Usher syndrome. Prevalence and phenotype - genotype correlations

Abstract: Aims: the main purpose of this thesis was to estimate the prevalence of Usher syndrome type I, II and III in Sweden (study I) and to determine the clinical differences between Usher syndrome subtypes (studies II-IV). The hypothesis to be tested was that different genes for Usher syndrome will produce different phenotypes even when they belong to the same clinical type (studies II and III).Material and Methods: study I: subjects with Usher syndrome were ascertained through multiple sources in Sweden. Study II: in total 167 subjects with Usher type II participated in this study. Data were obtained from Sweden (116) and from the USA (51). Study III: twenty-eight subjects with Usher syndrome type III (USH3) participated. Study IV: 145 subjects with Usher I and 183 subjects with Usher II were evaluated in this study. Study subjects were included in these studies based on clinical findings of retinitis pigmentosa, sensorineural hearing loss and in some subjects, vestibular areflexia and genetic evaluations (studies I-IV).Results: in total 293 subjects with Usher syndrome were identified. The prevalence of Usher syndrome in Sweden was estimated to 1.6, 1.4 and 0.3/100.000 for type I, II and III respectively. The prevalence of Usher I was found to be significantly higher (8.6 /100.000) in the two northernmost counties (Study I). Study II: the hearing loss in subjects with Usher IIA was found to be more severe and the progression started earlier than in non-IIA (IIB and IIC). Study III: progression of hearing loss in subjects with Usher III (USH3) begins early and approximately 50% of subjects become profoundly deaf by the age of 40 years. Various vestibular abnormalities were found in about 50% of the tested subjects with USH3. Study IV: visual acuity and visual field loss in subjects with Usher syndrome type I and II was both progressive and permanent. Subjects with Usher I was seen to be more visually impaired than subjects with Usher II. Occurrence of cataract was slightly more common in subjects with Usher I than in subjects with Usher II.Conclusions: clinical and phenotype-genotype correlation studies such as those performed in this thesis are necessary to obtain correct clinical diagnosis. The results show that affected subjects with identical genotype had different expressions of the disease, even when they are from the same family maybe because of other environmental and genetic modifiers. The results will also open new possibilities for investigating the etiology, pathogenesis, clinical expression, diagnosis, prognosis and treatment of Usher syndrome.