A.G. Robson

Lack of Interphotoreceptor Retinoid Binding Protein Caused by Homozygous Mutation of RBP3 Is Associated With High Myopia and Retinal Dystrophy.

PURPOSE We present a detailed clinical and molecular study of four patients from two consanguineous families with a similar childhood-onset retinal dystrophy resulting from novel homozygous nonsense mutations in RBP3. METHODS Four children with mutations in RBP3 encoding interphotoreceptor binding protein (IRBP) were ascertained by whole exome sequencing and subsequent direct Sanger sequencing. Detailed phenotyping was performed, including full clinical evaluation, electroretinography, fundus photography, fundus autofluorescence (FAF) imaging, and spectral-domain optical coherence tomography (OCT). RESULTS Two novel homozygous nonsense mutations (c.1530T>A;p.Y510* and c.3454G>T;p.E1152*) in RBP3 were identified in four patients from two families. All four patients had a similar, unusual retinal dystrophy characterized by childhood onset high myopia, generalized rod and cone dysfunction, and an unremarkable fundus appearance. The FAF imaging showed multiple paracentral foci of low autofluorescence in one patient and patchy increased FAF in the region of the vascular arcades in another. The OCT showed loss of outer retinal bands over peripheral macular areas in all 4 cases. CONCLUSIONS To our knowledge, this report is the first to describe the retinal dystrophy in children caused by homozygous nonsense RBP3 mutations, highlighting the requirement for IRBP in normal eye development and visual function. Longitudinal study will reveal if the four children reported here will progress to a more typical retinitis pigmentosa phenotype described previously in adults with RBP3 mutations. The RBP3-related disease should be considered in children with high myopia and retinal dystrophy, particularly when there are no significant fundus changes.

Clinicopathological case series of four patients with inherited macular disease

PURPOSE To correlate the phenotype of four patients with inherited macular disease with the immunohistopathology of retinal tissue collected at the time of retinal pigment epithelium (RPE)-choroidal transplantation. METHODS A clinicopathologic case series describing the phenotype of four patients, including confocal immunohistochemistry and electron microscopy (EM), and the results of genetic testing. RESULTS In Case 1, electrophysiology showed only macular dysfunction. Confocal microscopy revealed minor abnormalities. EM showed abnormal cone inner segments with swollen mitochondria. In case 2 (R172W mutation in RDS), electrophysiology demonstrated generalized cone system dysfunction with severe macular involvement. Peripherin labeling of outer segments was nonuniform, and EM showed discs arranged in whorllike structures. Case 3 showed severe central macular dysfunction on multifocal electroretinogram (ERG). Peripherin staining was irregular and disorganized. EM revealed abnormal inner segment morphology, particularly in rods, and disorganized irregular outer segments. Case 4 had localized central macular dysfunction on multifocal ERG. Confocal microscopy was grossly normal, with evidence of early redistribution of cone opsin to the inner segment. EM showed variable rod morphology and normal cones. CONCLUSIONS RPE transplantation provides a unique opportunity to gain insight into retinal disorders by enabling phenotypic correlation with the immunohistopathology of retinal tissue collected during surgery.

An unusual fundus phenotype of inner retinal sheen in X-linked retinoschisis.

1 Martin DF, Awh CC, McCuen II BW, Jaffe GJ, Slott JH, Machemer R. Treatment and pathogenesis of traumatic chorioretinal rupture (sclopetaria). Am J Ophthalmol 1994; 117(2): 190–200. 2 Richards RD, West CE, Meisels AA. Chorioretinitis sclopetaria. Am J Ophthalmol 1968; 66(5): 852–860. 3 Beatty S, Smyth K, Au Eong KG, Lavin MJ. Chorioretinitis sclopetaria. Injury 2000; 31(1): 55–60. 4 Williams DF, Mieler WF, Williams GA. Posterior segment manifestations of ocular trauma. Retina 1990; 10(Suppl 1): S35–S44.

Bilateral giant macular schisis in a patient with enhanced S-cone syndrome from a family showing pseudo-dominant inheritance

Enhanced S-cone syndrome (ESCS) is a rare autosomal recessive disorder related to mutations in NR2E3 . There is early nyctalopia with peripheral field loss and possible macular involvement with loss of central vision.1 Signs include nummular pigmentary deposition at the level of the retinal pigment epithelium (RPE) around the vascular arcades and foveal schisis. There are no rods; most of an increased number of cones are short-wavelength sensitive.2–4 There are pathognomonic electroretinography (ERG) changes. NR2E3 encodes a transcription factor which promotes differentiation and survival …

Reevaluation of the Retinal Dystrophy Due to Recessive Alleles of RGR With the Discovery of a Cis-Acting Mutation in CDHR1.

PURPOSE Mutation of RGR, encoding retinal G-protein coupled receptor was originally reported in association with retinal dystrophy in 1999. A single convincing recessive variant segregated perfectly in one family of five affected and two unaffected siblings. At least one further individual, homozygous for the same variant has since been reported. The aim of this report was to reevaluate the findings in consideration of data from a whole genome sequencing (WGS) study of a large cohort of retinal dystrophy families. METHODS Whole genome sequencing was performed on 599 unrelated probands with inherited retinal disease. Detailed phenotyping was performed, including clinical evaluation, electroretinography, fundus photography, fundus autofluorescence imaging (FAF) and spectral-domain optical coherence tomography (OCT). RESULTS Overall we confirmed that affected individuals from six unrelated families were homozygous for both the reported RGR p.Ser66Arg variant and a nearby frameshifting deletion in CDHR1 (p.Ile841Serfs119*). All had generalized rod and cone dysfunction with severe macular involvement. An additional proband was heterozygous for the same CDHR1/RGR haplotype but also carried a second null CDHR1 mutation on a different haplotype. A comparison of the clinical presentation of the probands reported here with other CDHR1-related retinopathy patients shows the phenotypes to be similar in presentation, severity, and rod/cone involvement. CONCLUSIONS These data suggest that the recessive retinal disorder previously reported to be due to homozygous mutation in RGR is, at least in part, due to variants in CDHR1 and that the true consequences of RGR knock-out on human retinal structure and function are yet to be determined.

A detailed phenotypic description of autosomal dominant cone dystrophy due to a de novo mutation in the GUCY2D gene.

PurposeThe purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D.Materials and methodsFive subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene.ResultsThe youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother.ConclusionsAutosomal dominant cone dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins.

Inherited retinal dystrophy and asymmetric axial length.

The prenatal and postnatal development of the eye is determined by complex interactions between a number of genes, their products, and certain environmental factors.1,2 Since each eye is influenced by precisely the same processes as its fellow, mutations in regulatory genes usually lead to symmetric phenotypes. In this report, we describe two siblings of Asian ethnicity, born to unrelated parents with no family history of ocular disease, who have an unusual bilateral retinal dystrophy associated with very asymmetrical ocular growth. Sib 1 was an 8 year old boy with epilepsy who had been born at term after an uneventful pregnancy. Pendular nystagmus had been noted soon after birth and his visual acuity in each eye was 3/60; refraction −17.00 DS right, plano left. Anterior segment examination was unremarkable with normal intraocular pressures. Examination of the right eye (Fig 1A and B) revealed generalised retinal pigment epithelial and …

Disease expression in autosomal recessive retinal dystrophy associated with mutations in the DRAM2 gene

PURPOSE To determine the disease course of retinal dystrophy caused by recessive variants in the DRAM2 (damage-regulated autophagy modulator 2) gene. METHODS Sixteen individuals with DRAM2-retinopathy were examined (six families; age range, 19-56 years, includes one pre-symptomatic case). The change in visual acuity over time was studied, and electrophysiology (n = 6), retina-tracking perimetry (n = 1), fundus autofluorescence (FAF) imaging (n = 6), and optical coherence tomography (OCT; n = 12) were performed. RESULTS All symptomatic patients presented with central visual loss (15/15) unaccompanied either by nyctalopia or light-hypersensitivity; most (11/15) developed symptoms in the third decade of life. A granular macular appearance, often with associated white/yellow dots, was an early fundoscopic feature. There was an ill-defined ring of hyperautofluorescence on FAF. Optical coherence tomography revealed loss of the ellipsoid zone perifoveally in a 19-year-old pre-symptomatic individual. The central atrophic area enlarged over time and fundoscopy showed peripheral degeneration in seven of the nine individuals that were examined ≥ 10 years after becoming symptomatic; some of these subjects developed nyctalopia and light hypersensitivity. Electrophysiology revealed generalized retinal dysfunction in three of the five individuals that were tested ≥ 10 years after becoming symptomatic. CONCLUSIONS Patients with DRAM2-retinopathy are typically asymptomatic in the first two decades of life and present with central visual loss and a maculopathy. A faint hyperautofluorescent ring on FAF can be a suggestive feature. The retinal periphery is frequently affected later in the disease process. Photoreceptor degeneration is likely to be the primary event and future studies on DRAM2-retinopathy are expected to provide important insights into retinal autophagy.

Angioid streaks with severe macular dysfunction and generalised retinal involvement due to a homozygous duplication in the ABCC6 gene

Angioid streaks with severe macular dysfunction and generalised retinal involvement due to a homozygous duplication in the ABCC6 gene

Congenital high myopia and central macular atrophy: a report of 3 families

AimsTo report the clinical phenotype in a series of four children from three families with the rare association of high myopia, central macular atrophy, and normal full-field electroretinography (ERG).MethodsFour male patients were ascertained with reduced vision, nystagmus, and atrophy of the macula from early childhood. Patients underwent full ophthalmic examination, electrophysiological testing, and retinal imaging.ResultsMinimum duration of follow-up was 8 years. At last review, visual acuity ranged from 0.22 to 1.20 logMAR (6/9.5–6/95 Snellen) at a mean age of 10.5 years (median 9.5 years, range 9–14 years). Refractive error ranged from a spherical equivalent of −7.40 D to −24.00 D. Three had convergent squint. Fundus examination and imaging demonstrated bilateral macular atrophy in all patients that varied from mild atrophy of the retinal pigment epithelium (RPE) to well-demarcated, punched-out atrophic lesions of retina, RPE, and choroid. Flash ERG was normal under photopic and scotopic conditions in all patients. Pattern ERG, performed in three patients, was consistent with mild to severe macular dysfunction. Progression of the area of atrophy was evident in one patient and of the myopia in two patients but all patients had stable visual acuity.ConclusionsPatients with congenital high myopia and macular atrophy present in infancy with reduced visual acuity and nystagmus. The macular atrophic lesions vary in size and severity but electrophysiological testing is consistent with dysfunction confined to the macula. There was no deterioration in visual acuity over 8–10 years of monitoring.