Suzanne de Bruijn

20 Chapter 1.1 (OCT) is an imaging technique that allows the investigation of the (dis)organization of the retinal layers. 15 In RP, the photoreceptor outer nuclear layer is severely attenuated, whereas the inner nuclear layer and the ganglion cell layer remain fairly well preserved until the late stages of disease. 8 Additional examinations that can be performed to measure visual acuity include specialized charts to determine color vision, dark adaptation thresholds or contrast sensitivity. 8 Electroretinography (ERG) on the other hand provides a more quantitative measure of visual acuity as it measures the electrical response of the retina to flashes of light recorded using an electrode contact lens or an electrode applied to the eye lid. Using dark-adapted dim light (scotopic) or light- adapted bright light (photopic) flashes that stimulate a cone- or rod-driven response, respectively, dysfunctionality of specific photoreceptor types can be distinguished. 15 To date, there are 89 genes associated with non-syndromic RP. 13 RP can be mostly explained by monogenic causes, but there are few cases described with a digenic or mitochondrial inheritance. Additionally, six loci have been described for which the genetic defects are still elusive. In 30-40% of the cases, RP is dominantly inherited, 50- 60% recessively and 5-15% of all cases has an X-linked mode of inheritance. Frequently mutated genes are RHO (25% of dominant RP cases), USH2A (5-10% of recessive RP cases) and RPGR (80% of X-linked cases). 11,15,17 Together these three genes genetically explain one-fifth of all non-syndromic RP cases. Syndromic retinitis pigmentosa In 20-30% of the cases, RP coexists with non-ocular symptoms. 8 Usher syndrome is the most frequent syndromic form of RP. In this syndrome, RP is accompanied with HL and in part of the cases with vestibular dysfunction. Three clinical types of Usher syndrome can be distinguished based on the severity and age of onset of HL and the presence or absence of vestibular symptoms. HL can be profound and congenital, and combined with a vestibular dysfunction (Usher syndrome type I), moderate to severe and non-progressive, without clear vestibular dysfunction (type II) or progressive with a postlingual onset and a variable vestibular phenotype (type III). 8,18 More recently, reports have appeared that describe atypical forms of Usher syndrome that do not fit within one of these categories. Examples of genes that are associated with atypical forms of Usher syndrome are ARSG 19 , CEP250 20 and CEP78 21,22 . Pathogenic variants in these genes have only been reported in a small number of cases, and additional genotype- phenotype studies are required to describe the associated phenotypes in more detail. Other syndromic forms of RP include Bardet-Biedl syndrome, Joubert syndrome and Alström syndrome, which are ciliopathies that originate from defects in ciliary function, and involve multiple organ dysfunction. 11