Non-syndromic OTX2-associated pattern dystrophy: a 10-year multimodal imaging study.

PURPOSE: To report novel multimodal imaging features and long-term follow-up of Orthodenticle Homeobox 2 (OTX2)-associated pattern Gdystrophy. METHODS: A 14-year-old boy referred with glaucoma suspect and macular pigmentation underwent fundus autofluorescence imaging, optical coherence tomography, fluorescein and indocyanine green angiography, visual field test, microperimetry and electrophysiology over a ten-year period. Next-generation sequencing panel identified a de novo heterozygous likely pathogenic OTX2 variant, c.259G>A, [p.(Glu87Lys)]. RESULTS: Visual acuity was 20/40 OD and 20/30 OS. Examination showed bilateral enlarged optic nerve heads and increased disc cupping, multiple cilioretinal arteries, a pigmentary maculopathy with stellate-shaped region of hypoautofluorescence, shallow serous macular detachment, subretinal deposits and temporal avascular retina. Angiography showed no source of leakage and absence of retinal neovascularisation despite extensive peripheral non perfusion. Electrophysiological assessments demonstrated mild progressive rod and cone pathway abnormalities, reduced light-adapted b:a ratio, and reduced Arden ratio on electro-oculogram. Ten-year follow-up confirmed a stable disease course despite persistent submacular fluid. There was no associated pituitary structural abnormality or dysfunction. CONCLUSIONS: This case study contributes to further understanding of OTX2-associated pattern dystrophy, highlighting its stability over 10 years. Further investigation into inter-individual and intrafamilial variability is warranted.

Quantitative and qualitative characterization of retinal dystrophies in canine models of inherited retinal diseases using spectral domain optical coherence tomography (SD-OCT).

The purpose of this study was to establish spectral domain optical coherence tomography (SD-OCT) assessment data in well-established canine models of inherited retinal dystrophies: PDE6B-rod-cone dysplasia 1 (RCD1: early onset retinitis pigmentosa), PRCD-progressive rod-cone degeneration (PRCD: late onset retinitis pigmentosa), CNGB3-achromatopsia, and RPE65-Leber congenital amaurosis (LCA). High resolution SD-OCT images of the retina were acquired from both eyes in 5 planes: temporal; superotemporal; superior; nasal; and inferior in adult dogs with: RCD1 (n = 4 dogs, median age: 1.5 yrs); PRCD (n = 2, 4.3 yrs); LCA (n = 3, 5.2 yrs); achromatopsia (n = 3, 4.2 yrs); and wild types (wt, n = 6, 5.5 yrs). Total, inner and outer retinal thicknesses and ellipsoid zone were analyzed. In selected animals, histomorphometric evaluations were performed. In dogs with RCD1, PRCD, and LCA, the thickness of the outer retina was, compared to wt, significantly decreased (p ≤ 0.02) in all OCT imaging planes, and in superotemporal and inferior imaging planes in dogs with achromatopsia. No significant thinning was observed in inner retina thickness in any disease model except in the inferior imaging plane in dogs with RCD1. Dogs with RCD1, PRCD, and LCA had significantly more areas with disrupted ellipsoid zone in the presumed area centralis than wt (p ≤ 0.001). OCT findings provide baseline information for research of retinal dystrophies using these canine models.

Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome.

CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants' kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature.

Novel variants in PNPLA6 causing syndromic retinal dystrophy.

PNPLA6-related disorders include several phenotypes, such as Boucher-Neuhäuser syndrome, Gordon Holmes syndrome, spastic paraplegia, photoreceptor degeneration, Oliver-McFarlane syndrome and Laurence-Moon syndrome. In this study, detailed clinical evaluations and genetic testing were performed in five (4 Chinese and 1 Caucasian/Chinese) syndromic retinal dystrophy patients. Genotype-phenotype correlations were analyzed based on review of the literatures of previously published PNPLA6-related cases. The mean age of patients and at first visit were 20.8 years (11, 12, 25, 28, 28) and 14.2 years (4, 7, 11, 24, 25), respectively. They all presented with severe chorioretinal dystrophy and profoundly decreased vision. The best corrected visual acuity (BCVA) ranged from 20/200 to 20/2000. Systemic manifestations included cerebellar ataxia, hypogonadotropic hypogonadism and hair anomalies. Six novel and three reported pathogenic variants in PNPLA6 (NM_001166111) were identified. The genotypes of the five cases are: c.3134C > T (p.Ser1045Leu) and c.3846+1G > A, c.3547C > T (p.Arg1183Trp) and c.1841+3A > G, c.3436G > A (p.Ala1146Thr) and c.2212-10A > G, c.3436G > A (p.Ala1146Thr) and c.2266C > T (p.Gln756*), c.1238_1239insC (p.Leu414Serfs*28) and c.3130A > G (p.Thr1044Ala). RT-PCR confirmed that the splicing variants indeed led to abnormal splicing. Missense variants p.Thr1044Ala, p.Ser1045Leu, p.Ala1146Thr, p.Arg1183Trp and c.3846+1G > A are located in Patatin-like phospholipase (Pat) domain. In conclusion, we report the phenotypes in five patients with PNPLA6 associated syndromic retinal dystrophy with variable systemic involvement and typical choroideremia-like fundus changes. Ocular manifestations may be the first and the only findings for years. All of our patients carried one severe deleterious variant (stop-gain or splicing variant) and one milder variant (missense variant). Retinal involvement was significantly correlated with severe deleterious variants and variants in Pat domain.

DEEP PHENOTYPING AND FURTHER INSIGHTS INTO ITM2B-RELATED RETINAL DYSTROPHY.

PURPOSE: To reappraise the presentation and the course of ITM2B-related retinal dystrophy and give further insights into ITM2B expression in the retina. METHODS: The clinical data of nine subjects with ITM2B-related retinal dystrophy were retrospectively reviewed. The genetic mutation was assessed for its influence on splicing in cultured fibroblasts. The cellular expression of ITM2B within the inner retina was investigated in wild-type mice through mRNA in situ hybridization. RESULTS: All patients complained of decreased vision and mild photophobia around their twenties-thirties. The peculiar feature was the hyperreflective material on optical coherence tomography within the inner retina and the central outer nuclear layer with thinning of the retinal nerve fiber layer. Although retinal imaging revealed very mild or no changes over the years, the visual acuity slowly decreased with about one Early Treatment Diabetic Retinopathy Study letter per year. Finally, full-field electroretinography showed a mildly progressive inner retinal and cone dysfunction. ITM2B mRNA is expressed in all cellular types of the inner retina. Disease mechanism most likely involves mutant protein misfolding and/or modified protein interaction rather than misplicing. CONCLUSION: ITM2B-related retinal dystrophy is a peculiar, rare, slowly progressive retinal degeneration. Functional examinations (full-field electroretinography and visual acuity) seem more accurate in monitoring the progression in these patients because imaging tends to be stable over the years.

Molecular and phenotypic investigation of a New Zealand cohort of childhood-onset retinal dystrophy.

Inherited retinal diseases are clinically heterogeneous and are associated with nearly 300 different genes. In this retrospective, observational study of a consecutive cohort of 159 patients (134 families) with childhood-onset (<16 years of age) retinal dystrophy, molecular investigations, and in-depth phenotyping were performed to determine key clinical and molecular characteristics. The most common ocular phenotype was rod-cone dystrophy in 40 patients. Leber Congenital Amaurosis, the most severe form of retinal dystrophy, was present in 10 patients, and early onset severe retinal dystrophy in 22 patients. Analysis has so far identified 131 pathogenic or likely pathogenic variants including 22 novel variants. Molecular diagnosis was achieved in 112 of 134 families (83.6%) by NGS gene panel investigation in 60 families, Sanger sequencing in 27 families, and Asper microarray in 25 families. An additional nine variants of uncertain significance were also found including three novel variants. Variants in 36 genes have been identified with the most common being ABCA4 retinopathy in 36 families. Five sporadic retinal dystrophy patients were found to have variants in dominant and X-linked genes (CRX, RHO, RP2, and RPGR) resulting in more accurate genetic counseling of inheritance for these families. Variants in syndromic associated genes including ALMS1, SDCCAG8, and PPT1 were identified in eight families enabling directed systemic care.

Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile.

BACKGROUND: Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. METHODS: Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. RESULTS: The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G > A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. CONCLUSIONS: We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB. Our findings helped improve the understanding of ARB mechanisms.

Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum.

Purpose: To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods: A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results: Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions: Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.

SPECTRAL FUNDUS AUTOFLUORESCENCE EXCITATION AND EMISSION IN ABCA4-RELATED RETINOPATHY.

PURPOSE: To systematically and longitudinally investigate the characteristics of flecks in ABCA4-related retinopathy under different fundus autofluorescence (AF) excitation and emission spectra. METHODS: A total of 132 eyes of 66 patients with ABCA4-related retinopathy were investigated using multimodal AF imaging and spectral domain optical coherence tomography. Autofluorescence imaging with blue (BAF), green (GAF), and near-infrared (NIR-AF) excitation wavelengths obtained by a confocal scanning laser ophthalmoscope was compared with AF imaging obtained by an innovative confocal light-emitting diode-based retinal imaging system (Color-AF) that allows for separation of short (green emission fluorescent component) and long (red emission fluorescent component) autofluorescence emission components. RESULTS: Color-AF, BAF, and GAF, overall, revealed similar presentation of hyperautofluorescent flecks. Flecks that showed predominantly red emission fluorescent component matched with hyperautofluorescent flecks in NIR-AF. Over the observation time of 5 to 14 months, flecks showed a transition in the AF emission spectrum to shorter wavelengths (red emission fluorescent component to green emission fluorescent component), associated with a progressed disruption of overlaying outer retinal bands in optical coherence tomography. Newer hyperautofluorescent flecks usually revealed predominantly red emission fluorescent component. CONCLUSION: By separation of the AF spectra, the remodeling of fluorophores and associated structural changes can be monitored over time indicating a novel and susceptible surrogate marker for disease progression and potential therapeutic effects.

Comparative Analysis of Functional and Structural Decline in Retinitis Pigmentosas.

Retinitis pigmentosa (RP) is a category of inherited retinal dystrophies that is best prognosticated using electroretinography (ERG). In this retrospective cohort study of 25 patients with RP, we evaluated the correlation between 30 Hz flicker ERG and structural parameters in the retina. Internationally standardized 30 Hz flicker ERG recordings, short-wavelength autofluorescence (SW-AF), and spectral domain-optical coherence tomography (SD-OCT) were acquired at two visits at least one year apart. Vertical and horizontal hyperautofluorescent ring diameter measurements with SW-AF, as well as ellipsoid zone (EZ) line width measurements with SD-OCT, were used as structural parameters of disease progression. The 30 Hz flicker ERG amplitude decreased by 2.2 ± 0.8 µV/year (p = 0.011), while implicit times remained unchanged. For SD-OCT, the EZ line decreased by 204.1 ± 34.7 µm/year (p < 0.001). Horizontal and vertical hyperautofluorescent ring diameters decreased by 161.9 ± 25.6 µm/year and 146.9 ± 34.6 µm/year, respectively (p = 0.001), with SW-AF. A correlation was found between the progression rates of the 30 Hz flicker amplitude recorded with Burian-Allen electrodes and both the horizontal ring diameter (p = 0.020) and EZ line (p = 0.044). SW-AF and SD-OCT, two readily available imaging techniques, may be used to prognosticate disease progression because of the reliability of their measurements and correlation with functional outcome.

An N-terminal heterozygous missense CASK mutation is associated with microcephaly and bilateral retinal dystrophy plus optic nerve atrophy.

Heterozygous loss-of-function mutations in the X-linked gene CASK are associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) and ophthalmological disorders including optic nerve atrophy (ONA) and optic nerve hypoplasia (ONH). Recently, we have demonstrated that CASK(+/-) mice display ONH with 100% penetrance but exhibit no change in retinal lamination or structure. It is not clear if CASK loss-of-function predominantly affects retinal ganglion cells, or if other retinal cells like photoreceptors are also involved. Here, we report a heterozygous missense mutation in the N-terminal calcium/calmodulin-dependent kinase (CaMK) domain of the CASK protein in which a highly conserved leucine is mutated to the cyclic amino acid proline. In silico analysis suggests that the mutation may produce destabilizing structural changes. Experimentally, we observe pronounced misfolding and insolubility of the CASKL209P protein. Interestingly, the remaining soluble mutant protein fails to interact with Mint1, which specifically binds to CASK's CaMK domain, suggesting a mechanism for the phenotypes observed with the CASKL209P mutation. In addition to microcephaly, cerebellar hypoplasia and delayed development, the subject with the L209P mutation also presented with bilateral retinal dystrophy and ONA. Electroretinography indicated that rod photoreceptors are the most prominently affected cells. Our data suggest that the CASK interactions mediated by the CaMK domain may play a crucial role in retinal function, and thus, in addition to ONH, individuals with mutations in the CASK gene may exhibit other retinal disorders, depending on the nature of mutation.

Multimodal Imaging in Autosomal Dominant Cone-Rod Dystrophy Caused by Novel CRX Variant.

AIM: To characterize by multimodal approach the phenotype of patients from a 3 generations pedigree, affected by autosomal dominant cone-rod dystrophy (CRD), found to carry a novel pathogenic variant in the cone-rod homeobox-containing (CRX) gene. METHODS: Examination of the adult patients included the following tests: visual acuity, multicolour imaging, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and OCT angiography (OCT-A) recordings. In a 2.5-year-old child, cycloplegic refraction, fundoscopy, ocular motility evaluation and electrophysiological exams were performed. Next Generation Sequencing of patients' DNA has been carried out. RESULTS: A novel CRX pathogenic variant has been identified in our patients. The 2.5-year-old child in the third generation was found to have inherited the variant, with no clinical signs of the condition, but electroretinographic abnormalities in the scotopic component. In the adult patients, diffuse atrophy of the retinal pigment epithelium/photoreceptor complex in the macular region was evident at the OCT and FAF, while OCT-A showed choriocapillaris density reduction. CONCLUSIONS: Multimodal study allowed the characterization of a peculiar form of CRD. The novel pathogenic variant seems to have a different effect on the phenotype if compared with a previously described similar one, giving an insight into the pathogenic mechanism of CRX-related retinal dystrophies and offering valuable information that could lead to the development of possible future therapies.

SD-OCT and Adaptive Optics Imaging of Outer Retinal Tubulation.

PURPOSE: To investigate outer retinal tubulation (ORT) using spectral domain optical coherence tomography (SD-OCT) and an adaptive optics scanning laser ophthalmoscope (AOSLO). To document the frequency of ORT in atrophic retinal conditions and quantify ORT dimensions versus adjacent retinal layers. METHODS: SD-OCT images were reviewed for the presence of retinal atrophy, scarring, and/or exudation. The greatest width of each ORT was quantified. Inner and outer retinal thicknesses adjacent to and within the area of ORT were measured for 18 patients. AOSLO imaged ORTs in five subjects with direct and scattered light imaging. RESULTS: ORT was identified in 47 of 76 subjects (61.8%) and in 65 eyes via SD-OCT in a wide range of conditions and ages, and in peripapillary atrophy. ORTs appeared as finger-like projections in atrophy, seen in the en face images. AOSLO showed some ORTs with bright cones that guide light within atrophic areas. Multiply scattered light mode AOSLO visualized variegated lines (18-35 µm) radiating from ORTs. The ORTs' width on OCT b-scan images varied from 70 to 509 µm. The inner retina at the ORT was significantly thinner than the adjacent retina, 135 vs.170 µm (P = .004), whereas the outer retina was significantly thicker, 115 vs. 80 µm (P = .03). CONCLUSIONS: ORTs are quite common in eyes with retinal atrophy in various disorders. ORTs demonstrate surviving photoreceptors in tubular structures found within otherwise nonsupportive atrophic areas that lack retinal pigment epithelium and choriocapillaris.

Prominent Optic Disc Featured in Inherited Retinopathy.

Background We investigated the relationship between prominent optic disc (POD) and inherited retinal dystrophy (IRD). Patients and Methods A cross-sectional consecutive study was performed in 10 children and 11 adults of 7 non-related families. We performed clinical phenotyping, including a detailed examination, fundus autofluorescence, and colour fundus and OCT imaging. Genetic testing was subsequently performed for all family members presenting retinal pathology. Results In 4 members of a 3-generation family, hyperfluorescent deposits on the surface of POD were related to a p.(L224M) heterozygous mutation in BEST1. In the second family, one member presented deposits located on the surface on hyperaemic OD and a compound p.(R141H);(A195V) mutation in BEST1. In the third family, POD was observed in father and child with early onset cone-rod dystrophy and a novel autosomal recessive p.(W31*) homozygous mutation in ABCA4. In the fourth family, POD with "mulberry-like" deposits and attenuated vessels were observed in a 7-year old girl, with a mutation in USH1A, and with early onset rod-cone dystrophy, associated with hearing loss. In the fifth family, blurry OD with tortuous vessels was observed in 4 consanguineous female carriers and a hemizygous boy with a p.(R200H) mutation in the X-linked retinoschisis RS1. In the sixth family, a mother and her son were both affected with POD and attenuated peripapillary vessels, and presented with a p.(Y836C) heterozygous mutation in TOPORS, thus confirming autosomal dominant RP. In the seventh family, in 3 family members with POD, compound p.(L541P;A1038 V);(G1961E) mutations in ABCA4 confirmed the diagnosis of Stargardt disease. Conclusions A variety of OD findings are found in a genetically heterogeneous group of IRDs. In the presence of POD, an inherited progressive photoreceptor disease should be ruled out.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF CHOROIDAL NEOVASCULARIZATION IN FOUR INHERITED RETINAL DYSTROPHIES.

PURPOSE: To demonstrate the clinical utility of optical coherence tomography (OCT) angiography (OCT-A) in inherited retinal dystrophies complicated by choroidal neovascularization (CNV). METHODS: Optical coherence tomography angiography and structural OCT were performed using a 70-kHz spectral domain OCT system using the split-spectrum amplitude-decorrelation angiography algorithm. Semiautomated image processing software was used to segment and measure the CNV. RESULTS: Four participants were enrolled to study the following inherited retinal dystrophies complicated by CNV: choroideremia, EFEMP1-related retinopathy, Best vitelliform dystrophy, and adult-onset vitelliform dystrophy. Interpretation of fluorescein angiography was difficult because of abnormal retinal architecture but suggested the presence of CNV. Structural OCT revealed subretinal or subretinal pigment epithelium fibrovascular tissue, within which flow signal was observed on OCT-A. The CNV morphology varied from dense capillary networks in active lesions to asymptomatic large caliber loops. Baseline CNV vessel areas ranged from 0.07 mm to 0.98 mm. After treatment with intravitreal bevacizumab, the CNV in choroideremia decreased in the vessel area then rebounded, whereas the one in EFEMP1-related retinopathy remained largely unchanged. CONCLUSION: Optical coherence tomography angiography enables morphologic characterization and quantification of CNV in patients with retinal dystrophies despite distorted retinal architecture, can assess response to treatment, and may facilitate differentiation between active and regressed lesions.

[Objective method to recognize warning signs in peripheral vitreoretinal dystrophies]. / Sposob opredeleniya priznakov prognosticheskoi opasnosti perifericheskikh vitreoretinal'nykh distrofii.

AIM: to compare the effectiveness of biomicroscopy (BMS) and optical coherence tomography (OCT) in recognizing prognostically unfavorable signs in peripheral vitreoretinal dystrophy (PVRD) patients. MATERIAL AND METHODS: A total of 131 cases of equatorial PVRD (91 eyes of 56 patients) were assessed. The mean patient's age was 24.7 years. The length of the anterior-posterior axis of the eyeball averaged 25.36±1.12 mm. Prevalence of particular warning signs in PVRD patients at BMS or OCT was comparatively analyzed. RESULTS: In 46 eyes with lattice dystrophy it was difficult to determine the presence of vitreoretinal traction at BMS; at OCT, areas of retinal adhesion to the posterior hyaloid membrane (PHM) along the edges of PVRD zones were revealed in all eyes. Of 31 eyes with «snail tracks¼ defects of the retina, 6 were diagnosed at BMS; in OCT scans of these patients, the PHM appeared firmly fixed along the edges of PVRD zones in all cases. As to horseshoe retinal tears (valve-like tears), BMS allowed to visualize vitreoretinal tractions in 7 of 12 eyes, while OCT revealed a tight contact between the PHM and the apex of the retinal flap in 11 of 12 eyes. In 7 eyes with retinoschisis we failed to detect any retinal traction at either BMS or OCT. In «non-differentiable¼ PVRD, BMS was also not able to reveal any vitreoretinal traction, while OCT was - in all 12 cases. CONCLUSION: OCT has proved much more effective than BMS in recognizing prognostically unfavorable signs in particular clinical forms of PVRD, such as vitreoretinal tractions, retinal defects, and intraretinal cavities.

Adaptive Optics Retinal Imaging in RDH12-Associated Early Onset Severe Retinal Dystrophy.

Purpose: RDH12 is among the most common genes found in individuals with early-onset severe retinal (EOSRD). Adaptive optics scanning light ophthalmoscopy (AOSLO) enables resolution of individual rod and cone photoreceptors in the retina. This study presents the first AOSLO imaging of individuals with RDH12-associated EOSRD. Methods: Case series of patients who attended Moorfields Eye Hospital (London, UK). Spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and blue autofluorescence imaging were analyzed. En face image sequences of photoreceptors were recorded using either of two AOSLO modalities. Cross-sectional analysis was undertaken for seven patients and longitudinal analysis for one patient. Results: Nine eyes from eight patients are presented in this case series. The mean age at the time of the assessment was 11.2 ± 6.5 years of age (range 7-29). A subfoveal continuous ellipsoid zone (EZ) line was present in eight eyes. Posterior pole AOSLO revealed patches of cone mosaics. Average cone densities at regions of interest 0.5° to the fovea ranged from 12,620 to 23,660 cells/mm2, whereas intercell spacing ranged from 7.0 to 9.7 µm. Conclusions: This study demonstrates that AOSLO can provide useful high-quality images in patients with EOSRD, even during childhood, with nystagmus, and early macular atrophy. Cones at the posterior pole can appear as scattered islands or, possibly later in life, as a single subfoveal conglomerate. Detailed image analysis suggests that retinal pigment epithelial stress and dysfunction may be the initial step toward degeneration, with NIR being a useful tool to assess retinal well-being in RDH12-associated EOSRD.

Optical Coherence Tomography Split-Spectrum Amplitude-Decorrelation Optoretinography Detects Early Central Cone Photoreceptor Dysfunction in Retinal Dystrophies.

Purpose: To investigate if split-spectrum amplitude-decorrelation optoretinography (SSADOR) can detect and measure macular cone dysfunction in inherited retinal dystrophies (IRDs). Methods: This study was a case series of participants presenting with various IRD pathologies. Participants were recruited from the Ophthalmic Genetics clinic at the Casey Eye Institute from February to August 2023. Multimodal and SSADOR imaging was obtained in all cases. Results: We recruited nine participants, including four with macular dystrophy, one with fundus flavimaculatus, one with cone dystrophy, and three with retinitis pigmentosa. SSADOR decorrelation maps identified areas of cone functional impairment consistent with disease phenotypes. A correlation between the SSADOR signal and retinal sensitivity measured by microperimetry within the central 20° diameter area was observed. Additionally, SSADOR was able to demonstrate a decreased signal in mild cases when microperimetry measurements were still normal but subtle changes were also apparent on structural OCT. Conclusions: SSADOR is sensitive at detecting functional changes in macular cones, even prior to abnormalities in perimetry testing. We highlight the potential benefits of this innovative technology for the early detection of cone dysfunction and their potential contributions to earlier diagnosis and more accurate monitoring of progression. Translational Relevance: SSADOR is an innovative technology that detects early macular cone function changes, allowing for early diagnosis and precise monitoring of cone dysfunction progression. By serving as a potential clinical trial endpoint, SSADOR facilitates the translation of scientific findings into practical applications, ultimately improving patient care and outcomes.

Stargardt's pigmentosa: A novel combination of two inherited retinal dystrophies.

60-year-old woman referring visual disability. She presented bone spicule pigmentation and retinal atrophy in all peripheral retina, as well as macular retinal flecks. Multimodal imaging showed typical findings of both inherited retinal dystrophies (IRD). Electroretinogram confirmed rod dysfunction. Biallelic mutations were found in ABCA4 and CNGA1 genes. Although not common, different IRDs may be present in a same patient at the same time. This is the first reported case of the combination of RP with late-onset Stargardt's disease. We propose the name 'Stargardt's pigmentosa' for this novel clinical entity.

RETINAL DYSTROPHY IN JEUNE SYNDROME: A MULTIMODAL IMAGING CHARACTERIZATION.

PURPOSE: To report multimodal imaging findings in a patient affected by Jeune syndrome-associated retinal dystrophy. METHODS: Observational case report. RESULTS: An 18-year-old girl affected by Jeune syndrome was referred to our low vision unit. She presented with bilateral high myopia, reduced visual acuity, exotropia, and nystagmus. Fundus examination detected posterior myopic staphyloma and diffuse retinal dystrophy confirmed using a full-field electroretinogram as a cone-rod dystrophy. Spectral domain optical coherence tomography detected a thick anomalous hyperreflective band located beneath an irregular and disrupted external limiting membrane, showing the primary involvement of the photoreceptors outer segment with relative sparing of the retinal pigment epithelium, as confirmed by fundus autofluorescence. CONCLUSION: This is a case of Jeune syndrome with retinal abnormalities studied with fundus autofluorescence and optical coherence tomography. Retinal noninvasive multimodal imaging could provide significant insight in the retinal involvement of patients affected by Jeune syndrome and should have an essential role in the multidisciplinary diagnostic approach and follow-up.