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Clinical and Genetic Aspects PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/58910 Please be advised that this information was generated on 2021-10-03 and may be subject to change. Hereditary Deaf-Blindness clinical and genetic aspects Ronald Pennings HEREDITARY DEAF-BLINDNESS clinical and genetic aspects Print: PrintPartners Ipskamp, Enschede Cover: The U of Usher is shown in hand alphabet on the cover, whereas the word Usher is shown on the rearside of this thesis. The hands belong to the parents of the author. ISBN 90-9017938-0 © 2004 by Pennings, Ronald Johannes Elisabeth Hereditary Deaf-Blindness, clinical and genetic aspects. Thesis University Nijmegen. All rights reserved. No part of this publication may be reproduced in any form or by any means, electronically, mechanically, by print or otherwise without written permission of the copyright owner. HEREDITARY DEAF-BLINDNESS clinical and genetic aspects Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Katholieke Universiteit Nijmegen, op gezag van de Rector Magnificus, prof. dr. C.W.P.M. Blom, volgens besluit van het College van Decanen in het openbaar te verdedigen op donderdag 29 april 2004 des namiddags om 1:30 precies door Ronald Johannes Elisabeth Pennings geboren op 17 april 1975 te 's-Hertogenbosch Promotores: Prof. Dr. C.W.R.J. Cremers Prof. Dr. A.F. Deutman Copromotor: Dr. H. Kremer Dr. P.L.M. Huygen Manuscriptcommissie: Prof. Dr. H.G. Brunner (voorzitter) Prof. Dr. G. Van Camp (Universiteit Antwerpen) Prof. Dr. C.H. van Os Prof. Dr. H.P.H. Kremer Prof. Dr. L.L.A. Monnens This study was supported by grants from: Forschung contra Blindheit - Initiative Usher syndrom - e.V. ZonMw (AGIKO-project) Nijmegen ORL Research Foundation Heinsius Houbolt Foundation Publication of this thesis was financially supported by: Audire, Oticon Nederland, Beter Horen, Veenhuis Medical Audio, EmiD audiologische apparatuur, Beltone Nederland, Stichting Atze Spoor Fonds, Zon MW, ALVA BV, Glaxo Wellcome, URSAPHARM Benelux BV, Kooij Optiek Hoortoestellen, Schering Plough, UCB Pharma, Mediprof & Carl Zeiss. tu remanebis amicus maximus perpetuo CONTENTS ABBREVIATIONS PREFACE AND AIMS OF THE STUDY page CHAPTER 1: GENERAL INTRODUCTION 13 1.1 Usher syndrome 15 1.2 Wolfram syndrome 31 1.3 A molecular genetic approach to sensorineural hearing impairment 45 1.4 A review of progressive phenotypes in nonsyndromic 79 autosomal dominant hearing impairment. R ] £ Penmngs, Ρ L M Huygen, G Van Camp, CWR J Cremers Audiological Medicine 2003,1 47-55 CHAPTER 2: METHODS 95 2.1 Characterising and distinguishing progressive phenotypes in 97 nonsyndromic autosomal dominant hearing impairment. Ρ h M Huygen, R J E Penmngs, CWR] Cremers Audiological Medicine 2003,1 37-46 CHAPTER 3: USHER SYNDROME 111 3.1 Variable clinical features in patients with CDH23 mutations 123 (USHld-DFNB12). R/E Pennmgs, V Topsakal, L Astuto, Α Ρ M de Brouwer, M Wagenaar, Ρ LM Huygen, W ƒ Kimberhng, A F Deutman, H Kremer, CWR J Cremers Otology & Neurotology 2004, conditionally accepted 3.2 Evaluation of visual impairment in Usher syndrome lb and 129 Usher syndrome Ha. R I E Penmngs, Ρ LM Huygen, D ƒ Orten, M Wagenaar, A van Aarem, H Kremer, W] Kimberlmg, C W R j Cremers Acta Ophthalmologica Scandmavica 2004, in press 3.3 Pure tone hearing thesholds and speech recognition scores 247 in Dutch patients carrying mutations in the USH2A gene. R.J.E. Penmngs, Ρ LM. Huygen, M.D. Weston, A. van Aarem, M Wagenaar, WJ Kimberling, C.W.R.J. Cremers Otology & Neurotology 2003;24 58-63. 3.4 Analysis of optokinetic and vestibular responses related to 161 advancing age and increasing visual impairment in Usher syndrome type Ha. Ρ LM Huygen, R.J.E. Penmngs, M.GM. Nicolasen, A. van Aarem, M.D. Weston, A.F. Deutman, W.I.M. Verhagen, Η. Kremer, W.J. Kimberling, C.W.R.J. Cremers Experimental Brain Research 2004, submitted. 3.5 USH2A mutation analysis in 70 Dutch families with Usher 189 syndrome type II. R.J.E. Penmngs, H. te Bnnke, M D. Weston, A. Claassen, D.J Orten, H. Weekamp, A. van Aarem, P.L.M. Huygen, A.F. Deutman, L.H. Hoefsloot, F Ρ M. Cremers, C.W.R ƒ Cremers, W.J. Kimberling, H. Kremer Human Mutation 2004; conditionally accepted. 3.6 Usher syndrome type III can mimic other types of 203 Usher syndrome. R.J.E. Penmngs, R.R. Fields, P.L.M Huygen, A.F. Deutman, W.J. Kimberling, C.W.R.J. Cremers Annals of Otology, Rhinology & Laryngology 2003;112.525-530. CHAPTER 4: WOLFRAM SYNDROME 217 4.1 Sex-related hearing impairment in Wolfram syndrome 219 patients identified by inactivating WFS1 mutations. R.J E Penmngs, P.L.M. Huygen, j.M.W. van den Ouweland, K. Cryns, L.D. Dikkeschei, G. Van Camp, C W.R.J. Cremers Audiology Neuro-Otology 2004;9:51-62. CHAPTER 5: AUTOSOMAL DOMINANT 239 NONSYNDROMIC LOW-FREQUENCY HEARING IMPAIRMENT (DFNA6/14) 5.1 Progression of low-frequency sensorineural hearing loss 241 (DFNA6/14-WFSÎ) R ƒ E Penmngs, S ƒ H Bom, Κ Cryns, Κ Flothmann, PLM Huygen, Η Kremer, C Van Camp, CVVRj Cremers Archives of Otolaryngology-Head & Neck Surgery 2003,129:421-426 CHAPTER 6: GENERAL DISCUSSION 255 CHAPTER 7: SUMMARY AND CONCLUSIONS 267 Summary and conclusions 269 Samen va tting en conclusies 2 75 Dankwoord 283 Curriculum Vitae 285 List of publications 286 ABBREVIATIONS ANCOVA analysis of covariance ANOVA analysis of variance ARTA age-related typical audiograms CEDOKAN cumulative eye displacement during OKAN DFNA autosomal dominant inherited sensorineural HI DFNB autosomal recessive inherited sensorineural HI DP directional preponderance FFS functional field score FAS functional acuity score FVS functional vision score G gesampt amplitude HI hearing impairment IHC inner hair cell OHC outer hair cell OKAN optokinetic afternystagmus OKN optokinetic nystagmus RP retinitis pigmentosa RPA retinitis punctata albescens RPE retinal pigment epithelium RPSP retinitis pigmentosa sine pigmento SNP single nucleotide polymorphism SPV slow phase velocity Τ time constant ToKAN OKAN time constant TFA threshold features array USH2a Usher syndrome type IIa (genetic subtype) USH2A locus of USH?a USH2A gene of USH2a VoKAN initial velocity of OKAN V initial velocity VA visual acuity VAS visual acuity score VFS visual field score VOR vestibulo-ocular reflex PREFACE AND AIMS OF THIS STUDY Preface This thesis is part of the ongoing Nijmegen Usher syndrome research project, which is directed by Cor Cremers. In this project, families and individual patients with Usher syndrome are contacted and examined to evaluate their clinical features. In addition, blood samples are taken from the patients and their relatives to perform linkage studies and mutation analysis of Usher syndrome genes. These genetic studies are performed at the Center for the Study and Treatment of Usher syndrome, in the Boys Town National Research Hospital in Omaha, USA (Bill Kimberling) and, since 2000, DNA samples of Usher syndrome families are also analysed at the Department of Human Genetics of the UMC St Radboud at Nijmegen, the Netherlands (Hannie Kremer, Heleen te Brinke, Lies Hoefsloot and Frans Cremers). The first Nijmegen PhD thesis on Usher syndrome has been written by Annelies van Aarem (1996, Heterogeneity in the Usher syndrome) and the second PhD study was written by Mariette Wagenaar (2000, The Usher syndrome, a clinical and genetic correlation). This is the third thesis, bearing on the third Usher syndrome project that started in april 2001. It was facilitated by a grant from the German foundation Forschung Contra Blindheit- Initiative Usher syndrom (Mr. And Mrs. Ger & Angelika König). At the beginning of this project, the PhD student involved had to learn how to perform a family study. A family with low-frequency hearing impairment was examined and within two months mutations in the Wolfram syndrome 1 gene (WFS1) were found to be responsible for the hearing impairment (DFNA6/14) in that family. As Wolfram syndrome, similar to Usher syndrome, is a deaf-blindness syndrome, it was decided to study families with this syndrome as well. This was done in close cooperation with the Department of Medical Genetics of the University of Antwerp in Antwerp, Belgium (Guy Van Camp & Kim Cryns), and the Department of Clinical Chemistry of the Isaia Clinics in Zwolle, the Netherlands (Bert Dikkeschei & Jody van den Ouweland). In May 2003, the fourth Nijmegen Usher syndrome research project has started (Rutger Plantinga). This project will study the genotype-phenotype correlation in Finnish Usher syndrome type III patients and is performed in close cooperation with Finnish scientists, who have examined many of these patients exhibiting progressive hearing loss (Leenamaija Kleemola) and who have cloned the USH3 gene (Eeva-Marja Sankila). Aims of the study 1. To develop in more detail a useful method to analyse audiometrie data and thus to classify and distinguish families with hearing impairment in order to guide future linkage and gene identification studies. 2. To further delineate the phenotype of several genetic subtypes of Usher syndrome, hereby focusing on audiometrie, ophthalmological and vestibular examination results. 3. To perform linkage and mutation analysis of the ÜSH2A gene in Dutch Usher syndrome type II families in order to support the DNA diagnostics and genetic counselling of Usher syndrome families. 4. To evaluate and analyse the audiovestibular features ofWolfram syndrome patients and their relatives. 5. To evaluate and analyse the audiometrie findings associated with DFNA6/14. The general introduction is divided into four sections. In the first two sections specific attention is paid to Usher syndrome and Wolfram syndrome. The historical perspective, clinical characteristics and genetic characteristics are described for these two syndromes.
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