RESUMO
INTRODUCTION: The aim of this study was to evaluate the progression of atrophy as determined by spectral-domain optical coherence tomography (SD-OCT) in patients with molecularly confirmed ABCA4-associated Stargardt disease type 1 (STGD1) over a 24-month period in a multicenter prospective cohort study. METHODS: SD-OCT images from 428 eyes of 236 patients were analyzed. Change of mean thickness (MT) and intact area were estimated after semiautomated segmentation for the following individual layers in the central subfield (CS), inner ring (IR), and outer ring (OR) of the ETDRS grid: retinal pigment epithelium (RPE), outer segments (OSs), inner segments (IS), outer nuclear layer (ONL) inner retina (IR), and total retina. RESULTS: Statistically significant decreases of all outer retinal layers (RPE, OS, IS, and ONL) could be observed over a 24-month period both in decline of mean retinal thickness and intact area (p < 0.0001, respectively), whereas the IR showed an increase of retinal thickness in the CS and IR and remained unchanged in the OR. CONCLUSIONS: Significant loss could be detected in outer retinal layers by SD-OCT over a 24-month period in patients with STGD1. Loss of thickness and/or intact area of such layers may serve as potential endpoints for clinical trials that aim to slow down the disease progression of STGD1.
Assuntos
Progressão da Doença , Degeneração Macular , Epitélio Pigmentado da Retina , Doença de Stargardt , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Tomografia de Coerência Óptica/métodos , Doença de Stargardt/diagnóstico , Masculino , Estudos Prospectivos , Feminino , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Degeneração Macular/diagnóstico , Degeneração Macular/congênito , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/diagnóstico por imagem , Adolescente , Seguimentos , Retina/diagnóstico por imagem , Retina/patologia , CriançaRESUMO
Modern advances in disease genetics have uncovered numerous modifier genes that play a role in the severity of disease expression. One such class of genetic conditions is known as inherited retinal degenerations (IRDs), a collection of retinal degenerative disorders caused by mutations in over 300 genes. A single missense mutation (K42E) in the gene encoding the enzyme dehydrodolichyl diphosphate synthase (DHDDS), which is required for protein N-glycosylation in all cells and tissues, causes DHDDS-IRD (retinitis pigmentosa type 59 (RP59; OMIM #613861)). Apart from a retinal phenotype, however, DHDDS-IRD is surprisingly non-syndromic (i.e., without any systemic manifestations). To explore disease pathology, we selected five glycosylation-related genes for analysis that are suggested to have disease modifier variants. These genes encode glycosyltransferases (ALG6, ALG8), an ER resident protein (DDOST), a high-mannose oligosaccharyl transferase (MPDU1), and a protein N-glycosylation regulatory protein (TNKS). DNA samples from 11 confirmed DHDDS (K42E)-IRD patients were sequenced at the site of each candidate genetic modifier. Quantitative measures of retinal structure and function were performed across five decades of life by evaluating foveal photoreceptor thickness, visual acuity, foveal sensitivity, macular and extramacular rod sensitivity, and kinetic visual field extent. The ALG6 variant, (F304S), was correlated with greater macular cone disease severity and less peripheral rod disease severity. Thus, modifier gene polymorphisms may account for a significant portion of phenotypic variation observed in human genetic disease. However, the consequences of the polymorphisms may be counterintuitively complex in terms of rod and cone populations affected in different regions of the retina.
Assuntos
Alquil e Aril Transferases , Glucosiltransferases , Proteínas de Membrana , Degeneração Retiniana , Humanos , Genes Modificadores , Glucosiltransferases/genética , Proteínas de Membrana/genética , Mutação , Retina , Degeneração Retiniana/genéticaRESUMO
Mutations in BEST1 cause an autosomal recessive disease in dogs where the earliest changes localize to the photoreceptor-RPE interface and show a retina-wide micro-detachment that is modulated by light exposure. The purpose of this study was to define the spatial and temporal details of the outer retina and its response to light with ultra-high resolution OCT across a range of ages and with different BEST1 mutations. Three retinal regions were selected in each eye: near the fovea-like area, near the optic nerve, both in the tapetal area, and inferior to the optic nerve in the non-tapetal area. The OS+ slab thickness was defined between the peak near the junction of inner and outer segments (IS/OS) and the transition between basal RPE, Bruch membrane, choriocapillaris and proximal tapetum (RPE/T). In wildtype (WT) dogs, two tapetal regions showed additional hyperscattering OCT peaks within the OS+ slab likely representing cone and rod outer segment tips (COST and ROST). The inferior non-tapetal region of WT dogs had only one of these peaks, likely ROST. In dogs with BEST1 mutations, all three locations showed a single peak, likely suggesting optical silence of COST. Light-dependent expansion of the micro-detachment by about 10 um was detectable in both tapetal and non-tapetal retina across all ages and BEST1 mutations.
Assuntos
Retina , Tomografia de Coerência Óptica , Cães , Animais , Células Fotorreceptoras Retinianas Cones , Visão OcularRESUMO
PURPOSE: To gain an insight into the pathophysiology of RAB28-associated inherited retinal degeneration through detailed phenotyping and long-term longitudinal follow-up. METHODS: The patient underwent complete ophthalmic examinations. Visual function was assessed with microperimetry, full-field electroretinography (ffERG), imaging with optical coherence tomography (OCT), short-wave (SW), and near-infrared (NIR) fundus autofluorescence (FAF). RESULTS: A healthy Haitian woman with homozygous pathogenic variants (c.68C > T; p.Ser23Phe) in RAB28 presented at 16 years of age with a four-year history of blurred vision. Visual acuities were 20/125 in each eye, which remained relatively stable since. At age 27, cone ffERGs were non-detectable and borderline for rod-mediated responses. Kinetic fields were full to a V-4e target, undetectable to a small I-4e stimulus. Microperimetry showed an absolute central scotoma surrounded by a pericentral relative scotoma. SD-OCT showed an undetectable or barely detectable foveal and parafoveal photoreceptor outer nuclear layer (ONL), photoreceptor outer segment (POS), and retinal pigment epithelium (RPE) signals and loss of the SW- and NIR-FAF signals. This atrophic region was separated from a normally laminated retina by a narrow transition zone (TZ) of hyper SW- and NIR-FAF that co-localized with preserved ONL but abnormally thinned POS and RPE. There was minimal centrifugal (<100 µm) expansion over a six-year period. CONCLUSION: The cone-rod dystrophy phenotype documented herein supports a critical role of RAB28 for cone function and POS maintenance. Severe central photoreceptor and RPE loss with a predilection for POS loss in TZs suggests possible disruptions of complex mechanisms that maintain central cone photoreceptor and RPE homeostasis.
RESUMO
Purpose: To describe the retinal phenotype of an unusual case of anti-TRPM1 autoantibody-positive unilateral melanoma-associated retinopathy (MAR) triggered by nivolumab therapy and compare with the phenotype of TRPM1-associated Congenital Stationary Night Blindness (TRPM1-CSNB). Observations: Unilateral MAR was diagnosed 3 months after starting nivolumab therapy for consolidation of a successfully treated melanoma. Retinal autoantibodies against TRPM1 were identified. ffERG, microperimetry and static chromatic perimetry confirmed unilateral ON-Bipolar Cell (ON-BPC) dysfunction and central rod sensitivity losses in the left eye; the contralateral eye was normal. There was borderline ganglion cell (GCL) and inner nuclear layer (INL) thinning, but a significantly thinner inner plexiform layer (IPL) in the affected compared to the unaffected eye. Longitudinal reflectivity profiles (LRPs) demonstrated an abnormal inner plexiform layer (IPL) lamination in the involved eye. Nearly identical changes were documented in two cases of TRMP1-cCSNB and in a case of anti-TRPM1 autoantibody-negative MAR. The functional changes partially recovered with discontinuation of the medication without added immunosuppression. Conclusions and Importance: Comparisons between the affected and unaffected eye in this unilateral MAR case revealed inner retinal abnormalities and abnormal lamination of the IPL associated with the classical retina-wide ON-BPC dysfunction, and localized central rod-mediated sensitivity losses. A nearly identical structural phenotype in two cases of cCSNB and a case of anti-TRPM1 autoantibody-negative MAR supports a specific structural-functional phenotype for these conditions with ON-BPC dysfunction.
RESUMO
Purpose: 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. Methods: 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. Results: Critical age for the initiation of photoreceptor loss ranged from 48 years 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 25 µm in the extrafoveal retina and 19 µm in the fovea at critical age. Loss of light sensitivity preceded shortening of outer segments and loss of photoreceptors by more than a decade. Conclusions: Retinal regions providing an ideal treatment window exist across all severity stages of L-ORD.