Claes Möller

Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II.

Usher syndrome type II (USH2) is a genetically heterogeneous autosomal recessive disorder with at least three genetic subtypes (USH2A, USH2B, and USH2C) and is classified phenotypically as congenital hearing loss and progressive retinitis pigmentosa. The VLGR1 (MASS1) gene in the 5q14.3-q21.1 USH2C locus was considered a likely candidate on the basis of its protein motif structure and expressed-sequence-tag representation from both cochlear and retinal subtracted libraries. Denaturing high-performance liquid chromatography and direct sequencing of polymerase-chain-reaction products amplified from 10 genetically independent patients with USH2C and 156 other patients with USH2 identified four isoform-specific VLGR1 mutations (Q2301X, I2906FS, M2931FS, and T6244X) from three families with USH2C, as well as two sporadic cases. All patients with VLGR1 mutations are female, a significant deviation from random expectations. The ligand(s) for the VLGR1 protein is unknown, but on the basis of its potential extracellular and intracellular protein-protein interaction domains and its wide mRNA expression profile, it is probable that VLGR1 serves diverse cellular and signaling processes. VLGR1 mutations have been previously identified in both humans and mice and are associated with a reflex-seizure phenotype in both species. The identification of additional VLGR1 mutations to test whether a phenotype/genotype correlation exists, akin to that shown for other Usher syndrome disease genes, is warranted.

Localization of Usher syndrome type II to chromosome 1q

Usher syndrome is characterized by congenital hearing loss, progressive visual impairment due to retinitis pigmentosa, and variable vestibular problems. The two subtypes of Usher syndrome, types I and II, can be distinguished by the degree of hearing loss and by the presence or absence of vestibular dysfunction. Type I is characterized by a profound hearing loss and totally absent vestibular responses, while type II has a milder hearing loss and normal vestibular function. Fifty-five members of eight type II Usher syndrome families were typed for three DNA markers in the distal region of chromosome 1q: D1S65 (pEKH7.4), REN (pHRnES1.9), and D1S81 (pTHH33). Statistically significant linkage was observed for Usher syndrome type II with a maximum multipoint lod score of 6.37 at the position of the marker THH33, thus localizing the Usher type II (USH2) gene to 1q. Nine families with type I Usher syndrome failed to show linkage to the same three markers. The statistical test for heterogeneity of linkage between Usher syndrome types I and II was highly significant, thus demonstrating that they are due to mutations at different genetic loci.

Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11

Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization establishes the existence of a new and independent locus for Usher syndrome.

The high prevalence of otitis media with effusion in children with cleft lip and palate as compared to children without clefts

OBJECTIVES Children with cleft lip and palate universally present with otitis media with effusion. This prevalence has not been systematically studied. The purpose of the present study was to examine and compare the prevalence of otitis media with effusion, hearing sensitivity, and audiometry method utilised for assessment in children with and without clefts. METHODS Two groups of children (children with unilateral cleft lip and palate, N=22, and children without clefts, N=20) were followed prospectively and longitudinally from 1 to 5 years of age. Data were collected at four points (1, 1.5, 3, and 5 years of age). Assessments at each of the four points included: (1) otomicroscopy, (2) tympanometry, and (3) hearing assessment. RESULTS Overall the children with unilateral cleft lip and palate demonstrated a significantly higher prevalence of otitis media with effusion (121 ears, 74.7%) than children without clefts (31 ears, 19.4%) (p<0.001). This higher prevalence was also significant at 1, 1.5, 3, and 5 years of age (p<0.001). Of those ears with otitis media with effusion, 83.1% of the ears exhibited a hearing loss (PTA >20 dB), with this loss more prevalent in the cleft group (89.7% UCLP and 70.0% non-cleft). The hearing loss was significantly more pronounced in the cleft (group 35.71 dB HL UCLP and 26.41 dB HL non-cleft group). Children with unilateral cleft lip and palate utilised a lower age-appropriate audiometry testing method than age-matched children with no cleft at 1, 1.5, and 3 years of age. CONCLUSIONS Children with unilateral cleft lip and palate present with a significantly higher prevalence of otitis media with effusion than children without cleft. Also, the hearing loss associated with otitis media with effusion is demonstrated in this study. Furthermore, the method of audiometry has been examined and children with unilateral cleft lip and palate had to be assessed with a lower level of method than children without cleft.

Usher syndrome: An otoneurologic study

Usher syndrome is an autosomal recessive disorder characterized by severe hearing loss or deafness and retinitis pigmentosa. Eleven families with 25 affected members were studied. The test battery included genetic studies, clinical examination, audiological, ophthalmologic, and otoneurological tests, and magnetic resonance imaging. Sixteen affected persons had profound hearing loss or were considered anacusic, with absent bilateral vestibular responses. These patients had varying degrees of retinitis pigmentosa. These 16 patients were considered to have type I Usher syndrome. Nine persons were diagnosed as Usher type II with a moderate to profound hearing loss, normal vestibular function, and retinitis pigmentosa of varying degree. Magnetic resonance imaging was normal in all cases. Otoneurological tests indicated no central nervous system disturbances. The conclusion is that hearing loss and balance problems in Usher syndrome are due to inner ear damage with no evidence of central nervous system disturbances. Furthermore, the ataxia seen in Usher type I is due to a combination of retinitis pigmentosa and bilateral peripheral vestibular deficiency.

Assessment of hearing and hearing disorders in rock/jazz musicians: Evaluación de la audición y de los problemas auditivos en músicos de rock y jazz

The aim of this study was to assess hearing and hearing disorders among rock/jazz musicians. One hundred and thirty-nine (43 women and 96 men) musicians participated. The results are based on pure-tone audiometry and questionnaire responses. According to our definition of hearing loss, tinnitus, hyperacusis, distortion and/ or diplacusis as hearing disorders, we found disorders in 74% of the rock/jazz musicians studied. Hearing loss, tinnitus and hyperacusis were most common, and the latter two were found significantly more frequently than in different reference populations. The women showed bilateral, significantly better hearing thresholds at 3–6 kHz than the men. Hyperacusis, and the combination of both hyperacusis and tinnitus, were found to be significantly more frequent among women than among men. Hearing loss and tinnitus were significantly more common among men than among women. It is important to evaluate all kinds of hearing problems (other than hearing loss) in musicians, since they represent an occupational group especially dependent on optimal, functional hearing. On the basis of our results, we suggest that hearing problems such as tinnitus, hyperacusis, distortion and/ or diplacusis should, in addition to hearing loss, be defined as hearing disorders. El objetivo de este estudio fue evaluar la audición y los problemas auditivos entre músicos de rock y jazz. Participaron ciento treinta y nueve músicos (43 mujeres y 96 hombres). Los resultados se basan en una audiometría tonal y las respuestas a un cuestionario. De acuerdo con nuestra definición de hipoacusia, acúfeno, hiperacusia, distorsión y/o diploacusia, encontramos problemas en un 74% de los músicos de rock y jazz estudiados. Las entidades más comunes fueron la hipoacusia, el acúfeno y la hiperacusia y éstas últimas dos, se hallaron más frecuentes que en diferentes poblaciones de referencia. Se encontró que la audición en 3–6kHz fue significativamente mejor en mujeres que en hombres. Así mismo se encontró que la hiperacusia y la combinación de hiperacusia y acúfeno, son significativamente más frecuentes entre las mujeres que entre los hombres. En los hombres fue más común la hipoacusia y el acúfeno. Es importante evaluar todo tipo de problema auditivo (además de la hipoacusia) en los músicos, puesto que se trata de un grupo especialmente dependiente del Óptimo funcionamiento de la audición. Con base en nuestros resultados, sugerimos que además de la hipoacusia, se considere que el acúfeno, la hiperacusia, la distorsión y/o la diploacusia deben ser definidos como problemas auditivos.

Spectrum of USH2A Mutations in Scandinavian Patients with Usher Syndrome Type II

Usher syndrome type II (USH2) is an autosomal recessive disorder, characterised by moderate to severe high‐frequency hearing impairment, normal balance function and progressive visual impairment due to retinitis pigmentosa. Usher syndrome type IIa, the most common subtype, is defined by mutations in the USH2A gene encoding a short and a recently discovered long usherin isoform comprising 21 and 73 exons, respectively. More than 120 different disease‐causing mutations have been reported, however, most of the previous reports concern mutations restricted to exons 1–21 of the USH2A gene. To explore the spectrum of USH2A disease‐causing mutations among Scandinavian USH2 cases, patients from 118 unrelated families of which 27 previously had been found to carry mutations in exons 1–21 were subjected to extensive DNA sequence analysis of the full size USH2A gene. Altogether, 122 USH2A DNA sequence alterations were identified of which 57 were predicted to be disease‐causing, 7 were considered to be of uncertain pathogenicity and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations 31 were located in exons 22–73, specific to the long isoform. USH2A mutations were identified in 89/118 (75.4%) families. In 79/89 (88.8%) of these families two pathogenic mutations were identified whereas in 10/89 (11.2%) families the second mutation remained unidentified. In 5/118 (4.2%) families the USH phenotype could be explained by mutations in the USH3A gene. The results presented here provide a comprehensive picture of the genetic aetiology of Usher syndrome type IIA in Scandinavia as it is known to date.

Genetic Heterogeneity of Usher Syndrome: Analysis of 151 Families with Usher Type I

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.

International classification of functioning, disability, and health core sets for hearing loss: a discussion paper and invitation

Abstract The World Health Organization’s International Classification of Functioning, Disability and Health (ICF) has adopted a multifactorial understanding of functioning and disability, merging a biomedical paradigm with a social paradigm into a wider understanding of human functioning. Altogether there are more than 1400 ICF-categories describing different aspects of human functioning and there is a need to developing short lists of ICF categories to facilitate use of the classification scheme in clinical practice. To our knowledge, there is currently no such standard measuring instrument to facilitate a common validated way of assessing the effects of hearing loss on the lives of adults. The aim of the project is the development of an internationally accepted, evidence-based, reliable, comprehensive and valid ICF Core Sets for Hearing Loss. The processes involved in this project are described in detail and the authors invite stakeholders, clinical experts and persons with hearing loss to actively participate in the development process. Sumario La Clasificación sobre Funcionalidad, Discapacidad y Salud de la Organización Mundial de la Salud (ICF) ha adoptado un acercamiento multifactorial de la funcionalidad y la discapacidad, fusionando un paradigma biomédico con un paradigma social de una forma más amplia. En su conjunto hay más de 1400 categorías ICF que describen diferentes aspectos de la funcionalidad humana y existe la necesidad de desarrollar una lista corta de categorías ICF para facilitar el uso de la clasificación en un esquema para la práctica clínica. Es de nuestro conocimiento que actualmente no existe un instrumento de medición estándar que facilite una forma válida y cómoda para evaluar los efectos de la hipoacusia en la vida de los adultos. El propósito de este proyecto es desarrollar un conjunto básico de condiciones de salud ICF para la hipoacusia que sea internacionalmente aceptado, basado en evidencia, confiable e integral. Se describen en detalle los procesos implicados en este proyecto y los autores invitan a las personas interesadas, a los expertos clínicos y a las personas con hipoacusia a participar activamente en el desarrollo de este proceso.

Genetic heterogeneity of Usher syndrome type II: localisation to chromosome 5q

Usher syndrome is a group of autosomal recessive disorders that includes retinitis pigmentosa (RP) with hearing loss. Usher syndrome type II is defined as moderate to severe hearing loss with RP. TheUSH2A gene at 1q41 has been isolated and characterised. In 1993, a large Usher II family affected with a mild form of RP was found to be unlinked to 1q41 markers. Subsequent linkage studies of families in our Usher series identified several type II families unlinked to USH2A andUSH3 on 3q25. After a second unlinked family with many affected members and a mild retinal phenotype was discovered, a genome search using these two large families showed another Usher II locus on 5q (two point lod = 3.1 at D5S484). To date, we have identified nine unrelated 5q linked families (maximum combined multipoint lod = 5.86) as well as three Usher II families that show no significant linkage to any known Usher loci. Haplotype analysis of 5q markers indicates that the new locus is flanked by D5S428 and D5S433. Review of ophthalmological data suggests that RP symptoms are milder in 5q linked families; the RP is often not diagnosed until patients near their third decade. Enamel hypoplasia and severe, very early onset RP were observed in two of the three unlinked families; dental anomalies have not been previously described as a feature of Usher type II.