Retinal dystrophy

PURPOSE OF REVIEW: The purpose of this review is to outline those systemic disorders that are associated with pediatric retinal dystrophy, summarize important retinal, and nonretinal clues that aid in syndromic diagnosis, provide an approach for ophthalmic and systematic systemic examination, describe the important systemic findings seen in pediatric syndromic retinal dystrophies and highlight the role of genetic testing. RECENT FINDINGS: With profound advances being made in the field of molecular genetics, a definitive molecular etiology is increasingly being made even in rare and unusual forms of retinal dystrophies...

A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c...

BACKGROUND: Developmental macular disorders are a heterogeneous group of rare retinal conditions that can cause significant visual impairment from childhood. Among these disorders, autosomal dominant North Carolina macular dystrophy (NCMD) has been mapped to 6q16 (MCDR1) with recent support for a non-coding disease mechanism of PRDM13. A second locus on 5p15-5p13 (MCDR3) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown. METHODS: Two families affected by a dominant developmental macular disorder that closely resembles NCMD in association with digit abnormalities were included in the study...

BACKGROUND: Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome characterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy. To date, nystagmus, cortical visual impairment, impairment of central vision, optic nerve hypoplasia, and optic atrophy have been described in this condition...

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown...

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. At least 21 candidate BBS-associated genes (BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole-exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants (c...

The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions -- (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106)...

The development of the eye has been a topic of extensive investigation, from the early studies on tissue induction to more recent breakthroughs in resolving the mechanism regulating progenitor patterning and their gradual and coordinated differentiation into diverse tissue types that function together throughout life. Among the ocular tissue types, the retinal pigmented epithelium (RPE) is at the forefront of developmental biology and stem cell research. The growing interest in this lineage stems from its importance for photoreceptor function as well as from its requirement during embryogenesis for the development of the photoreceptors and the choroid...

AIM: To present an integrated techno-economic analysis assessing the feasibility of affinity purification technologies using the manufacture of induced pluripotent stem cell-derived progenitor photoreceptors for retinal dystrophies as a case study. MATERIALS & METHODS: Sort purity, progenitor yield and viable cell recovery were investigated for three cell sorting techniques: fluorescent-activated cell sorting (FACS); magnetic-activated cell sorting (MACS); and a novel technology SpheriTech beads...

WDR19 has been reported as a causative gene of nephronophthisis-related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations...

Mutations in the RS1 gene cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy. We have recently shown that retinoschisin, the protein encoded by RS1, regulates ERK signaling and apoptosis in retinal cells. In this study, we explored an influence of retinoschisin on the functionality of the Na/K-ATPase, its interaction partner at retinal plasma membranes. We show that retinoschisin binding requires the β2-subunit of the Na/K-ATPase while the α-subunit is exchangeable. Our investigations revealed no impact of retinoschisin on Na/K-ATPase mediated ATP hydrolysis and ion transport...

PURPOSE OF REVIEW: A major cause of visual disorders is dysfunction and/or loss of the light-sensitive cells of the retina, the photoreceptors. To develop better treatments for patients, we need to understand how inherited retinal disease mutations result in the dysfunction of photoreceptors. New advances in the field of stem cell and gene editing research offer novel ways to model retinal dystrophies in vitro and present opportunities to translate basic biological insights into therapies...

We report retinal functional and structural changes of a 40-year-old man diagnosed with occult macular dystrophy. Comprehensive ophthalmological evaluation was performed, followed by spectral-domain optical coherence tomography (SD-OC - Heidelberg) and image acquisition using an adaptive optics (AO) camera (RTX1, Imagine Eyes) for photoreceptor density analysis. Functional tests included full-field ERG (ERG) and multifocal electroretinography (mfERG) (Diagnosys, LLC) and microperimetry with scanning laser ophthalmoscope (SLO) fixation controlled (MAIA, CenterVUE)...

AIM: We have previously described two unrelated Bukhara Jews (BJs) with a combination of oculopharyngeal muscular dystrophy (OPMD) and inherited retinal dystrophy (IRD), because of mutations in two linked genes: PABPN1 and NRL. Here we investigated the prevalence of the NRL mutation among BJs with OPMD. MATERIALS AND METHODS: PABPN1 and NRL mutation testing were performed by polymerase chain reaction amplification and direct sequencing on two cohorts of Bukhara Jewish patients: OPMD patients (with or without IRD) and IRD patients (without OPMD)...

Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology...

BACKGROUND: In this study, we present a juvenile retinoschisis patient with developmental delay, sensorineural hearing loss, and reduced axial tone. X-linked juvenile retinoschisis (XLRS) is a retinal dystrophy, most often not associated with systemic anomalies and also not showing any locus heterogeneity. Therefore it was of interest to understand the genetic basis of the condition in this patient. MATERIALS AND METHODS: RS1 gene screening for XLRS was performed by Sanger sequencing...

INTRODUCTION: To compare mean best-corrected visual acuity (BCVA), retinal sensitivity (RS), and bivariate contour ellipse area (BCEA) in patients with adult-onset foveomacular vitelliform dystrophy (AOFVD) and healthy subjects (HSs), reporting also functional disease-related changes in the different stages of the AOFVD disease. MATERIALS AND METHODS: In this observational cross-sectional study, a total of 19 patients (30 eyes; 12 female and 7 male) with AOFVD were enrolled, and 30 patients (30 eyes; 16 female and 14 male) were recruited as age-matched control group (74...

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7...

Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported...

"Omics" refers to high-throughput analyses of genes, proteins, or metabolites in a biological system, and is increasingly used for ophthalmic research. These system-based approaches can unravel disease-related processes and are valuable for biomarker discovery. Furthermore, potential therapeutic targets can be identified based on omics results, and targeted follow-up experiments can be designed to gain molecular understanding of the disease and to test new therapies. Here, we review the application of omics techniques in eye diseases, focusing on age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal detachment (RD), myopia, glaucoma, Fuchs' corneal dystrophy (FCD), cataract, keratoconus, and dry eyes...