Usher Syndrome.

Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) for Usher type 1; USH2A, ADGRV1, and WHRN for Usher type 2; CLRN1 for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.

The lived experiences of work and health of people living with deaf-blindness due to Usher syndrome type 2.

Purpose: This study aimed to explore lived experiences with working life from the perspective of people with deafblindness due to Usher syndrome type 2 (USH2). Background: A limited number of studies have explored working life of people with Usher syndrome. One study of individuals with USH2 showed that work active reported significantly better psychological health compared to non-working individuals. Methods: Seven participants aged 38-50 years with USH2 participated in interviews analysed by interpretative phenomenological analysis. Results: The analyses yielded four themes showing that work is a source of satisfaction and a commitment that needs to be balanced. It is also associated with facing limitations and feelings of uncertainty. Conclusion: Based on the psychology of work model we have demonstrated that work is associated with social connectedness, self-determination and a source of improved health outcomes. There are however also potential health hazards in people with USH2, indicating a need for balance between individual needs and resources, and an adapted environment, for maintaining or regaining health for actively working people with USH2.

Similarities and Differences in Health, Social Trust, and Financial Situation in People With Usher Syndrome, a Bio-Psychosocial Perspective.

PURPOSE: The primary aim was to describe the similarities and differences among the general health, physical health, psychological health, social trust, and financial situations of people with Usher syndrome (USH) types 1, 2, and 3. A second aim was to explore whether age, gender, clinical diagnosis, visual field, visual acuity, and degree of hearing impairment were associated with the general health, physical health, psychological health, social trust, and financial situations of people with USH. METHODS: In this study, 162 people with USH living in Sweden were included, and all three types of the disease were represented. Data concerning vision, hearing, and genetics were retrieved from the Swedish Usher database. Group comparison using frequencies, χ2-tests and Kruskal-Wallis tests for group comparison were used. To examine the effect of independent variables on poor health outcomes, a logistic regression analysis was conducted. RESULTS: Problems with poor health, social trust, and finances were found for all three types; however, more similarities than differences were found. The results of the regression model were ambiguous; it is not clear which independent measures contributed the most to poor outcomes. People with USH3 tended to report the most problems regarding the dependent outcome measures. CONCLUSION: The observations of the associations between the independent variables and poor health, social trust and finances made in the present study are important to bear in mind in a rehabilitation setting; however, they do not fully explain how people with USH actually feel or rate their health. More research is needed to confirm the knowledge that exists within the clinical setting and the life stories told by the people with USH to merge existing knowledge into a rehabilitation setting based on evidence.

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.

[Possibilities to diagnose hearing impairment in children]. / Möjligheter att fastställa orsak till hörselnedsättning hos barn.

Hearing impairment (HI) in children with a congenital or early onset is explained by genetic and environmental factors. Genetic factors are regarded as responsible for more than half of the cases of congenital HI and environmental factors are responsible for another 14-30%, but the etiology is still unknown in 20-40% [1]. Regarding the genetic causes, 30% are considered syndrome related, whereas 70% non-syndromic. Congenital infections and neonatal trauma may explain 20-30%. Without a well-run vaccination program, congenital rubella syndrome remains the most important cause of acquired infectious congenital HI, whereas in more developed areas, congenital cytomegalovirus (cCMV) has become the most common intrauterine infection. cCMV may cause 20% of congenital HI, but it is also responsible for late onset and progressive HI. Development, including advanced MRI, cellular biology and genetic analysis has within a few years provided diagnostic advancements in the etiology of HI.

Life strategies of people with deafblindness due to Usher syndrome type 2a - a qualitative study.

Purpose: To explore life strategies in people with Usher syndrome type 2a. Background: There are no studies on life strategies in people with Usher syndrome. People with deafblindness are often described in terms of poor health and low quality of life, or as being vulnerable. From a clinical point of view, it is of importance to balance this picture, with an increased knowledge of life strategies. Methods: The study had a qualitative explorative design. Fourteen people aged 20-64 years (4 women, 10 men) with USH2a in Sweden participated in focus group interviews, which were transcribed and analysed by qualitative content analysis. Results: The content analysis resulted in seven categories; remaining active, using devices, using support, sharing knowledge, appreciating the present, maintaining a positive image and alleviating emotional pain. Two sub-themes: resolve or prevent challenges and comforting oneself was abstracted forming a theme "being at the helm". Conclusion: The findings show that people with USH2a have a variety of life strategies that can be interpreted as highlighting different aspects of psychological flexibility in a life adjustment process. The study demonstrates that people with USH2a manage in many ways, and metaphorically, by "taking the helm", they strive to actively navigate towards their own chosen values.

Health, work, social trust, and financial situation in persons with Usher syndrome type 1.

BACKGROUND: Research has demonstrated that persons with Usher syndrome type 1 (USH1) have significantly poorer physical and psychological health compared to a reference group. PURPOSE: To explore the relation between work, health, social trust, and financial situation in USH1 compared to a reference group. MATERIAL: Sixty-six persons (18-65 y) from the Swedish Usher database received a questionnaire and 47 were included, 23 working and 24 non-working. The reference group comprised 3,049 working and 198 non-working persons. METHODS: The Swedish Health on Equal Terms questionnaire was used and statistical analysis with multiple logistic regression was conducted. RESULTS: The USH1 non-work group had a higher Odds ratio (95% CI) in poor psychological and physical health, social trust, and financial situation compared to the USH1 work group and reference groups. Age, gender, hearing, and vision impairment did not explain the differences. The relation between the USH1 work and non-work groups showed the same pattern as the reference groups, but the magnitude of problems was significantly higher. CONCLUSIONS: Both disability and unemployment increased the risk of poor health, social trust and financial situation in persons with USH1, but having an employment seemed to counteract the risks related to disability.

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.

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.

An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS.

Whole exome sequence analysis was performed in a Swedish mother-father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders.

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.

Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy.

BACKGROUND: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. MATERIALS AND METHODS: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity. RESULTS: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. CONCLUSIONS: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

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.

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.

A combination of two truncating mutations in USH2A causes more severe and progressive hearing impairment in Usher syndrome type IIa.

OBJECTIVES: Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. DESIGN: A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups. RESULTS: Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations. CONCLUSIONS: The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions.

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.

Aspects of learning from the perspective of people with Alström syndrome.

PURPOSE: The aim of the study was to explore aspects of learning, from a lifelong perspective, in individuals with Alström syndrome (AS). AS is an autosomal recessive disorder causing early blindness, progressive sensorineural hearing loss, cardiomyopathy, endocrine disorders, metabolic dysfunction, and abbreviated lifespan. METHOD: Eleven individuals with AS participated. The study had a qualitative explorative design, giving voice to the participants' perspectives on their situation. Data were collected using semi-structured interviews, which were subjected to conventional (inductive) qualitative content analysis. RESULTS: The analysis revealed in the participants a quest for independence and an image of themselves as capable people willing to learn, but in constant need of support to continue learning throughout their lives to be as independent as possible. CONCLUSION: Based on the levels of functioning, i.e. personal resources, revealed in the interviews, supervisors, caregivers, and teachers are encouraged to allow people with AS to be their own advocates, as they know best how, what, and with whom they learn, and what type of sensory material - tactile, auditory, visual, or a combination - is most helpful. IMPLICATIONS FOR REHABILITATION: Individuals with AS strive for independence, and to be independent they need to continue to learn throughout their lives. Individuals with AS know best how they learn, and should be asked what modalities are the most effective for them. The tactile modality for learning will continue throughout life and should be emphasized early in the individual's education and rehabilitation.

Theory-of-mind in individuals with Alström syndrome is related to executive functions, and verbal ability.

OBJECTIVE: This study focuses on cognitive prerequisites for the development of theory-of-mind (ToM), the ability to impute mental states to self and others in young adults with Alström syndrome (AS). AS is a rare and quite recently described recessively inherited ciliopathic disorder which causes progressive sensorineural hearing loss and juvenile blindness, as well as many other organ dysfunctions. Two cognitive abilities were considered; Phonological working memory (WM) and executive functions (EF), both of importance in speech development. METHODS: Ten individuals (18-37 years) diagnosed with AS, and 20 individuals with no known impairment matched for age, gender, and educational level participated. Sensory functions were measured. Information about motor functions and communicative skills was obtained from responses to a questionnaire. ToM was assessed using Happés strange stories, verbal ability by a vocabulary test, phonological WM by means of an auditory presented non-word serial recall task and EF by tests of updating and inhibition. RESULTS: The AS group performed at a significantly lower level than the control group in both the ToM task and the EF tasks. A significant correlation was observed between recall of non-words and EF in the AS group. Updating, but not inhibition, correlated significantly with verbal ability, whereas both updating and inhibition were significantly related to the ability to initiate and sustain communication. Poorer performance in the ToM and EF tasks were related to language perseverance and motor mannerisms. CONCLUSION: The AS group displayed a delayed ToM as well as reduced phonological WM, EF, and verbal ability. A significant association between ToM and EF, suggests a compensatory role of EF. This association may reflect the importance of EF to perceive and process input from the social environment when the social interaction is challenged by dual sensory loss. We argue that limitations in EF capacity in individuals with AS, to some extent, may be related to early blindness and progressive hearing loss, but maybe also to gene specific abnormalities.