FEATURE An update on inherited retinal disorders (part 1) – overview and assessment of inherited retinal disease BY STACEY STRONG, MICHEL MICHAELIDES nherited Retinal Disease (IRD) is the gene can result in varying phenotypes common inheritance pattern is autosomal leading cause of blindness certification [4], with marked inter- and intra-familial recessive (AR; 30-40%), with mutations in in the working age population (age 16-64 variability being commonplace [3]. the gene USH2A being the most common Iyears) in England and Wales and the This, together with the large number of cause [8]. AD inheritance occurs in 20-30% second most common in childhood [1]. genes that have been identified in IRDs of RP, with mutations in the Rhodopsin The term IRD incorporates a large group of (>300), can result in significant diagnostic (RHO) gene being the most common [8]. disorders that are clinically and genetically challenge. XL RP occurs in 15-20%, with mutations heterogeneous [2]. Well-characterised IRDs and those in the RP GTPase regulator (RPGR) gene IRDs may be sub-categorised in subject to / anticipated to be subject to accounting for the vast majority [8]. There several ways including: (i) according to clinical trial will be described below. is no known family history in 40-50% of photoreceptor involvement, for example, patients at presentation [9]. XLRP and rod or cone; when both are involved Retinitis pigmentosa ARRP are the most severe forms of RP with onset often in childhood. ADRP is milder the nomenclature reflects the order in Retinitis pigmentosa (RP) represents a and often of later onset. Digenic RP is rare which the photoreceptors are affected, group of disorders which are the most and is caused by disease-causing variants for example, rod-cone dystrophies affect common IRD, with an incidence of occurring in both PRPH2 and ROM1 [8]. the rods prior to the cones. Also by (ii) approximately one in 3000 in the USA RP can be isolated (most common) natural history – stationary or progressive and Europe [3,5]. RP is a clinically variable or syndromic. Examples of syndromic disorders; (iii) isolated macular or rod-cone dystrophy, characterised by RP include: Usher syndrome (RP and generalised retinal involvement; and (iv) nyctalopia, and progressive visual field loss neurosensory hearing loss), Bardet Biedl isolated ocular or additional systemic initially, with central visual involvement syndrome (RP with obesity, developmental manifestations (syndromic) [3]. later in the disease process (Figure 1). delay, polydactyly, hypogonadism and renal IRDs may be inherited in an autosomal Clinical examination is characterised abnormalities), Kearns-Sayre syndrome dominant (AD), autosomal recessive by bone-spicule retinal pigmentation, (RP with external ophthalmoplegia, ataxia (AR) or X-linked (XL) manner. IRDs are generalised vascular attenuation and optic and heart block), Abetalipoproteinemia genetically diverse and complex. While disc pallor. (RP with fat malabsorption and progressive certain phenotypes can be caused by RP is a genetically heterogeneous ataxia) and Refsum disease (RP with disease-causing sequence variants in disorder with over 60 genes currently anosmia, deafness, ataxia, neuropathy and different genes, mutations within the same known to cause RP [6,7]. The most icthyosis) [10]. The latter two syndromes can be managed with dietary modification. Multiple avenues of research are being explored in RP including gene and stem cell therapy, pharmacological approaches and artificial vision, with on-going or anticipated clinical trials [11-13]. Figure 1: OCT images centered on the macula Leber congenital amaurosis in a patient Leber congenital amaurosis (LCA) is a without RP (A) and a patient severe congenital / early-onset IRD with with RP (B). Red an incidence of three per 100,000 births arrows: intact [14]. The inheritance pattern is AR with 22 external limiting membrane; genes identified to date which account for Yellow arrows: approximately 70-80% of cases [15]. Three intact ellipsoid of the most common causative genes are: zone (IS/OS junction); Blue GUCY2D (6-21%), CEP290 (10-20%) and arrows: loss RPE65 (5-16%) [16]. of peripheral macular outer Patients present at birth or early retinal layers, infancy with severe visual impairment, with relative nystagmus and amaurotic pupils [5,16]. preservation centrally. Used Other symptoms and signs may include with permission. photoattraction or photophobia, eye news | OCTOBER/NOVEMBER 2016 | VOL 23 NO 3 | www.eyenews.uk.com FEATURE nyctalopia, the oculodigital sign, compared to later onset (adulthood- The fundus appearance in ACHM keratoconus and cataract [16]. LCA can be onset STGD and foveal-sparing STGD) is often normal but RPE disturbance isolated (most common) or syndromic, [13]. Fundus appearance may be normal or atrophy at the macula can be seen e.g. Joubert and Senior-Loken syndrome. in the early stages, with development of [33]. Electrophysiological assessment Fundus examination ranges from a normal increasing macular atrophy / bull’s-eye demonstrates reduced, or absent cone appearance especially at presentation, to maculopathy, and yellow-white flecks at responses with normal rod responses. marked maculopathy, white retinal dots the level of the RPE which are associated SD-OCT findings are variable in ACHM and and bone-spicule pigment migration [16]. with characteristic areas of increased and have implications for anticipated gene Electroretinography is typically non- decreased autofluorescence (Figure 2), therapy trials; outer retinal architecture detectable or severely reduced in LCA [16]; which changes over time. Spectral-domain may be classified as: (1) continuous inner and is helpful in distinguishing between optical coherence tomography (SD-OCT) segment ellipsoid (ISe), (2) ISe disruption, other causes of congenital / early-onset shows loss of outer retinal architecture at (3) absent ISe, (4) foveal hyporeflective nystagmus and reduced visual behaviour, the central macula [21]. zone (Figure 3), and (5) outer retinal including achromatopsia, congenital Electrophysiological assessment is atrophy [36]. stationary night blindness and albinism. useful for both diagnosis and, moreover, Successful rescue of multiple small and Gene therapy-based clinical trials are informing advice on prognosis: Group large animal models of CNGA3 and CNGB3 on-going or planned in the near future for 1 patients have a normal full-field ERG associated ACHM have led to on-going several genetic forms of LCA including (ffERG) in the presence of severe macular and anticipated gene replacement clinical RPE65, MERTK, CEP290, AIPL1 and GUCY2D dysfunction (pattern ERG or multifocal trials for both forms of ACHM [13,35]. [13,17,18]. ERG); Group 2 patients have generalised cone system dysfunction in addition to X-linked retinoschisis Stargardt disease macular dysfunction; and Group 3 patients X-linked retinoschisis (XLRS) affects Stargardt disease (STGD) is the most have both generalised cone and rod 1:5,000-1:20,000 [37], and is caused by common inherited macular dystrophy, system dysfunction in addition to macular disease-causing sequence variants in with a prevalence of one in 10,000 [19], and dysfunction [22,23]. Group 1 is associated the gene RS1, with over 200 variants is caused by recessive sequence variants with a better prognosis compared to Group identified to date. The encoded protein, in the ATP-binding cassette transporter 3; with Group 3 associated with a greater retinoschisin, is secreted and binds to (ABCA4) gene. STGD is characterised rate of progression, worse visual acuity and both photoreceptors and bipolar cells to by toxic accumulation of lipofuscin and loss of peripheral vision over time [22]. help maintain the integrity of the retina related products including the bis-retinoid Multiple avenues of intervention [32]. While penetrance is complete, N-retinylidene-N-retinylethanolamine are currently being explored, including clinical expression is highly variable. (A2E) within retinal pigment epithelium gene therapy, stem cell therapy and Boys typically present in the first or (RPE) cells, resulting in RPE cell pharmacological approaches, with on- second decade of life with strabismus, dysfunction / death, with subsequent going clinical trials in all three areas [13,21]. amblyopia, anisometropia, or having photoreceptor cell dysfunction / loss. failed school vision screening [32,38]. Over 900 disease-causing sequence Achromatopsia The characteristic fundus abnormality variants have been identified in ABCA4 Achromatopsia (ACHM) is an autosomal is a cystic spokewheel-like maculopathy to date, resulting in marked phenotypic recessive cone dysfunction syndrome (foveal schisis), present in about two- heterogeneity including variable age [24]. Disease-causing sequence variants thirds of males, and most readily observed of onset and severity [19,20]. Typical have been identified in five genes that with SD-OCT (Figure 4). Fifty percent of presentation occurs during the first encode components of the cone-specific affected males show additional peripheral or second decade of life with bilateral phototransduction cascade (CNGA3, retinal changes – often a (usually lower central visual loss and dyschromatopsia. CNGB3, GNAT2, PDE6C and PDE6H) temporal) peripheral retinoschisis [19]. Earlier onset (childhood-onset STGD) is [25-30], and also ATF6, which has a role Other peripheral retinal changes include associated with a worse prognosis and in the maintenance of the endoplasmic pigmentary retinopathy,