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.

Adaptive optics (AO) is an insightful tool that has been increasingly applied to existing imaging systems for viewing the retina at a cellular level. By correcting for individual optical aberrations, AO offers an improvement in transverse resolution from 10-15 μm to~2 μm, enabling assessment of individual retinal cell types. One of the settings in which its utility has been recognised is that of the inherited retinal diseases (IRDs), the genetic and clinical heterogeneity of which warrants better cellular characterisation. In this review, we provide a summary of the basic principles of AO, its integration into multiple retinal imaging modalities and its clinical applications, focusing primarily on IRDs. Furthermore, we present a comprehensive summary of AO-based cellular findings in IRDs according to their associated disease-causing genes.

AimsUsing optical coherence tomography angiography (OCTA) to characterise microvascular changes in the retinal plexuses and choriocapillaris (CC) of patients with MYO7A and USH2A mutations and correlate with genotype, retinal structure and function.MethodsTwenty-seven patients with molecularly confirmed USH2A (n=21) and MYO7A (n=6) mutations underwent macular 6×6 mm OCTA using the AngioVue. Heidelberg spectral-domain OCT scans and MAIA microperimetry were also performed, the preserved ellipsoid zone (EZ) band width and mean macular sensitivity (MS) were recorded. OCTA of the inner retina, superficial capillary plexus (SCP), deep capillary plexus (DCP) and CC were analysed. Vessel density (VD) was calculated from the en face OCT angiograms of retinal circulation.ResultsForty-eight eyes with either USH2A (n=37, mean age: 34.4±12.2 years) or MYO7A (n=11, mean age: 37.1±12.4 years), and 35 eyes from 18 age-matched healthy participants were included. VD was significantly decreased in the retinal circulation of patients with USH2A and MYO7A mutations compared with controls (p<0.001). Changes were observed in both the SCP and DCP, but no differences in retinal perfusion were detected between USH2A and MYO7A groups. No vascular defects were detected in CC of the USH2A group, but peripheral defects were detected in older MYO7A patients from the fourth decade of life. VD in the DCP showed strong association with MS and EZ width (Spearman’s rho =0.64 and 0.59, respectively, p<0.001).ConclusionOCTA was able to detect similar retinal microvascular changes in patients with USH2A and MYO7A mutations. The CC was generally affected in MYO7A mutations. OCT angiography may further enhance our understanding of inherited eye diseases and their phenotype-genotype associations.

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Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 μm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.