry showed poorer hearing thresholds in children with tinnitus and in children who regularly listened with headphones. CONCLUSION: The present study of hearing, listening habits, and tinnitus in nine-year old children is, to our knowledge, the largest study so far. The main findings were that hearing thresholds in the right ear were poorer in children who used headphones than in children not using them, which could be interpreted as headphone listening may have negative consequences to children's hearing. Children with tinnitus showed poorer hearing thresholds compared to children without tinnitus.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

Hearing-related, health-related quality of life in patients who have undergone otosclerosis surgery: a long-term follow-up study.

OBJECTIVES: The aims of the study were to assess health-related quality of life and hearing-related disability in subjects with otosclerosis 30 years after surgery. DESIGN: An observational study was performed. Medical records were reviewed, a clinical examination as well as audiometric assessments were performed. Generic health-related quality of life was assessed by the SF-36v2 and hearing disability by a shortened version of SSQ (speech spatial and qualities of hearing scale). STUDY SAMPLE: Sixty-five individuals, who had undergone stapedectomy in 1977-79 at a tertiary referral center. RESULTS: Generic health-related quality of life according to SF-36 subscale scores was comparable to that of an age- and sex-matched reference population. The SF-36 mental component summary score (MCS) was, however, significantly better than that of the reference population. The mental and physical summary component scores correlated significantly to hearing disability measured by the SSQ but not to hearing impairment. Hearing disability was displayed in all SSQ sub-scores, especially in more complex listening situations and in the localization of sounds. CONCLUSIONS: This study shows that individuals with otosclerosis, 30 years after surgery, have a good generic health-related quality of life, despite moderate to severe hearing loss and significant hearing disabilities.

The ICF Core Sets for hearing loss--researcher perspective. Part I: Systematic review of outcome measures identified in audiological research.

OBJECTIVE: To review the literature in order to identify outcome measures used in research on adults with hearing loss (HL) as part of the ICF Core Sets development project, and to describe study and population characteristics of the reviewed studies. DESIGN: A systematic review methodology was applied using multiple databases. A comprehensive search was conducted and two search pools were created, pool I and pool II. STUDY SAMPLE: The study population included adults (≥ 18 years of age) with HL and oral language as the primary mode of communication. RESULTS: 122 studies were included. Outcome measures were distinguished by 'instrument type', and 10 types were identified. In total, 246 (pool I) and 122 (pool II) different measures were identified, and only approximately 20% were extracted twice or more. Most measures were related to speech recognition. Fifty-one different questionnaires were identified. Many studies used small sample sizes, and the sex of participants was not revealed in several studies. CONCLUSION: The low prevalence of identified measures reflects a lack of consensus regarding the optimal outcome measures to use in audiology. Reflections and discussions are made in relation to small sample sizes and the lack of sex differentiation/descriptions within the included articles.

The ICF Core Sets for hearing loss: researcher perspective, Part II: Linking outcome measures to the International Classification of Functioning, Disability and Health (ICF).

OBJECTIVE: To link outcome measures used in audiological research to the ICF classification and thereby describe audiological research from the ICF perspective. DESIGN: Through a peer-reviewed or a joint linking procedure, link outcome measures to the ICF classification system using standardized ICF linking rules. Additional linking rules were developed in combination with the established rules to overcome difficulties when connecting audiological data to ICF. Absolute and relative frequencies of ICF categories were reported. STUDY SAMPLE: The identified outcome measures from the previous study (Part I) constituted the empirical material. RESULTS: In total, 285 ICF categories were identified. The most prevalent categories were related to listening, hearing functions, auditory perceptions, emotions and the physical environment, such as noise and hearing aids. Categories related to communication showed lower relative frequencies, as did categories related to the social and attitudinal environment. CONCLUSIONS: Based on the linked outcome measures, communication as a research topic is subordinated to other research topics. The same conclusion can be drawn for research targeting the social and attitudinal environment of adults with HL. Difficulties in the linking procedure were highlighted and discussed, and suggestions for future revisions of the ICF from the audiological perspective were described.

The ICF core sets for hearing loss project: International expert survey on functioning and disability of adults with hearing loss using the international classification of functioning, disability, and health (ICF).

OBJECTIVE: To identify relevant aspects of functioning, disability, and contextual factors for adults with hearing loss (HL) from hearing health professional perspective summarized using the ICF classification as reference tool. DESIGN: Internet-based cross-sectional survey using open-ended questions. Responses were analysed using a simplified content analysis approach to link concept to ICF categories according to linking rules. STUDY SAMPLE: Hearing health professionals (experts) recruited through e-mail distribution lists of professional organizations and personal networks of ICF core set for hearing loss steering committee members. Stratified sampling according to profession and world region enhanced the international and professional representation. RESULTS: Sixty-three experts constituted the stratified sample used in the analysis. A total of 1726 meaningful concepts were identified in this study, resulting in 209 distinctive ICF categories, with 106 mentioned by 5% or more of respondents. Most categories in the activities & participation component related to communication, while the most frequent environmental factors related to the physical environment such as hearing aids or noise. Mental functions, such as confidence or emotional functions were also frequently highlighted. CONCLUSIONS: More than half (53.3%) of the entire ICF classification categories were included in the expert survey results. This emphasizes the importance of a multidimensional tool, such as the ICF, for assessing persons with hearing loss.

The ICF core sets for hearing loss project: functioning and disability from the patient perspective.

OBJECTIVE: To explore areas of functioning, disability, and environmental factors of adults with hearing loss (HL) by using the ICF classification as a tool to determine and document each element. DESIGN: A qualitative study applying mainly focus-group methodology was applied. STUDY SAMPLE: Thirty-six Dutch and South African adults (≥ 18 years of age) with HL (20-95 dB HL) who used oral communication as first communication. Summative content analysis was performed on the transcripts by linkage to appropriate ICF categories. RESULTS: 143 ICF categories were identified, most of which belonged to the Activities & Participation (d) component, closely followed by the Environmental factors component. Participants specifically mentioned categories related to oral communication and interaction. Assistive technology (such as hearing aids), noise, and support by and attitudes of others in the environment of the participants were considered highly influential for functioning and disability. CONCLUSIONS: The present study illustrates the complex and encompassing nature of aspects involved in functioning and disability of adults with HL. Findings highlight the necessity of using a multidimensional tool, such as the ICF, to map functioning and disability with hearing loss, allowing consideration and evaluation of aspects that are both internal and external.

A longitudinal study of hearing and middle ear status of individuals with cleft palate with and without additional malformations/syndromes.

Objective : To describe and compare the middle ear status and hearing sensitivity in adolescence with isolated cleft palate plus additional malformations and/or syndromes with those with only an isolated cleft palate. Design : Retrospective and longitudinal. Two groups of individuals with isolated cleft palate were compared. Participants : A cohort of individuals born over 4 years in the western region of Sweden. The cohort was divided into one group with isolated cleft palate (n = 31; ICP) and one group with isolated cleft palate plus additional malformations and/or syndromes (n = 37; ICP+). Methods : Middle ear status and hearing thresholds were collected from the medical records at 7, 10, 13, and 16 years of age, examined, and compared within and between groups over time. Results : The ICP+ group demonstrated a significantly higher prevalence of abnormal middle ear status and elevated hearing thresholds as compared with the ICP group. As the individuals aged, the prevalence of abnormal middle ear status decreased. The hearing levels in both groups decreased in the low to middle frequencies as individuals aged; however, the hearing in the high frequencies did not. Conclusions : Individuals with cleft palate need to be followed routinely for middle ear status and hearing thresholds to ensure optimal audiological rehabilitation, with particular attention to those with additional malformations and/or syndromes.

Cognitive skills and the effect of noise on perceived effort in employees with aided hearing impairment and normal hearing.

The aim of the following study was to examine the relationship between working memory capacity (WMC), executive functions (EFs) and perceived effort (PE) after completing a work-related task in quiet and in noise in employees with aided hearing impairment (HI) and normal hearing. The study sample consisted of 20 hearing-impaired and 20 normally hearing participants. Measures of hearing ability, WMC and EFs were tested prior to performing a work-related task in quiet and in simulated traffic noise. PE of the work-related task was also measured. Analysis of variance was used to analyze within- and between-group differences in cognitive skills, performance on the work-related task and PE. The presence of noise yielded a significantly higher PE for both groups. However, no significant group differences were observed in WMC, EFs, PE and performance in the work-related task. Interestingly, significant negative correlations were only found between PE in the noise condition and the ability to update information for both groups. In summary, noise generates a significantly higher PE and brings explicit processing capacity into play, irrespective of hearing. This suggest that increased PE involves other factors such as type of task that is to be performed, performance in the cognitive skill required solving the task at hand and whether noise is present. We therefore suggest that special consideration in hearing care should be made to the individual's prerequisites on these factors in the labor market.

Hearing of 75-year old persons over three decades: has hearing changed?

OBJECTIVE: The state of hearing in 75-year old persons was measured in a population based epidemiological study with the aim of studying if hearing had changed during a time span of 29 years. DESIGN: An epidemiological study of generational effects in three age cohorts. STUDY SAMPLE: Three age cohorts were included: cohort 1 (n: 267) born in 1976-77, cohort 4 (n: 197) in 1990-91, and cohort 6 (n: 570) in 2005. The same test procedures using pure-tone audiometry and a short questionnaire were applied to the three cohorts of 75-year old residents in the same city. RESULTS: The hearing was essentially unchanged during the span of the investigation-almost three decades. Low-frequency hearing was up to about 10 dB poorer in the most recently studied cohort compared to the previously studied cohorts. The reason for this difference is considered to depend on methodological factors. Self-assessed hearing and tinnitus was mainly unchanged, or had minor changes both to the better and to the worse. CONCLUSIONS: The hearing, both measured with pure-tone audiometry and with a short questionnaire, of 75-year old persons has not changed at all, or only marginally, over three decades.

Hearing-aid use and benefit: a long-term follow-up in patients undergoing surgery for otosclerosis.

OBJECTIVES: The aims of the study were to assess hearing-aid uptake in patients with otosclerosis 28-30 years after stapedectomy and to evaluate hearing-aid benefit to users. DESIGN: A retrospective study was performed; it included a review of medical records and follow-up 28-30 years after surgery, including audiometry, clinical examination, structured interview, and a validated questionnaire, IOI-HA. STUDY SAMPLE: Sixty-five patients, who had undergone stapedectomy at a tertiary referral center in 1977-79. RESULTS: In 95% of the subjects there was a theoretical need for hearing-aid amplification at follow-up; 46% of the subjects had no hearing aids, while 26% had unilateral and 28% bilateral hearing aids. Hearing sensitivity in the best ear predicted hearing-aid uptake. Of the subjects with a hearing aid, 94% were everyday users and 54% were full-time users (> 8 hours/day). The subjects reported a high level of satisfaction (mean 4.5) and benefit (mean 4.2), but also residual activity limitations (mean 3.1). CONCLUSIONS: The study shows that there is an unmet need for long-term hearing rehabilitation among patients previously undergoing surgery for otosclerosis. The patients who were using hearing aids were generally very satisfied with their hearing aids, but they still reported residual activity limitations.

Quality of life, effort and disturbance perceived in noise: a comparison between employees with aided hearing impairment and normal hearing.

OBJECTIVES: The aims were to compare health-related quality of life (HRQOL) and hearing handicap between two groups of employees with normal hearing and aided hearing impairment (HI). HRQOL was also compared to a normative population. The second aim was to compare perceived effort (PE) and disturbance after completing a task in office noise between the two study groups. DESIGN: A Swedish version of the short form-36 (SF-36) and the hearing handicap inventory for adults (HHIA) was used to determine HRQOL and hearing handicap. The Borg-CR 10 scale was used to measure PE and disturbance. STUDY SAMPLE: Hearing impaired (n = 20) and normally hearing (n = 20) participants. The normative sample comprised of 597 matched respondents. RESULTS: Hearing-impaired employees report relatively good HRQOL in relation to the normative population, but significantly lower physical functioning and higher PE than their normally-hearing peers in noise. Results from the HHIA showed mild self-perceived hearing handicap. CONCLUSIONS: The current results demonstrate that physical health status can be negatively affected even at a mild-moderate severity of HI, and that a higher PE is reported from this group when performing a task in noise, despite the regular use of hearing aids.

Expressivity of hearing loss in cases with Usher syndrome type IIA.

OBJECTIVE: The purpose of this study was to compare the genotype/phenotype relationship between siblings with identical USH2A pathologic mutations and the consequent audiologic phenotypes, in particular degree of hearing loss (HL). Decade audiograms were also compared among two groups of affected subjects with different mutations of USH2A. DESIGN: DNA samples from patients with Usher syndrome type II were analysed. The audiological features of patients and affected siblings with USH2A mutations were also examined to identify genotype-phenotype correlations. STUDY SAMPLE: Genetic and audiometric examinations were performed in 18 subjects from nine families with Usher syndrome type IIA. RESULTS: Three different USH2A mutations were identified in the affected subjects. Both similarities and differences of the auditory phenotype were seen in families with several affected siblings. A variable degree of hearing loss, ranging from mild to profound, was observed among affected subjects. No significant differences in hearing thresholds were found the group of affected subjects with different pathological mutations. CONCLUSIONS: Our results indicate that mutations in the USH2A gene and the resulting phenotype are probably modulated by other variables, such as modifying genes, epigenetics or environmental factors which may be of importance for better understanding the etiology of Usher syndrome.