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Inherited retinal diseases

Stuti Joshi, Wayne Yau, Allan Kermode
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease, manifesting as recurrent ischaemic events, migraine with aura, behavioural disturbance and cognitive decline. We report two patients with CADASIL masquerading as multiple sclerosis (MS). A 23year old female presented with a visual scotoma and was discovered to have a corresponding retinal cotton wool spot. MRI brain revealed diffuse T2 hyperintensities suggestive of demyelination...
October 20, 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Kari Branham, Hiroko Matsui, Pooja Biswas, Aditya A Guru, Michael Hicks, John J Suk, He Li, David Jakubosky, Tao Long, Amalio Telenti, Naoki Narai, John R Heckenlively, Kelly A Frazar, Paul A Sieving, Radha Ayyagari
While more than 250 genes are known to cause inherited retinal degenerations (IRD), nearly 40-50% of families have the genetic basis for their disease unknown. In this study we sought to identify the underlying cause of inherited retinal degeneration (IRD) in a family by whole genome sequence (WGS) analysis. Clinical characterization including standard ophthalmic examination, fundus photography, visual field testing, electroretinography, and review of medical and family history was performed. WGS was performed on affected and unaffected family members using Illumina HiSeq X10...
October 7, 2016: Physiological Genomics
Brian P Hafler
PURPOSE: Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies...
October 6, 2016: Retina
Bing Lin, Xue-Bi Cai, Zhi-Li Zheng, Xiu-Feng Huang, Xiao-Ling Liu, Jia Qu, Zi-Bing Jin
Stargardt disease (STGD1) is a juvenile macular degeneration predominantly inherited in an autosomal recessive pattern, characterized by decreased central vision in the first 2 decades of life. The condition has a genetic basis due to mutation in the ABCA4 gene, and arises from the deposition of lipofuscin-like substance in the retinal pigmented epithelium (RPE) with secondary photoreceptor cell death. In this study, we describe the clinical and genetic features of Stargardt patients from four unrelated Chinese cohorts...
October 14, 2016: Scientific Reports
Kinga M Bujakowska, Rosario Fernandez-Godino, Emily Place, Mark Consugar, Daniel Navarro-Gomez, Joseph White, Emma C Bedoukian, Xiaosong Zhu, Hongbo M Xie, Xiaowu Gai, Bart P Leroy, Eric A Pierce
PURPOSE: Despite substantial progress in sequencing, current strategies can genetically solve only approximately 55-60% of inherited retinal degeneration (IRD) cases. This can be partially attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy-number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs. METHODS: Twenty-eight cases previously unsolved with a targeted NGS were investigated with whole-genome single-nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays...
October 13, 2016: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, Koh-Hei Sonoda
Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog-mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation...
September 22, 2016: JCI Insight
Maan Alkharashi, Anne B Fulton
Leber congenital amaurosis (LCA) is a group of severe inherited retinal dystrophies that lead to early childhood blindness. In the last decade, interest in LCA has increased as advances in genetics have been applied to better identify, classify, and treat LCA. To date, 23 LCA genes have been identified. Gene replacement in the RPE65 form of LCA represents a major advance in treatment, although limitations have been recognized. In this article, we review the clinical and genetic features of LCA and evaluate the evidence available for gene therapy in RPE65 disease...
September 29, 2016: Seminars in Ophthalmology
Panagiotis I Sergouniotis, Stephanie J Barton, Sarah Waller, Rahat Perveen, Jamie M Ellingford, Christopher Campbell, Georgina Hall, Rachel L Gillespie, Sanjeev S Bhaskar, Simon C Ramsden, Graeme C Black, Simon C Lovell
BACKGROUND: Although the majority of small in-frame insertions/deletions (indels) has no/little affect on protein function, a small subset of these changes has been causally associated with genetic disorders. Notably, the molecular mechanisms and frequency by which they give rise to disease phenotypes remain largely unknown. The aim of this study is to provide insights into the role of in-frame indels (≤21 nucleotides) in two genetically heterogeneous eye disorders. RESULTS: One hundred eighty-one probands with childhood cataracts and 486 probands with retinal dystrophy underwent multigene panel testing in a clinical diagnostic laboratory...
2016: Orphanet Journal of Rare Diseases
Matthew Carrigan, Emma Duignan, Conor P G Malone, Kirk Stephenson, Tahira Saad, Ciara McDermott, Andrew Green, David Keegan, Peter Humphries, Paul F Kenna, G Jane Farrar
Inherited retinopathies affect approximately two and a half million people globally, yet the majority of affected patients lack clear genetic diagnoses given the diverse range of genes and mutations implicated in these conditions. We present results from a next-generation sequencing study of a large inherited retinal disease patient population, with the goal of providing clear and actionable genetic diagnoses. Targeted sequencing was performed on 539 individuals from 309 inherited retinal disease pedigrees...
2016: Scientific Reports
Gavin Arno, Sarah Hull, Keren Carss, Arundhati Dev-Borman, Christina Chakarova, Kinga Bujakowska, Ingeborgh van den Born, Anthony G Robson, Graham E Holder, Michel Michaelides, Frans P M Cremers, Eric Pierce, F Lucy Raymond, Anthony T Moore, Andrew R Webster
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...
September 1, 2016: Investigative Ophthalmology & Visual Science
Katariina Vapalahti, Anna-Maija Virtala, Tara A Joensuu, Katriina Tiira, Jaana Tähtinen, Hannes Lohi
A comprehensive feline health survey was conducted to reveal breed-specific inheritable diseases in Finnish pedigree cats for genetic research. Prevalence of 19 disease categories and 227 feline diseases were defined in a study population of 8175 cats belonging to 30 breeds. Dental and oral diseases, with a prevalence of 28%, and dental calculus and gingivitis (21 and 8%, respectively) were the most prevalent disease category and diseases among all cats and in most of the breeds. An exception was Korats, which were more often affected by the diseases of the respiratory tract (23%) and asthma (19%)...
2016: Frontiers in Veterinary Science
Jianli Li, Jia Tang, Yanming Feng, Mingchu Xu, Rui Chen, Xuan Zou, Ruifang Sui, Emmanuel Y Chang, Richard A Lewis, Victor W Zhang, Jing Wang, Lee-Jun C Wong
Retinitis pigmentosa (RP) is the most common form of retinal dystrophy. The disease is characterized by the progressive degeneration of photoreceptors, ultimately leading to blindness. The exon ORF15 of RP GTPase regulator (RPGR) is a mutation hot spot for X-linked RP and one form of cone dystrophy. However, accurate molecular testing of ORF15 is challenging because of a large segment of highly repetitive purine-rich sequence in this exon. ORF15 performs poorly in next-generation sequencing-based panels or whole exome sequencing analysis, whereas Sanger sequencing of ORF15 requires special reagents and PCR conditions with multiple pairs of overlapping primers that often do not provide a clean sequence...
September 9, 2016: Journal of Molecular Diagnostics: JMD
Yi Shiau Ng, Steven A Hardy, Venice Shrier, Gerardine Quaghebeur, David R Mole, Matthew J Daniels, Susan M Downes, Jane Freebody, Carl Fratter, Monika Hofer, Andrea H Nemeth, Joanna Poulton, Robert W Taylor
Mitochondrial DNA disease is one of the most common groups of inherited neuromuscular disorders and frequently associated with marked phenotypic and genotypic heterogeneity. We describe an adult patient who initially presented with childhood-onset ataxia without a family history and an unremarkable diagnostic muscle biopsy. Subsequent multi-system manifestations included basal ganglia calcification, proteinuria, cataract and retinitis pigmentosa, prompting a repeat muscle biopsy that showed features consistent with mitochondrial myopathy 13 years later...
October 2016: Neuromuscular Disorders: NMD
Viara Shoumnalieva-Ivanova, Ivan Tanev, Yani Zdravkov, Simeon Monov, Russka Shumnalieva
Aagenaes syndrome, also called lymphoedema cholestasis syndrome 1 (LSC1), is characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age and severe chronic lymphoedema, mainly affecting the lower extremities. The condition is autosomal recessively inherited, and the gene is located on chromosome 15q. The locus, LCS1, was mapped to a 6.6 cM region on chromosome 15. Angioid streaks are visible irregular crack-like dehiscences in bruch's membrane that are associated with atrophic degeneration of the overlying retinal pigment epithelium...
September 10, 2016: International Ophthalmology
Adrienne W Scott
Sickle cell disease (SCD), the most common inherited blood disorder, is characterized by defective oxygen transport. Every part of the eye can be affected by microvascular occlusions from SCD; however, the major cause of vision loss is proliferative sickle cell retinopathy (PSR). Although individuals with the HbSS genotype of SCD manifest more systemic morbidity and those with the HbSC genotype have a milder clinical course, those with HbSC have an increased risk of developing PSR and resultant vision loss...
September 2016: Southern Medical Journal
Qi Zhang, Mingchu Xu, Jennifer D Verriotto, Yumei Li, Hui Wang, Lin Gan, Byron L Lam, Rui Chen
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. The prevalence of RP and the mutation spectrum vary across populations. Hispanic people account for approximately 17% of the United States population, and the genetic etiologies of RP of this ethnic group still remain not well defined. Utilizing next-generation sequencing (NGS), we screened mutations in known retinal disease-causing genes in an RP cohort of 35 unrelated Hispanic probands from the Miami area. We achieved a solving rate of 66% and identified 15 novel putative pathogenic mutations, including a frequent founder mutation disrupting PRPF31 splicing...
2016: Scientific Reports
Prasanthi Namburi, Rinki Ratnapriya, Samer Khateb, Csilla H Lazar, Yael Kinarty, Alexey Obolensky, Inbar Erdinest, Devorah Marks-Ohana, Eran Pras, Tamar Ben-Yosef, Hadas Newman, Menachem Gross, Anand Swaroop, Eyal Banin, Dror Sharon
Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL...
September 1, 2016: American Journal of Human Genetics
Bo Y Chun, Joseph F Rizzo
PURPOSE OF REVIEW: Review recent advances in clinical and experimental studies of dominant optic atrophy (DOA) to better understand the complexities of pathophysiology caused by the optic atrophy 1 (OPA1) mutation. RECENT FINDINGS: DOA is the most commonly diagnosed inherited optic atrophy, causing progressive bilateral visual loss that begins early in life. During the past 25 years, there has been substantial progress in the understanding of the clinical, genetic, and pathophysiological basis of this disease...
November 2016: Current Opinion in Ophthalmology
F S Sorrentino, C E Gallenga, C Bonifazzi, P Perri
Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by a complex association between tremendous genotypic multiplicity and great phenotypic heterogeneity. The severity of the clinical manifestation depends on penetrance and expressivity of the disease-gene. Also, various interactions between gene expression and environmental factors have been hypothesized. More than 250 genes with ~4500 causative mutations have been reported to be involved in different RP-related mechanisms. Nowadays, not more than the 50% of RPs are attributable to identified genes, whereas the rest of molecular defects are still undetectable, especially in populations where few genetic screenings have been performed...
August 26, 2016: Eye
K Jiao, A Sahaboglu, E Zrenner, M Ueffing, P A R Ekström, F Paquet-Durand
Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway...
2016: Cell Death Discovery
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