Table 1.
Summary of cellular findings using adaptive optics (AO) in inherited retinal diseases (IRDs) according to the disease-associated gene. Phenotypic characterisation studies applying AO in genetically-defined IRD patients were included following a literature search in February 2018. Diseases are listed in alphabetical order with nomenclature as per the online Mendelian inheritance in man (OMIM) database. Abbreviations: AO-FIO, adaptive optics flood illumination ophthalmoscopy; AOSLO, adaptive optics scanning laser ophthalmoscopy; RPE, retinal pigment epithelium; SD-OCT, spectral domain optical coherence tomography
| Inherited Retinal Disease | Gene Symbol | Gene OMIM # | Phenotype OMIM # | Imaging Modality | Retinal Findings | Citations |
|---|---|---|---|---|---|---|
| Achromatopsia 2 | CNGA3 | #600053 | #216900 | AOSLO | Varied findings, from reduced cone density and reflectivity, to complete cone and rod mosaic. | [124] |
| Achromatopsia 3 | CNGB3 | #605080 | #262300 |
AO-FIO AOSLO |
Severely disrupted foveal and parafoveal photoreceptor mosaic. Residual foveal cone structure varies from sparse arrangement to absent. Presence of an ‘intraretinal bubble' noted in some patients. | [51, 73, 125] |
| Achromatopsia 4 | GNAT2 | #139340 | #613856 |
AO-FIO AOSLO |
Clearly defined parafoveal mosaic with slightly reduced foveal cone density. Residual cone density and reflectivity greater than in patients with CNGA3/CNGB3-associated achromatopsia. | [83, 126] |
| Bietti crystalline corneoretinal dystrophy | CYP4V2 | #608614 | #210370 |
AO-FIO AOSLO |
Decreased cone density at parafoveal regions corresponding to RPE loss, with otherwise normal cone spacing. Microscopic bright spots visible, which correspond to small yellow-white crystalline deposits seen on fundoscopy; these are possibly residual cones over the crystals. | [127–129] |
| Blue cone monochromacy |
OPN1LW OPN1MW |
#300822 #300821 |
#303700 | AOSLO | Decreased cone density, partly attributable to cone misidentification in areas with low cone reflectivity. On imaging with split-detection AOSLO, these areas contain remnant inner segment structures. In patients with L/M interchange mutations, a large foveal lesion was present with slightly improved parafoveal cone density as compared to those with a p.Cys203Arg mutation. | [130–135] |
| Bornholm eye disease | BED | #300843 | #300843 |
AO-FIO AOSLO |
Significant but variable degree of mosaic disruption and macular thinning. Cone density ranged from normal to reduced by over 75%. Two siblings showed different degrees of retinal thickness and cone mosaic disruption despite having the same disease-causing sequence variant. | [135, 136] |
| Bradyopsia |
RGS9 R9AP |
#604067 #607814 |
#608415 | AOSLO | Intact and structurally normal photoreceptor mosaic, in contrast with the clinically very similar oligocone trichromacy. In the patient with RGS9-associated disease, a hyporeflective lesion was seen at the foveal centre corresponding to an outer retinal defect, but with a normal mosaic elsewhere. | [6] |
| Central areolar choroidal dystrophy 2 |
PRPH2/ RDS |
#179605 | #613105 | AOSLO | Decreased foveal cone density with increased foveal reflectivity of the photoreceptor outer segment-RPE junction. Irregular cone packing and increased spacing. Reduced parafoveal cone density even in early stages of disease. | [137–140] |
| Choroideremia | CHM | #300390 | #303100 |
AO-FIO AOSLO |
Central island of relatively regular cone mosaic but with reduced density. Patches of RPE atrophy peripherally over which there is either abrupt loss of cones or remnant cone inner segments in outer retinal tubulations. Reduced peripheral photoreceptors with foveal sparing present in asymptomatic female carriers. Patchy cone loss seen in symptomatic female carriers. | [56, 57, 141–145] |
| Cone dystrophy with supernormal rod responses | KCNV2 | #607604 | #610356 | AOSLO | Significantly reduced cone density, with the macula affected early in disease course. Groups of waveguiding cones are surrounded by patches of hyporeflectivity, representing absent or non-waveguiding cones. | [146] |
| Cone-rod dystrophy | DFNB31 | #607084 | - | AO-FIO | Mild decrease in parafoveal cone density compared to peripheral cone density. | [147] |
| Cone-rod dystrophy 14 | GUCA1A | #600364 | #602093 | AOSLO | Range of findings, from near-normal cone density to widespread cone loss in younger patients. Few identifiable cones in older patients. An identical disease-causing sequence variant in a family (p.Ile143delinsAsnThr) can lead to different degrees of photoreceptor mosaic disruption, albeit with the same clinical features. | [148, 149] |
| Cone-rod dystrophy 20 | POC1B | #614784 | #615973 | AO-FIO | Sparse cone density around central fovea with minimal detection of cones elsewhere. Hyperreflectivity in foveal areas containing residual cones. | [150] |
| Congenital stationary night blindness 1B | GRM6 | #604096 | #257270 | AOSLO | Normal photoreceptor mosaic and normal density at all locations. Decreased parafoveal thickness of the inner retinal layers. | [104] |
| Doyne honeycomb retinal dystrophy | EFEMP1 | #601548 | #126600 | AOSLO | Normal photoreceptor mosaic with hyperreflectivity in areas that correlate with drusen deposition. | [151] |
| Enhanced S-cone syndrome | NR2E3 | #604485 | #268100 | AOSLO | Disrupted cone mosaic with varying reflectivity from each cone in the central retina. Increased cone spacing and larger cone size. Dark, patchy lesions seen in the macula. | [152, 153] |
| Fundus albipunctatus | RDH5 | #601617 | #136880 | AOSLO | Decreased macular cone density with dark patches representing areas of cone loss that were not detected on fundoscopy or SD-OCT. Hyperreflective regions are surrounded by hyporeflective rings in areas corresponding to white dots seen on fundoscopy, which contain no photoreceptors or RPE cells. | [154–157] |
| Gyrate atrophy | OAT | #613349 | #258870 | AOSLO | Centrally preserved RPE and photoreceptors with normal cone density, with a peripheral ring of degenerated retina where no cones are seen. Slightly reduced cone density at the border between preserved and degenerated retina. | [158] |
| Late-onset retinal degeneration | C1QTNF5 | #608752 | #605670 | AOSLO | Reticular pseudodrusen are seen as hyperreflective cores encapsulated by hyporeflective annuli, which underlie cone photoreceptors. Cones overlying lesions have widened inner segment diameters compared to those elsewhere. | [55] |
| Leber congenital amaurosis 1 | GUCY2D | #600179 | #204000 | AOSLO | Decreased parafoveal cone density with sporadic hyporeflective cones. Enlarged residual cone inner segments seen using split-detection AOSLO. | [54] |
| Occult macular dystrophy | RP1L1 | #608581 | #613587 | AO-FIO | Severe reduction in cone density and increased cone spacing seen in a ring-shaped distribution around the fovea. However, no cone abnormalities seen in asymptomatic family members with the same genetic variant (p.Arg45Trp). | [80, 159–163] |
| Oguchi disease 2 | GRK1 | #180381 | #613411 | AOSLO | Normal rod and cone mosaic, with normal foveal cone density. Increased perifoveal rod reflectivity during the light-adapted state compared to the dark-adapted state. Normal cone reflectivity. | [104] |
| Oligocone trichromacy | Unknown | - | - | AO-FIO | Irregular cone mosaic with reduced cone density peripherally, the extent of which is variable. Foveal cone outer segment length significantly decreased and peripheral retinal layer thinning seen. Normal-appearing cone mosaic seen in some patients with an oligocone trichromacy-like clinical phenotype. | [164–166] |
| Retinitis pigmentosa 4 | RHO | #180380 | #613731 | AOSLO | Regions of increased cone spacing with a parafoveal annulus where cone identification is ambiguous. Frequent dark, patchy regions observed in mosaic where cones are mis-shapen. | [78, 167] |
| Retinitis pigmentosa 11 | PRPF31 | #606419 | #600138 | AOSLO | Intact central macular cone mosaic with normal cone density. | [168] |
| Retinitis pigmentosa 28 | FAM161A | #613596 | #606068 | AOSLO | Severe diffuse cone atrophy with hyporeflective areas signifying sparse residual cones. | [169, 170] |
| Retinitis pigmentosa 62 | MAK | #154235 | #614181 | AOSLO | Normal cone spacing in early disease, and increased cone spacing in advanced disease with maintenance of central foveal cone structure until late stages. | [171] |
| Retinitis pigmentosa 65 | CDHR1 | #609502 | #613660 | AOSLO | Increased cone spacing and reduced cone density in focal parafoveal regions. | [172] |
| Retinitis punctata albescens | RLBP1 | #180090 | #136880 | AO-FIO | Disorganised cone mosaic with increased cone spacing and empty spaces. Below these spaces, parafoveal white dot-like deposits are seen as elongated structures, which are not present in the fovea. | [173] |
| Stargardt disease 1 | ABCA4 | #601691 | #248200 | AOSLO | Variable foveal cone mosaic. Central atrophy with annulus of hyporeflectivity present in some patients, whereas others have a contiguous foveal mosaic with enlarged cone size and reduced density. Hyperreflective areas present that do not correlate with lipofuscin deposition seen on auto-fluorescence. Outer retinal tubulations containing photoreceptor-like structures are seen. | [4, 53, 103, 174–178] |
| Stargardt disease 3 | ELOVL4 | #605512 | #600110 | AO-FIO | Diffuse loss of central cone reflectivity with decreased density in early disease. Bull’s eye pattern of parafoveal decreased cone density seen in advanced disease. | [179] |
| Tritan colourblindness | OPN1SW | #613522 | #190900 | AO-FIO | Variability in cone mosaic, with near-normal S-cone density in early life progressing to complete S-cone loss in later life. Cone density remains in normal range due to low proportion of S-cones. | [180] |
| Usher syndrome 2A | USH2A | #608400 | #276901 | AOSLO | Reduced foveal cone density. Foveal clusters of low reflectivity cones seen with diseased outer segments. Remnant inner segments seen within dark patches using split-detection AOSLO. | [23] |
| Usher syndrome 3A | CLRN1 | #606397 | #276902 | AOSLO | Preserved central foveal cone density, which abruptly ends to peripheral photoreceptor degeneration. In advanced disease, RPE cells seen in areas where the cone mosaic is absent or outer segments are abnormal. | [181] |
| Vitelliform macular dystrophy 2 | BEST1 | #607854 | #153700 | AOSLO | Highly variable depending on disease stage, with hyporeflective patches of mosaic disruption correlating with the vitelliform lesion location. Split-detection AOSLO shows remnant inner segments of photoreceptors in these areas with varied morphology. Well-preserved photoreceptor density present in areas adjacent to lesions and elsewhere, except where subretinal fluid is present. | [182–185] |
| X-linked atrophic macular degeneration | RPGR | #312610 | #300834 | AOSLO | Variable cone mosaic, from normal appearance to asymmetrical shapes and irregularity. Small areas of varying rod loss and rod hyperreflectivity seen in patients, either with normal-appearing or reduced density mosaics. RPE-like cells seen at the boundaries of intact mosaic. | [66, 68, 186, 187] |
| X-linked retinoschisis | RS1 | #300839 | #312700 |
AO-FIO AOSLO |
Canal-like foveal schisis cavities seen, with a spoke wheel pattern of inner retinal folds. Increased parafoveal and cavity cone spacing. Normal photoreceptor mosaic elsewhere up until the edges of cavities. Widened cone diameters noted in macula due to inner segment swelling. | [188–192] |