Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy

Abstract

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype-phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: GUCA1A, PRPH2, ABCA4 and RPGR Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.

Keywords: dystrophy; genetics; imaging; retina.

Figure 1

Schematic diagram of the phototransduction cascade including genes related to progressive cone dystrophies (CODs) and cone-rod dystrophies (CORDs). The cascade is triggered in the photoreceptor disc membrane by light-induced activation of rhodopsin, which subsequently activates transducin and phosphodiesterase (PDE). Activated PDE leads to cGMP hydrolysis to GMP. The decreased intracellular cGMP levels induce cation channel closure in the outer segment membrane and result in photoreceptor hyperpolarisation. Steps leading to photoreceptor activation are denoted by green arrows, whereas those causing photoreceptor deactivation are marked by red arrows. Corresponding genes for the proteins associated with CODs/CORDs are indicated by dashed lines. COD-associated genes are coloured in light blue and CORD-associated genes in dark blue, while those that can cause either phenotype are in grey. cGMP, cyclic GMP; CNG, cyclic nucleotide-gated; GCAP, guanylate cyclase-activating protein; GDP, guanosine diphosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IRBP, interphotoreceptor retinoid-binding protein; LRAT, lecithin retinol acyltransferase; PDE, phosphodiesterase; RDH, retinol dehydrogenase; RPE65, retinal pigment epithelium 65 kDa.

Figure 2

Frequency of disease-causing genetic variants leading to progressive cone dystrophies (CODs) and cone-rod dystrophies (CORDs), using studies with clearly indicated cohort sizes (listed in online supplementary tables 1-3). (A) Prevalence of the mode of inheritance for CODs and CORDs. The underlying disease-causing gene is identified in 56.3% of COD/CORD cases, of which most (43.2%) are of autosomal recessive (AR) inheritance. This is followed by autosomal dominant (AD) inheritance (12.2%) and X linked (XL) inheritance (0.9%) patterns. The remaining 43.7% of patients are unsolved with regard to molecular causation. (B) AD inheritance of CODs and CORDs. Mutations in 10 genes are currently associated with AD-COD/CORD, over 75% of which are accounted for by GUCY2D, PRPH2, CRX and GUCA1A. (C) AR inheritance of CODs and CORDs. Mutations in 18 genes are currently associated with AR-COD/CORD, of which ABCA4 is by far the most common (62.2%). (D) XL inheritance of CODs and CORDs. Mutations in 4 genes are currently associated with XL-COD/CORD, of which RPGR accounts for 73.0% of cases.

Figure 3

Longitudinal analysis of phenotypically heterogeneous GUCA1A-associated retinopathy (p.(Tyr99Cys) substitution). Fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging in unrelated subjects (A and B) harbouring the p.(Tyr99Cys) (Y99C) variant in GUCA1A. The left column shows FAF at baseline, and the right column that at the same location on follow-up. Red arrowheads point to the transfoveal OCT line scan at the location denoted by red dashes on FAF. Subject (A): presented with cone dystrophy (A-I baseline) which progressed over a follow-up period of 8 years (A-I follow-up). High magnification (×5) of the same location in the foveal centre (A–II) at baseline and follow-up (left and right, respectively) shows a greater degree of disruption to the ellipsoid zone (EZ) in the latter (black arrows). Subject (B): presented with isolated macular dystrophy which progressed over a 4-year follow-up period. FAF and OCT scans are in the same scale; scale bar=200 µm.

Figure 4

Fundus photography, fundus autofluorescence (FAF) and optical coherence tomography (OCT) imaging in unrelated patients with PRPH2-associated and RPGR-associated cone-rod dystrophy (CORD). Subjects (A) and (B) possess the p.(Arg172Trp) (R172W) variant in PRPH2. Subject (C) possesses the c.2847_2848delinsCT, p.(E950*) variant in RPGR. Subject (A): fundus photographs of both eyes (I–II) show bilateral bull’s eye maculopathy-like retinal pigment epithelial (RPE) changes. FAF imaging of the left eye at baseline (III) and on 11-year follow-up (IV) displays a florid speckled appearance with areas of increased and decreased macular autofluorescence. The area of affected retina is substantially increased in (IV), with red dashes denoting the location of the OCT scan (V). The inner segment ellipsoid photoreceptor-derived layer (the ellipsoid zone, EZ) between the red arrows in (V) is absent. Subject (B): fundus photographs of both eyes (VI–VII) showing marked bilateral macular atrophy, peripheral areas of RPE atrophy and pigmentation. Corresponding FAF images are shown in (VIII–IX). This patient has severe CORD with an acuity of counting fingers bilaterally and constricted peripheral visual fields. Subject (C): fundus photographs of both eyes (X–XI) showing bilateral macular atrophy, which corresponds to the areas of decreased macular autofluorescence. FAF imaging of the right eye at baseline (XII) and on 7-year follow-up (XIII) shows an increase in the hypoautofluorescent area and surrounding hyperautofluorescent ring. The red dashes in (XIII) denote the location of the OCT scan (XIV), in which the temporal border of the photoreceptor layer is marked with a red arrow. At its nasal aspect, the integrity of the photoreceptor layer is disrupted.

Figure 5

Fundus autofluorescence (FAF) and adaptive optics (AO) imaging in ABCA4-associated cone-rod dystrophy (CORD). (A) FAF image at baseline showing a central region of hypoautofluorescence surrounded by increased signal, and (B) aligned FAF image on 2-year follow-up demonstrating disease progression with an increased area of hypoautofluorescence. The red square signifies the superimposed adaptive optics scanning light ophthalmoscopy (AOSLO) montage acquired from that region on follow-up. (C) Confocal AOSLO image (photoreceptor outer segments) and (D) split-detection AOSLO image (photoreceptor inner segments) over the transition zone between less affected and more affected retina. For comparison, the side bars on the left show AOSLO images of an unaffected control at similar retinal eccentricity. Cone photoreceptors (green arrows) can be more reliably identified using split-detection imaging due to the poor wave guiding ability of outer segments in the confocal modality. The border of the transition zone (red arrows) in (C) corresponds to the presence of remnant cone inner segments in (D). The photoreceptor mosaic in CORD is disorganised, with altered regularity and reflectance compared to that of an unaffected eye. The number of cones is decreased in areas that appear healthy on FAF, demonstrating a disconnect between imaging modalities and supporting the utility of multimodal imaging. AOSLO images were acquired using a custom-built AOSLO housed at University College London (UCL) / Moorfields Eye Hospital (MEH); scale bar=200 µm.