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https://www.readbyqxmd.com/read/28611652/a-novel-abca4-mutation-associated-with-a-late-onset-stargardt-disease-phenotype-a-hypomorphic-allele
#1
Cindy S Kaway, Madeleine K M Adams, Kevin Sean Jenkins, Christopher J Layton
BACKGROUND: Stargardt disease (STGD) is the most common juvenile hereditary macular dystrophy. In the majority of cases, the diagnosis is made prior to 20 years of age and usually leads to loss of central vision. Late-onset STGD affects a smaller number of patients. Identifying genetic changes which could be associated with clinically important differences in severity or presentation of the disease is important for understanding the mechanisms of visual loss and for planning future therapeutic approaches...
January 2017: Case Reports in Ophthalmology
https://www.readbyqxmd.com/read/28571903/next-generation-sequencing-in-the-diagnosis-of-stargardt-s-disease
#2
B Jimenez-Rolando, S Noval, I Rosa-Perez, E Mata Diaz, A Del Pozo, C Ibañez, J C Silla, V E F Montaño, R Martin-Arenas, E Vallespin
INTRODUCTION: Stargardt's disease is the most frequent form of inherited macular dystrophy in children and adults. It is a genetic eye disorder caused by mutations in ABCA4 gene with an autosomal recessive inheritance. ABCA4 is a very polymorphic and large gene containing 50 exons. The development of next generation sequencing (NGS) can be used for the genetic diagnosis of this disease. PATIENTS AND METHODS: A report is presented on two patients with a clinical diagnosis of Stargardt's disease whose genetic confirmation was performed by a NGS panel of 298 genes...
May 29, 2017: Archivos de la Sociedad Española de Oftalmología
https://www.readbyqxmd.com/read/28559085/clinically-focused-molecular-investigation-of-1000-consecutive-families-with-inherited-retinal-disease
#3
Edwin M Stone, Jeaneen L Andorf, S Scott Whitmore, Adam P DeLuca, Joseph C Giacalone, Luan M Streb, Terry A Braun, Robert F Mullins, Todd E Scheetz, Val C Sheffield, Budd A Tucker
PURPOSE: To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician. DESIGN: Retrospective series. PARTICIPANTS: One thousand consecutive families seen by a single clinician. METHODS: The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed, and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study...
May 27, 2017: Ophthalmology
https://www.readbyqxmd.com/read/28542697/incidence-of-atrophic-lesions-in-stargardt-disease-in-the-progression-of-atrophy-secondary-to-stargardt-disease-progstar-study-report-no-5
#4
Rupert W Strauss, Beatriz Muñoz, Alex Ho, Anamika Jha, Michel Michaelides, Saddek Mohand-Said, Artur V Cideciyan, David Birch, Amir H Hariri, Muneeswar G Nittala, SriniVas Sadda, Hendrik P N Scholl
Importance: Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease. Objective: To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging. Design, Setting, and Participants: In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)-binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits...
May 25, 2017: JAMA Ophthalmology
https://www.readbyqxmd.com/read/28542693/macular-sensitivity-measured-with-microperimetry-in-stargardt-disease-in-the-progression-of-atrophy-secondary-to-stargardt-disease-progstar-study-report-no-7
#5
Etienne M Schönbach, Yulia Wolfson, Rupert W Strauss, Mohamed A Ibrahim, Xiangrong Kong, Beatriz Muñoz, David G Birch, Artur V Cideciyan, Gesa-Astrid Hahn, Muneeswar Nittala, Janet S Sunness, SriniVas R Sadda, Sheila K West, Hendrik P N Scholl
Importance: New outcome measures for treatment trials for Stargardt disease type 1 (STGD1) and other macular diseases are needed. Microperimetry allows mapping of light sensitivity of the macula and provides topographic information on visual function beyond visual acuity. Objective: To measure and analyze retinal light sensitivity of the macula in STGD1 using fundus-controlled perimetry (microperimetry). Design, Setting, and Participants: This was a multicenter prospective cohort study...
May 25, 2017: JAMA Ophthalmology
https://www.readbyqxmd.com/read/28472177/ubiquitin-carboxyl-terminal-esterase-l1-uchl1-is-associated-with-stem-like-cancer-cell-functions-in-pediatric-high-grade-glioma
#6
Patricia C Sanchez-Diaz, Judy C Chang, Emily S Moses, Tu Dao, Yidong Chen, Jaclyn Y Hung
Pediatric high-grade gliomas represent 8-12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15-35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i...
2017: PloS One
https://www.readbyqxmd.com/read/28446513/frequent-hypomorphic-alleles-account-for-a-significant-fraction-of-abca4-disease-and-distinguish-it-from-age-related-macular-degeneration
#7
Jana Zernant, Winston Lee, Frederick T Collison, Gerald A Fishman, Yuri V Sergeev, Kaspar Schuerch, Janet R Sparrow, Stephen H Tsang, Rando Allikmets
BACKGROUND: Variation in the ABCA4 gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of ABCA4 identifies biallelic mutations in only 60%-70% of cases; 20%-25% remain with one mutation and no mutations are found in 10%-15% of cases with clinically confirmed ABCA4 disease...
April 26, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28395299/multimodal-fundus-imaging-of-sodium-iodate-treated-mice-informs-rpe-susceptibility-and-origins-of-increased-fundus-autofluorescence
#8
Jin Zhao, Hye Jin Kim, Janet R Sparrow
Purpose: By multimodal imaging, and the use of mouse and in vitro models, we have addressed changes in fundus autofluorescence (488 and 790 nm) and observed interactions between the photooxidative stress imposed by RPE bisretinoid lipofuscin and the oxidative impact of systemic sodium iodate (NaIO3). Methods: Abca4-/-, wild-type, and Rpe65rd12 mice were given systemic injections of NaIO3 (30 mg/kg). Analysis included noninvasive imaging of fundus autofluorescence (short-wavelength [SW-AF]; near-infrared excitation [NIR-AF]), quantitative fundus AF (qAF; 488 nm); light microscopy, RPE flat-mounts and measurements of outer nuclear layer (ONL) thickness...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28370415/top2b-is-involved-in-the-formation-of-outer-segment-and-synapse-during-late-stage-photoreceptor-differentiation-by-controlling-key-genes-of-photoreceptor-transcriptional-regulatory-network
#9
Ying Li, Hailing Hao, Mavis R Swerdel, Hyeon-Yeol Cho, Ki-Bum Lee, Ronald P Hart, Yi Lisa Lyu, Li Cai
Topoisomerase II beta (Top2b) is an enzyme that alters the topologic states of DNA during transcription. Top2b deletion in early retinal progenitor cells causes severe defects in neural differentiation and affects cell survival in all retinal cell types. However, it is unclear whether the observed severe phenotypes are the result of cell-autonomous/primary defects or non-cell-autonomous/secondary defects caused by alterations of other retinal cells. Using photoreceptor cells as a model, we first characterized the phenotypes in Top2b conditional knockout...
March 30, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28365912/multimodal-analysis-of-the-preferred-retinal-location-and-the-transition-zone-in-patients-with-stargardt-disease
#10
Tommaso Verdina, Vivienne C Greenstein, Andrea Sodi, Stephen H Tsang, Tomas R Burke, Ilaria Passerini, Rando Allikmets, Gianni Virgili, Gian Maria Cavallini, Stanislao Rizzo
PURPOSE: The purpose of our study was to investigate morpho-functional features of the preferred retinal location (PRL) and the transition zone (TZ) in a series of patients with recessive Stargardt disease (STGD1). METHODS: Fifty-two STGD1 patients with at least one ABCA4 mutation, atrophy of the central macula (MA) and an eccentric PRL were recruited for the study. Microperimetry, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) were performed...
July 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28355279/highly-sensitive-measurements-of-disease-progression-in-rare-disorders-developing-and-validating-a-multimodal-model-of-retinal-degeneration-in-stargardt-disease
#11
Stanley Lambertus, Nathalie M Bax, Ana Fakin, Joannes M M Groenewoud, B Jeroen Klevering, Anthony T Moore, Michel Michaelides, Andrew R Webster, Gert Jan van der Wilt, Carel B Hoyng
BACKGROUND: Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients...
2017: PloS One
https://www.readbyqxmd.com/read/28348233/complement-modulation-in-the-retinal-pigment-epithelium-rescues-photoreceptor-degeneration-in-a-mouse-model-of-stargardt-disease
#12
Tamara L Lenis, Shanta Sarfare, Zhichun Jiang, Marcia B Lloyd, Dean Bok, Roxana A Radu
Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4(-/-) (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28341476/panel-based-clinical-genetic-testing-in-85-children-with-inherited-retinal-disease
#13
Rachel L Taylor, Neil R A Parry, Stephanie J Barton, Christopher Campbell, Claire M Delaney, Jamie M Ellingford, Georgina Hall, Claire Hardcastle, Jiten Morarji, Elisabeth J Nichol, Lindsi C Williams, Sofia Douzgou, Jill Clayton-Smith, Simon C Ramsden, Vinod Sharma, Susmito Biswas, I Chris Lloyd, Jane L Ashworth, Graeme C Black, Panagiotis I Sergouniotis
PURPOSE: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). DESIGN: Single-center retrospective case series. PARTICIPANTS: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. METHODS: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate...
March 21, 2017: Ophthalmology
https://www.readbyqxmd.com/read/28327576/genotypic-spectrum-and-phenotype-correlations-of-abca4-associated-disease-in-patients-of-south-asian-descent
#14
Winston Lee, Kaspar Schuerch, Jana Zernant, Frederick T Collison, Srilaxmi Bearelly, Gerald A Fishman, Stephen H Tsang, Janet R Sparrow, Rando Allikmets
Variants in the ABCA4 gene are the most common cause of juvenile-onset blindness affecting close to 1 in 10 000 people worldwide. Disease severity varies largely according to genotype, which can be specific to ethnic and racial groups. Here we investigate the spectrum of ABCA4 variation and its phenotypic expression in 38 patients of South Asian descent, notably from India, Pakistan, Bangladesh and Sri Lanka. Sequencing of all exons and flanking intronic sequences of ABCA4 revealed disease-causing variants in all patients: 3 in 2...
June 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28302729/phagocytosis-dependent-ketogenesis-in-retinal-pigment-epithelium
#15
Juan Reyes-Reveles, Anuradha Dhingra, Desiree Alexander, Alvina Bragin, Nancy J Philp, Kathleen Boesze-Battaglia
Daily, the retinal pigment epithelium (RPE) ingests a bolus of lipid and protein in the form of phagocytized photoreceptor outer segments (OS). The RPE, like the liver, expresses enzymes required for fatty acid oxidation and ketogenesis. This suggests that these pathways play a role in the disposal of lipids from ingested OS, as well as providing a mechanism for recycling metabolic intermediates back to the outer retina. In this study, we examined whether OS phagocytosis was linked to ketogenesis. We found increased levels of β-hydroxybutyrate (β-HB) in the apical medium following ingestion of OS by human fetal RPE and ARPE19 cells cultured on Transwell inserts...
May 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28290600/possible-protective-role-of-the-abca4-gene-c-1268a-g-missense-variant-in-stargardt-disease-and-syndromic-retinitis-pigmentosa-in-a-sicilian-family-preliminary-data
#16
Rosalia D'Angelo, Luigi Donato, Isabella Venza, Concetta Scimone, Pasquale Aragona, Antonina Sidoti
In the wide horizon of ophthalmologically rare diseases among retinitis pigmentosa forms, Stargardt disease has gradually assumed a significant role due to its heterogeneity. In the present study, we aimed to support one of two opposite hypotheses concerning the causative or protective role of heterozygous c.1268A>G missense variant of the ABCA4 gene in Stargardt disease and in syndromic retinitis pigmentosa. This study was based on a family consisting of three members: proband, age 54, with high myopia, myopic chorioretinitis and retinal dystrophy; wife, age 65, with mild symptoms; daughter, age 29, asymptomatic...
April 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28285324/novel-therapeutics-for-stargardt-disease
#17
REVIEW
Louise J Lu, Ji Liu, Ron A Adelman
DESCRIPTION OF SITUATION: Stargardt disease, an inherited macular dystrophy caused by mutations in the ABCA4 gene encoding a retinal transporter protein, is the most prevalent form of macular degeneration in children. Patients with Stargardt disease develop severe vision loss within their first or second decades of life, which progresses to irreversible decreased visual acuity in almost all cases. Presently, there are no standard treatments for Stargardt disease. However, encouraging progress has been made in the development of innovative approaches to preventing vision loss in Stargardt patients...
March 11, 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28248825/ultrawidefield-autofluoresence-in-abca4-stargardt-disease
#18
Michael A Klufas, Irena Tsui, SriniVas R Sadda, Hamid Hosseini, Steven D Schwartz
PURPOSE: To report the ultrawidefield fundus autofluorescence (UWF-FAF) patterns in ABC4A Stargardt disease. METHODS: A retrospective cohort study of patients with a clinical diagnosis of Stargardt disease, confirmed ABCA4 genotype, and ultrawidefield fundus autofluorescence imaging using an Optos P200Tx. Four independent graders evaluated the images. Ultrawidefield fundus autofluorescence images were evaluated for the presence of posterior pole and peripheral findings, and were classified into one of three types (Type I: lesions confined to the macula with no peripheral findings; Type II: macular atrophy with flecks only in the periphery; Type III: macular atrophy and varying degrees of peripheral atrophy)...
February 28, 2017: Retina
https://www.readbyqxmd.com/read/28239514/a-fragmented-adeno-associated-viral-dual-vector-strategy-for-treatment-of-diseases-caused-by-mutations-in-large-genes-leads-to-expression-of-hybrid-transcripts
#19
Michelle E McClements, Peter Charbel Issa, Véronique Blouin, Robert E MacLaren
OBJECTIVE: Dual vector AAV systems are being utilised to enable gene therapy for disorders in which the disease gene is too large to fit into a single capsid. Fragmented adeno-associated viral (fAAV) vectors containing single inverted terminal repeat truncated transgenes have been considered as one such gene replacement strategy. Here we aim to add to the current understanding of the molecular mechanisms employed by fAAV dual vector systems. METHODS: Oversized (>8kb) transgene constructs containing ABCA4 coding sequence were packaged as truncated fragments <5kb in size into various AAV serotypes...
November 14, 2016: Journal of Genetic Syndrome & Gene Therapy
https://www.readbyqxmd.com/read/28219732/all-trans-retinal-levels-and-formation-of-lipofuscin-precursors-after-bleaching-in-rod-photoreceptors-from-wild-type-and-abca4-mice
#20
Leopold Adler, Chunhe Chen, Yiannis Koutalos
The accumulation of lipofuscin in the cells of the retinal pigment epithelium (RPE) is thought to play an important role in the development and progression of degenerative diseases of the retina. The bulk of RPE lipofuscin originates in reactions of the rhodopsin chromophore, retinal, with components of the photoreceptor outer segment. The 11-cis retinal isomer is generated in the RPE and supplied to rod photoreceptor outer segments where it is incorporated as the chromophore of rhodopsin. It is photoisomerized during light detection to all-trans and subsequently released by photoactivated rhodopsin as all-trans retinal, which is removed through reduction to all-trans retinol in a reaction requiring metabolic input in the form of NADPH...
February 2017: Experimental Eye Research
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