Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes.

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.

Non-vasogenic cystoid maculopathy in autosomal recessive bestrophinopathy: novel insights from NIR-FAF and OCTA imaging.

BACKGROUND: Autosomal Recessive Bestrophinopathy (ARB) is an inherited retinal disease caused by biallelic mutations in the BEST1 gene. Herein, we report the multimodal imaging findings of ARB presenting with cystoid maculopathy and investigate the short-term response to combined systemic and topical carbonic anhydrase inhibitors (CAIs). MATERIAL AND METHODS: An observational, prospective, case series on two siblings affected by ARB is presented. Patients underwent genetic testing and optical coherence tomography (OCT), blue-light fundus autofluorescence (BL-FAF), near-infrared fundus autofluorescence (NIR-FAF), fluorescein angiography (FA), MultiColor imaging, and OCT angiography (OCTA). RESULTS: Two male siblings, aged 22 and 16, affected by ARB resulting from c.598C>T, p.(Arg200*) and c.728C>A, p.(Ala243Glu) BEST1 compound heterozygous variants, presented with bilateral multifocal yellowish pigment deposits scattered through the posterior pole that corresponded to hyperautofluorescent deposits on BL-FAF. Vice versa, NIR-FAF mainly disclosed wide hypoautofluorescent areas in the macula. A cystoid maculopathy and shallow subretinal fluid were evident on structural OCT, albeit without evidence of dye leakage or pooling on FA. OCTA demonstrated disruption of the choriocapillaris throughout the posterior pole and sparing of intraretinal capillary plexuses. Six months of combined therapy with oral acetazolamide and topical brinzolamide resulted in limited clinical benefit. CONCLUSIONS: We reported two siblings affected by ARB, presenting as non-vasogenic cystoid maculopathy. Prominent alteration of NIR-FAF signal and concomitant choriocapillaris rarefaction on OCTA were noted in the macula. The limited short-term response to combined systemic and topical CAIs might be explained by the impairment of the RPE-CC complex.

Gene therapy in bestrophinopathies: Insights from preclinical studies in preparation for clinical trials.

The BEST1 gene encodes bestrophin-1, a homopentameric ion channel expressed in the retinal pigment epithelium (RPE), where it localizes to the basolateral plasma membrane. Pathogenic variants in this gene can cause different autosomal dominant and recessive inherited retinal diseases (IRDs), collectively named "bestrophinopathies." These disorders share a number of clinical and molecular features that make them an appealing target for gene therapy. Clinically, bestrophinopathies are often slowly progressive with a wide window of opportunity, and the presence of subretinal material (vitelliform deposits and/or fluid) as a hallmark of these conditions provides an easily quantifiable endpoint in view of future clinical trials. From a molecular standpoint, most BEST1 pathogenic variants have been shown to cause either loss of function (LOF) of the protein or a dominant-negative (DN) effect, with a smaller subset causing a toxic gain of function (GOF). Both LOF and DN mutations may be amenable to gene augmentation alone. On the other hand, individuals harboring GOF variants would require a combination of gene silencing and gene augmentation, which has been shown to be effective in RPE cells derived from patients with Best disease. In this article, we review the current knowledge of BEST1-related IRDs and we discuss how their molecular and clinical features are being used to design novel and promising therapeutic strategies.

Pars Plana Vitrectomy in Inherited Retinal Diseases: A Comprehensive Review of the Literature.

Inherited retinal diseases (IRDs) are a group of clinically and genetically heterogeneous disorders that may be complicated by several vitreoretinal conditions requiring a surgical approach. Pars plana vitrectomy (PPV) stands as a valuable treatment option in these cases, but its application in eyes with such severely impaired chorioretinal architectures remains controversial. Furthermore, the spreading of gene therapy and the increasing use of retinal prostheses will end up in a marked increase in demand for PPV surgery for IRD patients. The retinal degeneration that typically affects patients with hereditary retinal disorders may influence the execution of the surgery and the expected results. Considering the importance of PPV application in IRD-related complications, it is fundamental to try to understand from the literature what is adequate and safe in posterior eye segment surgery. Use of dyes, light toxicity, and risk of wounding scar development have always been themes that discourage the execution of vitreoretinal surgery in already impaired eyes. Therefore, this review aims to comprehensively summarize all PPV applications in different IRDs, highlighting the favorable results as well as the potential precautions to consider when performing vitreoretinal surgery in these eyes.

Clinical Applications of Optical Coherence Tomography Angiography in Inherited Retinal Diseases: An Up-to-Date Review of the Literature.

Optical coherence tomography angiography (OCT-A) is a valuable imaging technique, allowing non-invasive, depth-resolved, motion-contrast, high-resolution images of both retinal and choroidal vascular networks. The imaging capabilities of OCT-A have enhanced our understanding of the retinal and choroidal alterations that occur in inherited retinal diseases (IRDs), a group of clinically and genetically heterogeneous disorders that may be complicated by several vascular conditions requiring a prompt diagnosis. In this review, we aimed to comprehensively summarize all clinical applications of OCT-A in the diagnosis and management of IRDs, highlighting significant vascular findings on retinitis pigmentosa, Stargardt disease, choroideremia, Best disease and other less common forms of retinal dystrophies. All advantages and limitations of this novel imaging modality will be also discussed.

The pseudohypopyon stage in adult-onset foveomacular vitelliform dystrophy.

PURPOSE: To gain insight into the pathogenesis of adult-onset foveomacular vitelliform dystrophy (AFVD) via assessment of its pseudohypopyon stage (PHS). METHODS: Retrospectively, data were collected in a tertiary center from established cohorts of a genetically evaluated AFVD and best vitelliform macular dystrophy (BVMD) eyes in the pseudohypopyon stage. Best-corrected visual acuity (BCVA, LogMAR), lesion characterization, including lesion dimensions, liquefaction areas and patterns (altitudinal or lateral), and ellipsoid zone integrity were analyzed from spectral-domain optical coherence tomography images. RESULTS: Out of 167 eyes of 90 AFVD patients and 56 eyes of 28 BVMD patients, 8 eyes of six AFVD patients and five eyes of four BVMD patients were at the PHS were included. The mean LogMAR BCVA ± SD was 0.21 ± 0.20 and 0.41 ± 0.10 in AFVD and BVMD diseases, respectively (p = 0.13). Seven AFVD eyes (87.5%) demonstrated lateral liquefaction, while all BVMD eyes demonstrated an altitudinal pattern (p = 0.005). Maximal horizontal lesion diameters were 1.41 ± 0.46 mm and 2.64 ± 0.77 mm in AFVD and BVMD, respectively (p = 0.02). AFVD patients were older (69 ± 14) than BVMD patients (22 ± 13; p = 0.009). CONCLUSION: The pseudohypopyon stage in AFVD is often characterized by a lateral liquefaction pattern, unlike the altitudinal pattern characterizing BVMD. Age, lesion size, or pathogenesis pathways may underline the different pseudohypopyon stage patterns in AFVD and BVMD.

Atypical Foveal Hypoplasia in Best Disease.

PURPOSE: To determine the prevalence and characteristics of foveal hypoplasia (also called fovea plana) in patients with Best disease using spectral-domain (SD) optical coherence tomography (OCT) and OCT-angiography (OCT-A). DESIGN: A retrospective observational study including patients diagnosed with Best disease. SUBJECTS AND PARTICIPANTS: Fifty-nine eyes of thirty-two patients (fifteen females (46.9%) and seventeen males (53.1%), p = 0.9) diagnosed with Best disease were included. Patients' eyes were categorized into two groups: Eyes with a fovea plana appearance ('FP group') and eyes without fovea plana appearance ('no FP group'), based on the foveal appearance on B-scan SD-OCT. METHODS AND MAIN OUTCOME MEASURES: Cross-sectional OCT images were assessed for the persistence of inner retinal layers (IRL) and OCT-A was analyzed for the presence of a foveal avascular zone (FAZ), the size of which was determined when applicable. RESULTS: Overall, 16 eyes (27.1%) of 9 patients had a fovea plana appearance ('FP group') with the persistence of IRL, and 43 eyes (72.9%) of 23 patients did not have fovea plana appearance ('no FP group'). Among FP eyes, OCT-A performed in 13 eyes showed bridging vessels through the FAZ in 100% of eyes with OCT-A. Using Thomas classification, 14 out of the 16 eyes with fovea plana (87.5%) had atypical foveal hypoplasia, and the 2 others (12.5%) had a grade 1b fovea plana. CONCLUSION: In our series, foveal hypoplasia was present in 27.1% of patients with Best disease. OCT-A showed bridging vessels through the FAZ in all eyes. These findings highlight the microvascular changes associated with Best disease, which can be an early sign of the disease in patients with a family history.

Choroidal Neovascularization Is Common in Best Vitelliform Macular Dystrophy and Plays a Role in Vitelliform Lesion Evolution.

OBJECTIVE: Choroidal neovascularization (CNV) is usually considered to be a late-stage complication in Best vitelliform macular dystrophy (BVMD) and can be difficult to diagnose with fluorescein angiography. This study used swept-source (SS) OCT angiography (OCTA) to evaluate the prevalence of CNV in BVMD, identify structural features associated with CNV, and provide insight into the role of CNV in vitelliform lesion evolution. DESIGN: Institutional review board-approved, retrospective, cross-sectional, and longitudinal study. PARTICIPANTS: Patients with molecularly confirmed BVMD. METHODS: Charts from consecutive patients with BVMD imaged with SS-OCTA (PLEX Elite 9000, Carl-Zeiss Meditec Inc) at the University of Iowa from September 2017 to October 2021 were reviewed. Clinical data, including age, gender, best-corrected visual acuity (BCVA), and treatment with intravitreal anti-VEGF injections were recorded. The presence of CNV on SS-OCTA was determined by expert graders and correlated with structural features, such as interstitial fluid, subretinal fluid, nodular subretinal pillar, focal choroidal excavation (FCE), and subfoveal choroidal thickness, with a P value of < 0.05 considered statistically significant. MAIN OUTCOME MEASURES: Presence of CNV on SS-OCTA and correlation with structural features on SS-OCT. RESULTS: A total of 53 eyes from 27 patients (13 women; 48.1%) were included. The mean age was 45 years (range, 8-79 years), and the mean logarithm of the minimum angle of resolution BCVA was 0.38 (range, 0-1). Choroidal neovascularization was identified on SS-OCTA in 27 eyes (50.9%), of which 63.0% had a vitelliform (Gass stage 2) lesion. In 40.7% (11 of 27) of eyes, there was no prior clinical diagnosis of CNV. Other structural features associated with CNV included FCEs (15.1%, 8 of 53 eyes) and nodular pillars (15.1%, 8 of 53 eyes) (P < 0.01). Seven patients had available longitudinal imaging, and most of these patients had CNV visible on SS-OCTA (71.4%; 10 of 14 eyes). CONCLUSION: Choroidal neovascularization is common in BVMD, including in the early stages of the disease. The presence of FCEs or nodular pillars should heighten the clinical suspicion of CNV, which may accelerate vitelliform lesion evolution. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

IMPG2-associated unilateral adult onset vitelliform macular dystrophy.

Purpose: To present a case of unilateral IMPG2-associated adult onset vitelliform macular dystrophy (AVMD). Observations: A 68 year-old female presented with best corrected visual acuity (BCVA) of 20/20 and 20/40 for the right and left eye respectively. The patient had a left subfoveal yellow lesion on dilated fundus examination. Optical coherence tomography showed hyper-reflective material accumulation below the fovea in the left eye only. The patient was followed for 10 years with stable BCVA, and evolution of the subretinal vitelliform lesion to a "vitelliruptive" stage. The right eye did not develop vitelliform lesion. Genetic testing identified a heterozygous likely disease-causing variant in IMPG2; c.3423-7_3423-4del. Conclusions and importance: This is the first report of unilateral AVMD associated with IMPG2, expanding the phenotypic spectrum of IMPG2 retinopathy. We provide further evidence that IMPG2 variants can cause both autosomal recessive rod-cone dystrophy and autosomal dominant AVMD, with implications for patient counselling.

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation.

Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.

Clinical and visual electrophysiological characteristics of vitelliform macular dystrophies in the first decade of life.

Purpose: To evaluate patterns of pediatric vitelliform macular dystrophy (PVMD). Methods: This is a retrospective analysis of Indian children with vitelliform macular dystrophy (VMD) presenting within the first decade of life. Records were evaluated for clinical findings, family screening, and investigative findings including optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinogram (ERG) and electrooculogram (EOG). Electrophysiology was scrutinized and audited for acquisition and interpretation errors. Findings on follow-up were also recorded. Results: 46 eyes of 24 patients were included. Mean age at presentation was 7.17 ± 2.17 years. Mean follow-up duration was 1.55 ± 1.69 years. Best disease was the commonest type of VMD detected (21 patients), while autosomal recessive bestrophinopathy was seen in three cases. Mean logMAR BCVA was 0.364 which decreased to 0.402 on follow-up. Hyperopia was noted in 29 out of 46 eyes (mean being +3.87 D, range ebing +0.75 to +8.75 D). Four eyes of four children had choroidal neovascular membrane at presentation, while another child developed while in follow-up. Solid type subretinal deposit was the commonest OCT finding (n = 29/38) and central hyper FAF was the commonest pattern (n = 18/32). EOG was available for review in 32 eyes, but was unreliable in 11 eyes. Seven eyes demonstrated complete absence of light rise on EOG. Conclusion: PVMD can present in advanced forms. Progression to complications with loss of visual acuity can happen within the first decade of life. EOG shows grossly suppressed waveforms in the light phase in a large number of such children.

Adult-onset bestrophinopathy mistaken as central serous chorioretinopathy.

PURPOSE: To highlight cases of adult-onset bestrophinopathy mistaken as central serous chorioretinopathy (CSCR). METHODS: Retrospective case series. RESULTS: Two unrelated adult males (54 years old and 43 years old) with serous macular detachments were managed as CSCR. One had been treated with intraocular injections and oral mineralcorticoid inhibitors. Independently, each had an 8-year-old son who presented with classic Best disease, which raised suspicion for bestrophinopathy in their fathers. Bestrophin sequencing confirmed each son to be heterozygous for a pathogenic variant, and targeted testing confirmed each respective father to harbor the same heterozygous pathogenic variant as his son. Electro-oculography of the first father-son pair confirmed decreased Arden ratios. Review of multimodal imaging of the adult patients revealed a hyper-autofluorescent edge surrounding a serous macular detachment by short-wave autofluorescence and shaggy photoreceptors on the overlying edge of serous detachments by optical coherence tomography. DISCUSSION: Adult-onset bestrophinopathy can be mistaken as CSCR. Multimodal imaging findings, examination of potentially affected family members, electrophysiology, and genetic testing facilitate the correct diagnosis.

The best course of action.

An 11-year-old girl noted gradual visual loss in the right eye for 1 year with subfoveal yellow deposits in both eyes. Optical coherence tomography, electro-oculogram and electroretinogram was in-keeping with Best Disease. This disorder is discussed.

Best disease presenting as subretinal pigment epithelium hyperreflectivite lesion on spectral-domain optical coherence tomography: Multimodal imaging features.

PURPOSE: To report clinical and multimodal imaging features of Best disease in patients presenting with subretinal pigment epithelium hyperreflective lesions. DESIGN: Retrospective study. METHODS: Clinical examination findings and multimodal imaging features, including color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, fluorescein and indocyanine green angiography (ICGA), and optical coherence tomography angiography (OCTA) images were evaluated retrospectively. RESULTS: We assessed 27 eyes of 16 patients with the diagnosis of Best disease. Only patients presenting with serous macular detachment and subretinal pigment epithelium hyperreflective lesion in one or both eyes were included in this study. In 17 of 27 eyes (63%), fibrosis was identified by multimodal imaging techniques. Although there was no sign of active neovascularization on fundus examination or SD-OCT, a vascular network could be identified in 7 eyes (26%) (in 1 eye with OCTA only and in 6 eyes with both OCTA and ICGA). Active neovascularization was seen in 3 eyes (11%). Treatment was recommended for eyes with active neovascularization, and follow-up was scheduled for eyes with quiescent neovascularization and fibrosis. CONCLUSION: Eyes with Best disease with subretinal pigment epithelium hyperreflective lesion and serous macular detachment may show fibrosis, quiescent neovascularization, or active neovascularization. Multimodal imaging techniques are very important for differentiation of these lesions.

Intravitreal bevacizumab treatment for exudative choroidal neovascularisation in best vitelliform macular dystrophy.

PURPOSE: To describe results of intravitreal bevacizumab treatment of the secondary choroidal neovascularisation in Best vitelliform macular dystrophy in an adult and paediatric patient, and present the management of three asymptomatic patients with confirmed BEST1 gene mutation. CASE SERIES DESCRIPTION: Five patients from the same family with the Best vitelliform macular dystrophy are presented. In two patients (aged 63 and 4 years) secondary choroidal neovascularisation caused a rapid decline in visual acuity. In the adult patient with advanced Best vitelliform macular dystrophy, visual acuity did not improve despite eight intravitreal bevacizumab injections to the right eye. The formation of a central scar and rapid reoccurrence of choroidal neovascularisation three months after completing the initial treatment affected the outcome. As for the paediatric patient with bilateral choroidal neovascularisation in the vitelliform stage of Best vitelliform macular dystrophy, a complete recovery of visual acuity was observed after two (left eye) and three (right eye) bevacizumab injections, with adjunctive amblyopia treatment. The other three patients with an abnormal electrooculogram reported no visual problems during more than 10 years of follow-up. Minimal changes were seen on optical coherence tomography in the youngest patient. CONCLUSIONS: Intravitreal bevacizumab seems to be an effective treatment for exudative choroidal neovascularisation in the vitelliform stage of Best vitelliform macular dystrophy; however, it may not be beneficial in the advanced stages of Best vitelliform macular dystrophy. It is important to regularly screen all family members with an abnormal electrooculogram and confirmed mutation for vitelliform changes and choroidal neovascularisation from an early age. The decision for anti-vascular endothelial growth factor treatment should be made on a case-to-case basis as complications may arise.

The Role of Optical Coherence Tomography Angiography (OCTA) in Detecting Choroidal Neovascularization in Different Stages of Best Macular Dystrophy: A Case Series.

Best macular dystrophy (BMD) is an autosomal dominant macular dystrophy of childhood onset characterized by bilateral and symmetric vitelliform lesions. Several stages of disease have been well-described in the literature. Choroidal neovascularization (CNV) has traditionally been considered a hallmark of end-stage disease, and anti-vascular endothelial growth factor (anti-VEGF) agents have been used to improve visual prognosis. While CNV was historically detected with fluorescein angiography, optical coherence tomography angiography (OCTA) has recently been employed as a novel mechanism for identifying CNV in BMD. In this case series, we discuss our institutional experience with using OCTA to detect CNV in BMD and contextualize this experience within the broader emerging literature. While OCTA allows for the identification of CNV in less severe stages of BMD, the management of this CNV remains uncertain.

A novel phenotype in a family with autosomal dominant retinal dystrophy due to c.1430A > G in retinoid isomerohydrolase (RPE65) and c.37C > T in bestrophin 1 (BEST1).

PURPOSE: The c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant. METHODS: Members of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed. RESULTS: Vision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband. CONCLUSIONS: The coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members.

Cellular Changes in Retinas From Patients With BEST1 Mutations.

Best disease (BD), also known as vitelliform macular dystrophy, is an inherited disease of the central retina caused by more than 300 pathogenic variants in the BEST1 gene. The phenotype of BD is variable, and there are just a few reports on the histopathology of eyes from donors with BD. Here, we describe the histopathological comparison of donor's eyes from two patients with BD. Eyes obtained from 85-year-old (donor 1) and 65-year-old (donor 2) donors were fixed within 25 h postmortem. Perifoveal and peripheral retinal regions were processed for histology and immunocytochemistry using retinal-specific and retinal pigment epithelium (RPE)-specific antibodies. Three age-matched normal eyes were used as controls. DNA was obtained from donor blood samples. Sequence analysis of the entire BEST1 coding region was performed and identified a c.886A > C (p.Asn296His) variant in donor 1 and a c.602T > C (p.Ile201Thr) variant in donor 2; both mutations were heterozygous. Fundus examination showed that donor 1 displayed a macular lesion with considerable scarring while donor 2 displayed close to normal macular morphology. Our studies of histology and molecular pathology in the perifovea and periphery of these two BD donor eyes revealed panretinal abnormalities in both photoreceptors and RPE cellular levels in the periphery; donor 1 also displayed macular lesion. Our findings confirm the phenotypic variability of BD associated with BEST1 variants.

Inherited Macular Dystrophies in a Tertiary Care Centre.

BACKGROUND: Inherited macular dystrophies constitute a group of diseases characterized by bilateral central visual loss with symmetrical macular abnormalities usually presenting in the first two decades of life. The aim of this study were to find out the demographic characteristics and disease pattern of inherited retinal dystrophies in subjects attending retina outpatient department in a tertiary care center. METHODS: An observational study among twenty-six participants diagnosed as macular dystrophy visiting a tertiary care centre in Nepal, during January 2018 to June 2018 were included in the study. Detailed history, slit lamp examination, dilated fundus examination, coloured fundus photography, full field electroretinogram, multifocal electroretinogram, automated visual field and colour vision were done. RESULTS: A total of 52 eyes of 26 subjects were diagnosed with macular dystrophy. The male to female ratio was 1:1. The mean age of presentation was 28.38 years. Most common symptom was blurring of vision seen in 96.15%.The mean visual acuity was 0.67 log mar units in right eye and 0.71 log mar units in the left eye. The most common macular dystrophy was cone dystrophy followed by adult vitelliform macular dystrophy and Stargardts dystrophy. CONCLUSIONS: Cone dystrophy is the most common followed by Stargardt's disease and adult vitelliform macular dystrophy. Most presented in the first two decades of life and the most common presenting symptom was blurring of vision.

"Novel p.Tyr284Cys BEST1 genotype-phenotype correlations of Vitelliform Macular Dystrophy in a family with incomplete penetrance".

Purpose: Vitelliform Macular Dystrophy is an inherited autosomal dominant disease with variable expressivity, caused by a mutation in the BEST1 gene. We report a family with variable expressivity and incomplete penetrance in its members.Materials and Methods: A Mexican family was studied. It was comprised of six individuals (father, mother, and four children). A clinical history was taken, and a complete ophthalmological examination (distance best-corrected visual acuity, slit-lamp biomicroscopy, optical coherence tomography, fundus autofluorescence, optical coherence tomography angiography, and electrophysiological studies) was performed in each individual.Results: Two members presented low visual acuity and vitelliform lesions in different stages in the ocular fundus. The assessment suggested a diagnosis of Vitelliform Macular Dystrophy. Genetic analysis was performed by sequencing of exons 2, 4, 5, 7, 8, and 9 of the BEST1 gene. All patients were carriers of the A variant allele of SNP rs1109748 located in exon 2 (c.219 C > A; p.Ile73=). Also, a missense mutation was identified in exon 7 in the mother and two children (c.851A>G; p.Tyr284Cys). The mother has a normal visual acuity, no abnormal findings in the ophthalmological examination and an abnormal electrooculogram, exhibiting incomplete penetrance.Conclusion: This represents one of the few cases of Vitelliform Macular Dystrophy with incomplete penetrance, being the first in our country and Latin America, and with our reported mutation with this characteristic.