Subretinal Deposits Research Articles

First person – Brittany Carr

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Brittany Carr is first author on ‘ prominin-1-null Xenopus laevis develop subretinal drusenoid-like deposits, cone-rod dystrophy and RPE atrophy’, published in JCS. Brittany is an Assistant Professor in the Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada, where her lab investigates frog models of inherited and age-related blindness.

Review of type 3 macular neovascularization in age-related macular degeneration: no DRAMA (Deep Retinal Age-related Microvascular Anomalies).

Type 3 macular neovascularization (MNV) is a unique form of neovascular age-related macular degeneration (AMD) that presents distinct pathogenetic features, clinical manifestations, and prognostic considerations when compared to types 1 and 2 MNV. Insights gained from clinicopathological correlations, bridging in vivo examination techniques with ex vivo histological analysis, have significantly enhanced our comprehension of this MNV phenotype, shaped current management strategies and influenced future directions for therapeutics. The particularities of type 3 MNV, which may largely stem from its origin from the retinal vasculature, are critically important for predicting the disease course. Our current understanding suggests that type 3 MNV occurs in response to retinal pigment epithelium (RPE) disruption and photoreceptor loss when neovessels originating from the deep capillary plexus are accompanied by activated Müller glia as they infiltrate sub-retinal pigment epithelium basal laminar deposits. Dysregulation of angiogenic and angiostatic factors are thought to play a key role in its pathogenesis. The prognosis for type 3 MNV is likely bilateral involvement and progression towards macular atrophy. It may be imperative for practitioners to distinguish type 3 MNV from other mimicking pathologies such as intraretinal microvascular anomalies, which are also part of the type 3 disease spectrum. For instance, deep retinal age-related microvascular anomalies (DRAMA) may present with similar features on multimodal imaging yet may necessitate distinct management protocols. Distinguishing between these conditions may be vital for implementing tailored treatment regimens and improving patient outcomes in the diverse landscape of AMD phenotypes in the future.

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

PurposeTo report novel multimodal imaging features and long-term follow-up of Orthodenticle Homeobox 2 (OTX2)-associated pattern Gdystrophy.MethodsA 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)].ResultsVisual 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.ConclusionsThis 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.

Vitelliform subretinal deposits: shared pathogenesis and clinical diversity

Since its initial description, Best vitelliform macular dystrophy has been strongly linked to characteristic retinal lesions—subretinal yellowish accumulations, with a hyperreflective structure on optical coherence tomography, situated above the retinal pigment epithelium layer. However, research on this topic remains scarce. It is now recognized that, within the common pathophysiological mechanism of vitelliform lesion formation, this process may contribute to the pathogenesis of a broad spectrum of both genetic and acquired conditions.The purpose of this review is to update our understanding of genetically determined and acquired retinal diseases associated with the formation of such lesions.Materials and methods. analysis of scientific publications from databases including PubMed, ScienceDirect, and Cyberleninka was conducted. The review encompasses 16 studies, predominantly from the past decade.Results. Advances in instrumental and genetic diagnostics have revealed that vitelliform subretinal changes are not exclusive to Best disease but serve as another biomarker, indicating disruption in the metabolism of outer retinal layers. It is hypothesized that, irrespective of etiology, the primary triggering factor for lesion formation is the disjunction of outer segments of photoreceptors and impairment of phagocytic function in retinal pigment epithelial cells. This article presents a contemporary perspective on the presumed etiology and pathophysiology of vitelliform lesions, alongside clinical characteristics, manifestations, and prognosis of diseases associated with this phenomenon. Diseases with identified genetic mutations in the BEST1 gene (Bestrophinopathies) and PRPH2, as well as common acquired conditions like age-related macular degeneration and vitreoretinal traction syndrome, are discussed.Conclusions. The provided clinical characteristics, supported by multimodal visualization, are expected to aid in differential diagnosis and prognostication of the disease course.

Multimodal Imaging of Bilateral Retinal Pigment Epithelial Immunoglobulin Light Chain Deposition in Patients with Systemic Immunoglobulin Light Chain Deposition

ObjectiveTo describe multimodal imaging of peculiar bilateral globular subretinal deposits and acquired serous retinal detachment in patients with systemic immunoglobulin light chain deposition. DesignA retrospective observational case series. ParticipantsWe examined six eyes in three patients (one with multiple myeloma, one with membranous nephropathy, and one with immunoglobulin A nephropathy) at the Eye and ENT Hospital of Fudan University. The patients presented with peculiar globular subretinal deposits along the retinal pigment epithelium (RPE)‒Bruch’s membrane complex and acquired serous retinal detachment. MethodsFundus appearance was documented with multimodal imaging, which included fundus photography, fundus autofluorescence, spectral domain optical coherence tomography (OCT), swept-source OCT (SS-OCT), en-face OCT, and SS-OCT angiography. Additional evaluations included serum protein electrophoreses, positron emission tomography computed tomography, and renal and bone biopsies to assess the primary diseases. Main Outcome MeasuresMultimodal imaging, course, and prognosis of bilateral RPE immunoglobulin light chain deposition in patients with systemic immunoglobulin light chain deposition. ResultsBilateral, multiple, speckled, or patchy RPE changes in the posterior fundus that corresponded to striking multifocal hyperautofluorescence on fundus autofluorescence and lumpy, globular hyperreflective deposits along the RPE‒Bruch’s membrane complex were identified as characteristic features of bilateral RPE light chain deposition. These features may be accompanied by dense light chain deposits in the choriocapillaris and choroid vessels, diffuse choroidal thickening, and “angiographically silent” serous retinal detachment in patients with systemic immunoglobulin light chain deposition. ConclusionsWe have documented the characteristic features, clinical course, and prognosis of bilateral RPE immunoglobulin light chain deposition in patients with systemic immunoglobulin light chain deposition. Appropriate evaluations, including serum protein electrophoresis and hematologic consultation, are recommended to manage patients with this fundus abnormality.

Optical coherence tomography features in vitreoretinal lymphoma compared with non-infectious uveitis

BackgroundVitreoretinal lymphoma (VRL) is a rare intraocular malignancy that poses a diagnostic challenge due to the non-specific clinical presentation that resembles uveitis. The use of spectral domain optical coherence tomography (SD-OCT) has emerged as a valuable imaging tool to characterize VRL. Therefore, we sought to determine the specific OCT features in VRL compared to the uveitides.MethodsRetrospective chart review of patients who were seen at Mayo Clinic from January 1, 2010 through December 31, 2022.The medical records and SD-OCT images at time of initial presentation were reviewed in patients with biopsy-proven VRL, intermediate uveitis, or biopsy-confirmed sarcoid posterior uveitis. Patients with VRL or similar uveitides including intermediate uveitis or sarcoid posterior uveitis were included.ResultsThere were 95 eyes of 56 patients in the VRL group and 86 eyes of 45 patients in the uveitis group, of whom 15 (33.3%) were diagnosed with intermediate uveitis and 30 (66.7%) with sarcoid chorioretinitis. The SD-OCT features more commonly seen at initial presentation in VRL patients (vs. uveitis) included preretinal deposits (31.6% vs. 9.3%, p = 0.002), intraretinal infiltrates (34% vs. 3.5%, p < 0.001), inner retinal hyperreflective spots (15.8% vs. 0%, p < 0.001), outer retinal atrophy (22.1% vs. 2.3%, p < 0.001), subretinal focal deposits (21.1% vs. 4.7%, p = 0.001), retinal pigmented epithelium (RPE) changes (49.5% vs. 3.5%, p < 0.001), and sub-RPE deposits (34.7% vs. 0%, p < 0.001). Features more frequently seen in uveitis included epiretinal membrane (ERM) (82.6% vs. 44.2%, p < 0.001), central macular thickening (95.3% vs. 51.6%, p < 0.001), cystoid macular edema (36% vs. 11.7%, p < 0.001), subretinal fluid (16.3% vs 6.4%, p = 0.04), and subfoveal fluid (16.3% vs. 3.2%, p = 0.003). Multivariate regression analysis controlling for age and sex showed absence of ERM (OR 0.14 [0.04,0.41], p < 0.001) and absence of central macular thickening (OR 0.03 [0,0.15], p = 0.02) were associated with VRL as opposed to uveitis.ConclusionOCT features most predictive of VRL (vs. uveitis) included absence of ERM and central macular thickening.

Acquired vitelliform lesion: A lesser diagnosed entity

We report a case of 56-year-old female patient who came to our retina department with diminution of vision in both eyes (BE) for three years. She was treated with anti-vascular growth factor injections in BE for choroidal neovascular membrane (CNVM) at another medical facility three months back. Her best corrected visual acuity (BCVA) was 6/24, N18, and 6/9, N8 in the right and left eyes, respectively. Fundus showed vitelliform lesions and subretinal deposits in BE. We could not find any evidence of CNVM on optical coherence tomography (OCT) angiography. We made a provisional diagnosis of adult-onset foveomacular dystrophy (AOFVD). After the literature review and investigations, we made a clinical diagnosis of acquired vitelliform lesion (AVL). The lesion is usually located between the retinal pigment epithelium and photoreceptors, which may occur as an isolated entity or in conjunction with other comorbidities. Hence, it is very important to differentiate AVL from CNVM to avoid unnecessary treatment.

Two Different Nuclear Mitochondrial DNA Mutations Associated with Retinal Abnormalities

Purpose: To report the posterior pole imaging characteristics of two patients with pathogenic nuclear mitochondrial mutations. Methods: Case reports Results: The first case, a 61-year-old patient, initially diagnosed with age-related macular degeneration, exhibited focal hyperpigmentation and increased autofluorescence in the parafoveal macula, along with geographic atrophy and mild optic nerve pallor. Optical coherence tomography (OCT) showed ellipsoid zone (EZ) attenuation, hyperreflective foci colocalizing to the hyperpigmentation, subretinal deposits, and hypertransmission defects. He was found to have a pathogenic mutation of MFN2, a gene defect associated with Charcot-Marie-Tooth disease. The second case, a 65-year-old patient presented with loss of central vision with pallor of the optic nerve. OCT imaging showed widespread loss of the interdigitation zone and EZ attenuation peripheral to the foveal region. There was thinning of the ganglion cell and nerve fiber layers. A pathogenic OPA1 mutation, the leading cause of autosomal dominant optic atrophy, was found. Both MFN2 and OPA1 produce proteins integral in mitochondrial fusion. Conclusions: The findings of these cases suggest ocular examinations may be helpful in evaluating patients with nuclear mitochondrial mutations using the near microscopic resolution of OCT. Retinal imaging may highlight structural abnormalities related to mitochondrial problems and allows direct imaging of the EZ, a layer dominated by mitochondria and a place where direct imaging of mitochondria is possible, in vivo.

Optical Coherence Tomography-Based Positive Predictors of Eplerenone Therapy in Chronic Central Serous Chorioretinopathy: A Retrospective Study.

This study aimed to investigate optical coherence tomography (OCT) biomarkers as potential predictors of treatment response in chronic central serous chorioretinopathy (CSCR). It was a retrospective cohort study that included 42 patients with chronic CSCR. After complete ocular and hematological examinations, all patients received 50 mg/day of oral eplerenone for three months and were followed for at least six months. All participants were divided into two groups: Group 1 participants with a positive response to treatment (complete resolution of subretinal fluid (SRF) at six months) and Group 2 poor responders (moderate or less than 50% reduction in SRF from baseline). The primary outcome measure was the resolution of SRF, and various OCT biomarkers like central macular thickness (CMT), pigment epithelial detachments (PED), double-layer sign, elongation of the photoreceptor's outer segment, the integrity of the external limiting membrane, the integrity of the ellipsoid zone, hyperreflective foci in the outer segment, and subretinal deposits in the SRF were assessed. The mean age was 41.33 ± 10.75 years, and 34 participants were male. Thirty-seven (88.1%) of the participants had good responses to eplerenone, with the mean height of SRF decreasing significantly from a maximum of 269.74 µm to a minimum of 21.86 µm at six months (p<0.001). The mean CMT decreased from the first visit time point to the third visit time (p<0.001). Logistic regression analysis assessed the absence of PED and double-layer signs associated with a good response. The eplerenone therapy seems to be efficient for chronic CSCR, and OCT can be an invaluable aid to the treating physician.

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Detection of Novel BEST1 Variations in Autosomal Recessive Bestrophinopathy Using Third-generation Sequencing.

Autosomal recessive bestrophinopathy (ARB), a retinal degenerative disease, is characterized by central visual loss, yellowish multifocal diffuse subretinal deposits, and a dramatic decrease in the light peak on electrooculogram. The potential pathogenic mechanism involves mutations in the BEST1 gene, which encodes Ca2+-activated Cl- channels in the retinal pigment epithelium (RPE), resulting in degeneration of RPE and photoreceptor. In this study, the complete clinical characteristics of two Chinese ARB families were summarized. Pacific Biosciences (PacBio) single-molecule real-time (SMRT) sequencing was performed on the probands to screen for disease-causing gene mutations, and Sanger sequencing was applied to validate variants in the patients and their family members. Two novel mutations, c.202T>C (chr11:61722628, p.Y68H) and c.867+97G>A, in the BEST1 gene were identified in the two Chinese ARB families. The novel missense mutation BEST1 c.202T>C (p.Y68H) resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1. Another novel variant, BEST1 c.867+97G>A (chr11:61725867), located in intron 7, might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators. Our findings represent the first use of third-generation sequencing (TGS) to identify novel BEST1 mutations in patients with ARB, indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes. The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population.

Circular Perivascular Autofluorescence Pattern in Patients With Autoimmune Retinopathy.

Purpose: To report the characteristics and prevalence of a previously undescribed circular perivascular fundus autofluorescence (FAF) pattern in paraneoplastic and nonparaneoplastic autoimmune retinopathy. Methods: This retrospective case series used clinical and imaging data extracted from charts of patients with autoimmune retinopathy in whom FAF imaging was performed from the initial presentation to the last visit. Results: Six of 25 patients with autoimmune retinopathy and FAF imaging developed circular perivascular FAF changes. Three patients had paraneoplastic autoimmune retinopathy, and 3 had nonparaneoplastic autoimmune retinopathy. The lesions appeared a mean of 25 months after symptom onset; however, the timing varied from months to years and did not correlate with the overall disease course. The lesions were initially typically hyperautofluorescent and varied in progression, distribution, and quality. Optical coherence tomography showed hyperreflective subretinal deposits in the corresponding areas in most patients. Conclusions: To our knowledge, these are the first reported cases with this circular perivascular FAF pattern in nonparaneoplastic autoimmune retinopathy. This finding could also be a useful diagnostic imaging marker in some patients with autoimmune retinopathy.

Choroidal neovascularization as first sign of Best's vitelliform dystrophy in a child

Aims/Purpose: To report a case of choroidal neovascularization secondary to Best's vitelliform dystrophy in a child managed by intravitreal aflibercept.Methods: Interventional, case report.Results: A 9‐year‐old boy reported decreased visual acuity (VA) with metamorphopsia in his right eye (RE) for the previous month. VA was RE 20/100 and left eye (LE) 20/20. Funduscopy revealed right‐eye macular oedema with deep macular haemorrhage associated to a bilateral orange‐yellowish deposit. Optical coherence tomography (OCT) showed sub‐ and intraretinal fluid in the foveal area along with a hyperreflective subretinal deposit and a localized retinal pigment epithelium (RPE) elevation. Blue autofluorescence (BAF) imaging disclosed a central hyper autofluorescence area as well as a larger defect corresponding to the haemorrhage and the subretinal deposit. The LE was positive for a central deposit located under the RPE with hyper autofluorescence at BAF. Familiar history was unknown for ocular conditions and the clinical history was irrelevant for fever, inflammation, adenopathy, articular, neurological or respiratory conditions. The condition was diagnosed as choroidal neovascularization (CNV) secondary to Best's vitelliform dystrophy and a single intravitreal injection of aflibercept was performed under general anaesthesia. Genetic study revealed a likely pathogenic mutation c.874G&gt;C (p.Glu292Gln) in the BEST1 gene (missense change, not previously published) affecting a functional dominion. The subretinal bleeding and fluid resolved after one single injection of aflibercept and VA improved to 20/20. No recurrences have been observed during the subsequent five years in either eye.Conclusions: We report a case of CNV as first manifestation of a previously not reported mutation of Best's vitelliform dystrophy in a 9‐year‐old boy that was successfully treated with one single intravitreal injection of aflibercept.

Treatment Strategy With Gene Editing for Late-Onset Retinal Degeneration Caused by a Founder Variant in C1QTNF5.

Genome editing is an emerging group of technologies with the potential to ameliorate dominant, monogenic human diseases such as late-onset retinal degeneration (L-ORD). The goal of this study was to identify disease stages and retinal locations optimal for evaluating the efficacy of a future genome editing trial. Twenty five L-ORD patients (age range, 33-77 years; median age, 59 years) harboring the founder variant S163R in C1QTNF5 were enrolled from three centers in the United Kingdom and United States. Patients were examined with widefield optical coherence tomography (OCT) and chromatic perimetry under dark-adapted and light-adapted conditions to derive phenomaps of retinal disease. Results were analyzed with a model of a shared natural history of a single delayed exponential across all subjects and all retinal locations. Critical age for the initiation of photoreceptor loss ranged from 48years at the temporal paramacular retina to 74 years at the inferior midperipheral retina. Subretinal deposits (sRET-Ds) became more prevalent as critical age was approached. Subretinal pigment epithelial deposits (sRPE-Ds) were detectable in the youngest patients showing no other structural or functional abnormalities at the retina. The sRPE-D thickness continuously increased, reaching 25µm in the extrafoveal retina and 19µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.

Early and late chorioretinal complications of preeclampsia

Preeclampsia remains a serious problem of obstetric practice, the growth of severe forms of this complication of pregnancy is predicted in the future, which determines the scientific interest of specialists in the search for new markers of preeclampsia to prevent the progression of preeclampsia and maternal mortality. The ocular fundus is an area where vessels can be observed in real time, in addition, the structure of the retina predisposes to the development of edema, up to retinal detachment in severe preeclampsia. In the last decade, new diagnostic equipment has become available to study chorioretinal changes at the stage of preclinical manifestations. In order to study early and late complications of pre-eclampsia from the retina and vasculature, we analyzed domestic and foreign scientific sources published in the last five years. According to a number of authors, changes in the visual organ of varying degrees of severity in preeclampsia occur in 100% of cases. It is established that the key role in the pathogenesis of vascular disorders in preeclampsia belongs to endothelial dysfunction. Preeclampsia may be accompanied by hemorrhagic and ischemic retinal infarcts, retinal pigment epithelium detachment, corkscrew-shaped tortuosity of arterioles in the periphery of the retina, retinal detachment, optic disc edema, less frequently vitreous hemorrhages, lesions of the optic nerve, conjunctiva and cerebral cortex in the area of visual centers, which may resolve against the background of therapy when the patient's general condition improves. However, in some women endothelial dysfunction may persist for many years, the most frequent late complications of preeclampsia are retinal detachment and diabetic retinopathy. Along with traditional methods of ophthalmoscopy of the eye fundus for diagnostics of chorioretinal complications OCT for determination of serous retinal detachment, subretinal deposits and other pathologies of the vasculature, USDG of the central retinal artery, posterior short ciliary arteries, ocular artery for diagnostics of ophthalmologic complications of preeclampsia can be used. As a result of the analysis of scientific data, conclusions are drawn about the association of preeclampsia with the development of certain early and distant chorioretinal complications. The search for new, earlier changes on the ocular fundus may serve for early diagnosis of preeclampsia, prevention of severe complications of pregnancy.

ANATOMICAL AND FUNCTIONAL OUTCOMES OF BEVACIZUMAB TREATMENT IN PEDIATRIC AUTOSOMAL RECESSIVE BESTROPHINOPATHY.

The purpose of this study was to report functional and anatomical outcomes of anti-VEGF treatment in eyes with autosomal recessive bestrophinopathy (ARB) presenting in the first decade of life. The study included case series of four eyes from two siblings with compound heterozygous mutations in the BEST1 gene who were treated with eight monthly intravitreal bevacizumab injections. Response to treatment was analyzed using color fundus photography, fundus autofluorescence, optical coherence tomography, OCT angiography, and microperimetry. Patient 1 (male, age 9 years) had visual acuity of 20/20 in the right eye and 20/50 in the left eye. Patient 2 (female, age 10 years) had visual acuity of 20/25 in the right eye and 20/20 in the left eye. All eyes had multifocal subretinal deposition of lipofuscin and subretinal fluid, and three eyes had choroidal neovascularization (CNV). Lipofuscin material reabsorbed in 2 of 4 eyes, the CNV regressed in 3 of 3 eyes, a bacillary detachment resolved in 1 of 1 eye, but the subretinal fluid did not change. Functional improvement in visual acuity was noted, but MP showed scattered areas of reduced retinal sensitivity. No ocular or systemic side effects were detected. Anti-VEGF treatment of choroidal neovascularization in eyes with ARB resulted in anatomical changes that were only clinically significant in the eye with decreased visual acuity. The hyporeflective subretinal material remained unchanged suggesting a nonexudative cause. These findings provide new insights into the management of ARB, especially in pediatric subjects with CNV.

Characteristics of Vitamin A Deficiency Retinopathy at a Tertiary Referral Center in the United States

To explore the risk factors and fundus imaging features of vitamin A deficiency retinopathy (VADR) in an academic tertiary referral center in Atlanta, GA, United States, and to propose guidance regarding diagnostic workup and management of affected patients. Single-center retrospective case series. Nine patients seen between 2015 and 2021 at the Emory Eye Center diagnosed with VADR. Retrospective chart review. Baseline serum retinol level, Snellen visual acuity, multimodal fundus imaging findings, and electroretinography findings. Nine patients, 4 (44.4%) female, with a median (range) age of 68 (50-75) years were identified. The most common underlying etiologies for vitamin A deficiency included history of gastrointestinal surgery (55.6%), liver disease (44.4%), and nutritional depletion due to low-quality diet (44.4%). Only 1 (11.1%) patient had a history of bariatric surgery. Four (44.4%) patients were on some form of vitamin A supplementation before the diagnosis of VADR. Median (range) serum retinol level was 0.06 (< 0.06-0.19) mg/L. All patients had macular subretinal hyperreflective deposits resembling subretinal drusenoid deposits, although in some cases, these were scant and sparsely distributed. Six eyes of 3 patients with longstanding deficiency had defects in the external limiting membrane (ELM). Three of these eyes additionally had macular areas of complete retinal pigment epithelium and outer retinal atrophy (cRORA). Full-field electroretinography demonstrated severe rod dysfunction and mild to moderate cone system dysfunction. Many findings of VADR were reversible with vitamin A repletion. However, all eyes with ELM defects or cRORA had persistence or continued growth of these lesions. Vitamin A deficiency retinopathy is uncommon in the developed world. However, given that early intervention can lead to dramatic visual improvement and avoid potentially permanent retinal damage, retina specialists should be familiar with its clinical presentation. The presence of nyctalopia and subretinal hyperreflective deposits in a patient with a history of gastrointestinal surgery, liver disease, and/or poor diet can be suggestive of this diagnosis, even in the presence of ongoing vitamin A supplementation. Vitamin A supplementation can vary in route and dosage and can be tailored to the individual with serial testing of serum retinol. The authors have no proprietary or commercial interest in any materials discussed in this article.

Rare manifestation of familial vitreous amyloidosis caused by Gly103Arg transthyretin.

To identify and analyze the genotype of the patients with special ocular manifestations of familial vitreous amyloidosis (FVA) in a Chinese Han family. Pars plana vitrectomy (PPV) surgery was performed on a 52-year-old Chinese woman presented with vitreous amyloidosis and progressive visual impairment, without evidence of cardiac, renal, gastrointestinal, central nervous system or peripheral nervous system dysfunction. During the surgery, the patient presented with a gray-white dense and thick cotton wool-like change in the vitreous body, accompanied by complete retinal detachment. Additionally, hard, free and movable yellow-white deposits were observed in the posterior pole and surrounding retina, the vitreous and subretinal deposits were examined by Congo red staining and immunohistochemical pathological examination, and whole exome sequencing was performed on blood samples from the patient and her cousin. During the operation, it was discovered that there was a complete detachment of the retina and a significant amount of hard, free-floating yellow-white deposits were observed beneath the posterior pole and surrounding retina. This is an exceedingly rare ocular manifestation. Pathological examination of the vitreous and subretinal deposit specimens revealed positive Congo red staining, as well as elevated vascular endothelial growth factor (VEGF) expression in vascular endothelial cells within the sediment specimens upon immunohistochemical examination. The patient and her cousin both exhibited a heterozygous mutation in Glyl03Arg within the transthyretin (TTR) gene, resulting in a substitution of glycine (Gly) at position 103 with arginine (Arg). FVA may present with various ocular manifestations, but panretinal detachment is a rare occurrence. In cases where retinal detachment persists for an extended period of time, amyloid deposits may form under the retina through retinal tears, leading to subretinal deposits that can impede retinal reattachment and negatively impact visual prognosis. Elevated levels of VEGF in the eyes of FVA patients may indicate an overexpression state, necessitating careful postoperative follow-up. The heterozygous mutation Gly103Arg may represent a unique pathogenic site in Chinese individuals.

Autosomal recessive bestrophinopathy combined with neurofibromatosis type 1 in a patient

BackgroundNeurofibromatosis type 1 (NF1) is a multisystem genetic disorder that may affect multiple systems of the body. Autosomal recessive bestrophinopathy (ARB) is a rare retinal dystrophy caused by autosomal recessively mutations in bestrophin 1 (BEST1) gene. So far, we have not retrieved any case report of the same patient with both NF1 and BEST1 gene mutations.Case presentationAn 8-year-old female patient with café-au-lait spots, freckling on skin presented to our ophthalmology clinic for routine ophthalmological examination. Her best corrected visual acuity (BCVA) was 20/20 in both eyes. Slit-lamp examination of both eyes revealed few yellowish-brown dome-shaped Lisch nodules over the iris surface. Fundus examination was notable for bilateral confluent yellowish subretinal deposits at macula, few yellow flecks at temporal retina, and cup-to-disc ratio of 0.2. Optical coherence tomography (OCT) revealed subretinal fluid (SRF) involving the fovea, elongated photoreceptor outer segments and mild intraretinal fluid (IRF) at bilateral macula. Fundus autofluorescence demonstrated hyperautofluorescence in the area corresponding to the subretinal deposits. Whole-exome sequencing and Sanger sequencing were used to investigate genetic mutation in the patient and her parents. A BEST1 gene heterozygous missense c.604 C > T (p.Arg202Trp) was identified in the patient and her mother. Also, the patient carries an NF1 nonsense mutation c.6637 C > T (p.Gln2213*) with the mosaic generalized phenotype. There were no visual impairments or obvious neurological, musculoskeletal, behavioral or other symptoms in this patient, so she was managed conservatively and advised to follow up regularly for a long time.ConclusionsARB and NF1, which are caused by two different pathogenic gene mutations, have rarely coexisted in the same patient. The discovery of pathogenic gene mutations may play a crucial role in more accurate diagnostics and genetic consultations for individuals and their families.

Paradoxical autosomal recessive bestrophinopathy-like phenotypes shown in an autosomal dominant pedigree.

This study aimed to evaluate the clinical and genetic characteristics of eight members from a Chinese Han family who displayed autosomal recessive bestrophinopathy (ARB)-like retinal changes in autosomal dominant (AD) inheritance pattern. Clinical investigations included slit-lamp, tonometry, fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, electrooculography, and ultrasound biomicroscopy. Ocular axial length measurements were collected retrospectively. The targeted exome sequencing (TES) was applied for the genetic analysis of the proband. PCR-based Sanger sequencing was performed on the family for validation and co-segregation analysis. Eight members in the three-generation pedigree complained about vision loss and seven of them had detailed clinical assessments, demonstrating ocular phenotypes including extramacular and vascular arcades subretinal deposits and Arden ratio decline on electrooculography that resembled ARB. Bilateral anterior chamber structure abnormalities were observed in seven cases and three patients were diagnosed with angle-closure glaucoma. Despite clinical phenotypes supporting ARB, there was only a single heterozygous mutation of c.227T > C (p.Ile76Thr) in the BEST1 gene detected in all eight patients, which showcased AD inheritance. An ARB-like phenotype could be caused by a heterozygous mutation of the BEST1 gene and inherited in an AD fashion.