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{{Infobox disease | Name = {{PAGENAME}} | DiseasesDB = 2619 | ICD9 = {{ICD9|363.55}} | ICD10 = {{ICD10|H|31|2|1}} | OMIM = 303100 | MeshID = D015794 | MedlinePlus = 000595 }} = Disease Entity = [[File:Choroideremia Figure 3.jpg|thumb|This image is a fundus photograph of a patient with advanced chodoidermia. Note the diffuse absence of retina, RPE and choroid with a small island of choroid and retina remaining in the fovea.<ref>Welder D, Jeffrey D. Photographer: Toni Venckus. Choroideremia. © of EyeRounds.org of The University of Iowa. Permissions obtained from executive director and editor of Eyerounds.org.This image was originally published in the Ophthalmic Atlas Images by [http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/Choroideremia.htm EyeRounds.org of The University of Iowa].This image is licensed under the [https://creativecommons.org/licenses/by-nc-nd/3.0/deed.en_US Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License].</ref> |300x300px]] Choroideremia is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature: ICD-9: [http://www.icd9data.com/2012/Volume1/320-389/360-379/363/363.55.htm 363.55] ICD-10: [http://www.icd10data.com/ICD10CM/Codes/H00-H59/H30-H36/H31-/H31.21 H31.21] OMIM Entry # [http://omim.org/entry/303100 303100] == Disease == Choroideremia is an X-linked chorioretinal dystrophy characterized by the diffuse, progressive degeneration of the retinal pigment epithelium (RPE), photoreceptors and choriocapillaris. It is caused by a mutation in the CHM gene and is the focus of exciting basic and clinical research. Gene therapy through viral vectors has shown early promise in the possible treatment of this blinding disease. == History == [[File:Choroideremia Figure 1.jpg|thumb|Ludwig Mauthner (April 13, 1840 – October 20, 1894) was an Austrian neuroanatomist and ophthalmologist. He was the first to describe choroideremia in 1872.|390x390px]] Choroideremia was first described in 1872 by Ludwig Mauthnuer, an Austrian ophthalmologist.<ref name=":1">Barnard AR, Groppe M, MacLaren RE. Gene therapy for choroideremia using an adeno-associated viral (AAV) vector. ''Cold Spring Harbor'' perspectives in medicine. ''2014;5(3):a017293.''</ref> Initially, it was thought to be a developmental anomaly, similar to a choroidal coloboma, due to the near total lack of choroidal vessels.<ref name=":2">Sorsby A, Franceschetti A, Joseph R, Davey JB. Choroideremia; clinical and genetic aspects. ''The British journal of'' ophthalmology. ''1952;36(10):547-581.''</ref> Upon observation of less extreme cases, the progressive nature of the disease became apparent.<ref name=":2" /> An X-linked connection was proposed in 1942, but it wasn’t until 1990 that the specific gene was cloned. <ref name=":2" /><ref name=":3">Cremers FP, Brunsmann F, Berger W, et al. Cloning of the breakpoints of a deletion associated with choroidermia. ''Human'' genetics. ''1990;86(1):61-64.''</ref> The CHM gene was one of the first genes to be identified by positional cloning and was one of the first genes to be established as a cause of an inherited retinal degeneration.<ref name=":3" /><ref>van Bokhoven H, van den Hurk JA, Bogerd L, et al. Cloning and characterization of the human choroideremia gene. ''Human'' molecular genetics. ''1994;3(7):1041-1046.''</ref><ref name=":4">Huckfeldt RM, Bennett J. Promising first steps in gene therapy for choroideremia. ''Human gene therapy. ''2014;25(2):96-97.</ref><ref name=":5">Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase. ''Science (New'' York, N.Y.). ''1993;259(5093):377-381.''</ref> Since the early 1990s, over 106 pathogenic variations in the CHM gene have been discovered.<ref name=":6">Freund PR, Sergeev YV, MacDonald IM. Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy. ''Molecular genetics &'' genomic medicine. ''2016;4(3):344-358.''</ref> The most exciting developments have happened in the last several years, with the development of viral vectors designed to replace the mutated CHM gene.<ref name=":0">MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. ''Lancet (London, England). ''2014;383(9923):1129-1137.</ref> == Definitions == Choroideremia derives its name from the almost complete loss of retina, choroid and RPE that leads to exposure of the underlying white sclera.<ref name=":0" /> It is derived from “choroideremie”, which is thought to be a combination of the ancient Greek word “eremia,” meaning barren land or dessert, and “chorion”, which is ancient Greek for skin.<ref name=":1" /> == Epidemiology == Choroideremia is a rare chorioretinal dystrophy that is estimated to affect between 1 in 50,000 to 1 in 100,000 individuals.<ref name=":7">Khan KN, Islam F, Moore AT, Michaelides M. Clinical and Genetic Features of Choroideremia in Childhood. ''Ophthalmology. ''2016;123(10):2158-2165.</ref> Men are predominantly affected due to its X-linked etiology, but women can be asymptomatic carriers or rarely can be affected by the dystrophy as well. Northern Finland has the highest reported prevalence.<ref>Sankila EM, Tolvanen R, van den Hurk JA, Cremers FP, de la Chapelle A. Aberrant splicing of the CHM gene is a significant cause of choroideremia. ''Nature genetics. ''1992;1(2):109-113.</ref><ref>Karna J. Choroideremia. A clinical and genetic study of 84 Finnish patients and 126 female carriers. ''Acta ophthalmologica.'' Supplement. ''1986;176:1-68.''</ref> There are thought to be more than 500 affected males in the United Kingdom and around 3000 throughout Europe.<ref name=":8">MacDonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and review of recent literature. ''Survey of'' ophthalmology. ''2009;54(3):401-407.''</ref> == Genetics == Choroideremia is due to various mutations involving the CHM gene, which is located on chromosome Xq21.2, and is inherited in an X-linked recessive manner.<ref name=":9">Furgoch MJ, Mewes-Ares J, Radziwon A, Macdonald IM. Molecular genetic diagnostic techniques in choroideremia. ''Molecular vision. ''2014;20:535-544.</ref> The gene spans 186,382 bp and the mRNA is made up of 15 exons and is 5442 bp long.<ref name=":4" /> The open reading frame is 1,962 bp and produces a 653 amino acid long protein (95 kDa).<ref name=":9" /> One hundred and six pathogenic variants in the CHM gene have been identified. <ref name=":6" /> A variety of mutations have been discovered involving the CHM gene, including deletions, insertions, duplications, translocations, nonsense, splice-site, frameshift and missense mutations.<ref>Sanchez-Alcudia R, Garcia-Hoyos M, Lopez-Martinez MA, et al. A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice. ''PloS one. ''2016;11(4):e0151943.</ref> == Physiology and Pathology == [[File:Choroideremia mechanism.png|thumb|'''The role of REP-1 in the Rab cycle (A) '''Newly synthesized Rab proteins are transported by Rab escort proteins (REPs) to geranylgeranyl transferases. '''(B) '''Guanine exchange factors (GEFs) turn the membrane-associated Rab protein into its active state. '''(C) '''GTPase activating proteins (GAPs) promote efficient GTP hydrolysis resulting in an inactive state of the Rab protein. '''(D) '''GDP dissociation inhibitors (GDIs), extract inactive GDP-bound Rab from the membrane. '''(E) '''GDI displacement factors (GDFs) release the Rab protein from the GDIs and assist re-targeting and re-insertion of the Rab into the appropriate membrane<ref>Kotzcsh M, Goettig P, Soelch S, Magdolen V. RAB31 (Ras-related protein in brain 31); Atlas Genet Cytogenet Oncol Haematol. In press. On line version: [http://atlasgeneticsoncology.org/Genes/RAB31ID41978ch18p11.html http://atlasgeneticsoncology.org/Genes/RAB31ID41978ch18p11.html.] Permission to use image obtained from both corresponding author and journal. © Atlas of Genetics and Cytogenetics in Oncology and Haematology.</ref>]] The CHM gene encodes for Rab escort protein-1 (REP-1). REP-1 is one of two Rab escort proteins, both of which are found throughout the body.<ref name=":22">Preising M, Ayuso C. Rab escort protein 1 (REP1) in intracellular traffic: a functional and pathophysiological overview. ''Ophthalmic'' genetics. ''2004;25(2):101-110.''</ref> REP-1 is involved in a complex system of intracellular trafficking of various lipid membrane-bound structures. These vesicular structures are guided by GTP-binding proteins (Rab proteins).<ref name=":7" /> For Rab proteins to be connected to the lipid membrane and allow intracellular trafficking, they need to be prenylated, which is the addition of geranylgeranyl groups to a molecule.<ref name=":7" /><ref name=":22" /><ref>Seabra MC, Brown MS, Slaughter CA, Sudhof TC, Goldstein JL. Purification of component A of Rab geranylgeranyl transferase: possible identity with the choroideremia gene product. ''Cell. ''1992;70(6):1049-1057.</ref> REP-1 proteins aid in this process by bringing Rab proteins to the Rab geranylgeranyltransferase (GGTase) complex, where the prenylation occurs.<ref name=":22" /> REP-1 also facilitates the transfer of the prenylated Rab protein to its target location.<ref name=":22" /> Without this escort, the prenylated Rab would undergo inactivation.<ref name=":22" /> The figure to the left demonstrates the role of REP in the Rab cycle. <ref>Kotzcsh M, Goettig P, Soelch S, Magdolen V. RAB31 (Ras-related protein in brain 31); Atlas Genet Cytogenet Oncol Haematol. In press. On line version: http://atlasgeneticsoncology.org/Genes/RAB31ID41978ch18p11.html</ref> <nowiki> </nowiki>Mutations in the CHM gene create defects in REP-1. This leads to improper intracellular vesicular trafficking and is thought to impair the transport of proteins from the Golgi apparatus to the outer segments in photoreceptors, as well as the impairment of phagocytosis and degradation of shed outer segments by RPE cells.<ref name=":10">Xue K, Oldani M, Jolly JK, et al. Correlation of Optical Coherence Tomography and Autofluorescence in the Outer Retina and Choroid of Patients With Choroideremia. ''Investigative'' ophthalmology & visual science. ''2016;57(8):3674-3684.''</ref> Multiple types of mutations of the CHM gene have been described, but no particular type of mutation has been associated with a worse or better prognosis. This lack in phenotypic variability is not entirely surprising in that most mutations described show a near universal lack of REP-1 protein expression.<ref name=":4" /><ref name=":5" /><ref>Simunovic MP, Jolly JK, Xue K, et al. The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype. ''Investigative ophthalmology & visual science. ''2016;57(14):6033-6039.</ref> Variations in severity of disease must be due to factors other than the underlying mutation. The specific anatomic location of the initial pathologic degeneration remains controversial. Some studies have suggested that the primary pathology in choroideremia resides in the RPE followed by degeneration of the photoreceptor layer and choroid.<ref>Flannery JG, Bird AC, Farber DB, Weleber RG, Bok D. A histopathologic study of a choroideremia carrier. ''Investigative'' ophthalmology & visual science. ''1990;31(2):229-236.''</ref><ref>Morgan JI, Han G, Klinman E, et al. High-resolution adaptive optics retinal imaging of cellular structure in choroideremia. ''Investigative'' ophthalmology & visual science. ''2014;55(10):6381-6397.''</ref><ref name=":11">Mura M, Sereda C, Jablonski MM, MacDonald IM, Iannaccone A. Clinical and functional findings in choroideremia due to complete deletion of the CHM gene. ''Archives of ophthalmology (Chicago, Ill. : 1960). ''2007;125(8):1107-1113.</ref><ref>Jain N, Jia Y, Gao SS, et al. Optical Coherence Tomography Angiography in Choroideremia: Correlating Choriocapillaris Loss With Overlying Degeneration. ''JAMA ophthalmology. ''2016;134(6):697-702.</ref> Others have suggested the primary pathology develops in the photoreceptors, with subsequent loss of the RPE and choriocapillaris.<ref>Syed N, Smith JE, John SK, Seabra MC, Aguirre GD, Milam AH. Evaluation of retinal photoreceptors and pigment epithelium in a female carrier of choroideremia. ''Ophthalmology. ''2001;108(4):711-720.</ref><ref>Jacobson SG, Cideciyan AV, Sumaroka A, et al. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations. ''Investigative ophthalmology & visual science. ''2006;47(9):4113-4120.</ref><ref>Lazow MA, Hood DC, Ramachandran R, et al. Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP). ''Investigative'' ophthalmology & visual science. ''2011;52(13):9581-9590.''</ref> Finally, other examinations have suggested an independent loss of photoreceptors and RPE followed by degeneration of the choroid.<ref>Bonilha VL, Trzupek KM, Li Y, et al. Choroideremia: analysis of the retina from a female symptomatic carrier. ''Ophthalmic genetics.'' ''2008;29(3):99-110.''</ref><ref name=":12">Syed R, Sundquist SM, Ratnam K, et al. High-resolution images of retinal structure in patients with choroideremia. ''Investigative'' ophthalmology & visual science. ''2013;54(2):950-961.''</ref> A recent histopathologic study found an inflammatory component to the disease process along with prominent gliosis, with gliosis likely being a secondary event.<ref name=":8" /> = Diagnosis = == Symptoms == Choroideremia becomes symptomatic during the first decade of childhood with the development of nyctalopia. It then progresses to peripheral vision loss in teenage years with sparing of central vision and maintenance of good visual acuity until the fifth to seventh decade of life.<ref name=":7" /><ref name=":13">Heon E, Alabduljalil T, Iii DB, et al. Visual Function and Central Retinal Structure in Choroideremia. ''Investigative'' ophthalmology & visual science. ''2016;57(9):Oct377-387.''</ref> At around the fifth decade of life, most patients develop a rapid deterioration in central vision.<ref>Coussa RG, Kim J, Traboulsi EI. Choroideremia: effect of age on visual acuity in patients and female carriers. ''Ophthalmic'' genetics. ''2012;33(2):66-73.''</ref> Color vision is lost as degeneration of the macula takes place, and can occur prior to loss of visual acuity.<ref name=":13" /><ref>Jolly JK, Groppe M, Birks J, Downes SM, MacLaren RE. Functional Defects in Color Vision in Patients With Choroideremia. ''American journal of'' ophthalmology. ''2015;160(4):822-831.e823.''</ref> Phenotypic variation within a family can be striking, with some affected males significantly less affected than other males.<ref>Ponjavic V, Abrahamson M, Andreasson S, et al. Phenotype variations within a choroideremia family lacking the entire CHM gene. ''Ophthalmic'' genetics. ''1995;16(4):143-150.''</ref> Carriers, for the most part, are asymptomatic and even when female carriers are symptomatic their disease is less severe than their male offspring. == Fundus Examination == On fundus examination, the earliest manifestation is widespread pigment clumping at the level of the RPE, which is distinct from the characteristic perivascular bone-spicule pigment clumping seen in retinitis pigmentosa.<ref name=":7" /> Subsequently, patients develop well-defined regions of atrophy with visible underlying sclera and large choroidal vessels, most commonly in the postequatorial region just outside the vascular arcades. These areas of atrophy advance centripetally and are also found in a peripapillary and parapapillary manner (See image below).<ref name=":7" /> An island of foveal tissue may persist until later stages of the disease when central and color vision become affected from foveal atrophy. Patients have preserved larger choroidal blood vessels and normal appearing retinal vessels. In addition, choroideremia exhibits no optic atrophy, unlike the waxy pallor of optic discs seen in retinitis pigmentosa. Carrier patients can have mild RPE changes, and in severe cases, patchy RPE degeneration and areas of atrophy.<ref name=":7" /><ref name=":14">Renner AB, Fiebig BS, Cropp E, Weber BH, Kellner U. Progression of retinal pigment epithelial alterations during long-term follow-up in female carriers of choroideremia and report of a novel CHM mutation. ''Archives of ophthalmology (Chicago, Ill. : 1960). ''2009;127(7):907-912.</ref> This phenotypic variability in carriers is due to lyonization in which one copy of the X chromosome is randomly silenced early in embryogenesis. Other associated ocular findings include 31% of patients developing posterior subcapsular cataracts and a small risk of macular edema or choroidal neovascularization.<ref>MacDonald IM, Hume S, Chan S, Seabra MC. Choroideremia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. ''GeneReviews(R)''. Seattle (WA): University of Washington, Seattle University of Washington, Seattle. All rights reserved.; 1993.</ref> [[File:Choroideremia Figure 2.jpg|thumb|This image is a fundus photograph of a patient with advanced choroideremia. Note an island of fovea remaining, surrounded by generalized atrophy of the neurosensory retina, retinal pigmented epithelium and choroid.<ref>Kaplan JH, Piri N. Choroideremia. Retina Image Bank. March 29, 2013; Image Number 5373. © The American Society of Retina Specialists. Permission for use obtained from Director of Retina Image Bank and Members Section of the ASRS. This image was originally published in the Retina Image Bank. </ref> |300x300px|none]] == Fluorescein angiography == On [http://eyewiki.org/Fluorescein_Angiography fluorescein angiography], scalloped areas of missing choriocapillaris appear hypofluorescent next to brightly hyperfluorescent areas of perfused choriocapillaris (See image below). Although not a common feature, choroidal neovascularization secondary to choroideremia can develop, leading to leakage characteristic of neovascularization.<ref>Campos-Pavon J, Torres-Pena JL. Choroidal neovascularization secondary to choroideremia. ''Archivos de la Sociedad Espanola de Oftalmologia. ''2015;90(6):289-291.</ref><ref>Sawa M, Tamaki Y, Klancnik JM, Jr., Yannuzzi LA. Intraretinal foveal neovascularization in choroideremia. ''Retina (Philadelphia, Pa.). ''2006;26(5):585-588.</ref><ref>Endo K, Yuzawa M, Ohba N. Choroideremia associated with subretinal neovascular membrane. ''Acta ophthalmologica Scandinavica. ''2000;78(4):483-486.</ref><ref name=":15">Robinson D, Tiedeman J. Choroideremia associated with a subretinal neovascular membrane. Case report. ''Retina (Philadelphia, Pa.). ''1987;7(2):70-74.</ref><ref>Sanchez-Alcudia R, Garcia-Hoyos M, Lopez-Martinez MA, et al. A Comprehensive Analysis of Choroideremia: From Genetic Characterization to Clinical Practice. ''PloS one. ''2016;11(4):e0151943.</ref>[[File:Choroideremia Figure 4.jpg|thumb|This image is a fluorescein angiographic image in the early venous laminar phase demonstrating an irregular island of hyperfluorescence in the fovea surrounded by a generalized absence of choriocapillaris, retinal pigmented epithelium and retina.<ref>Kaplan HJ, Piri N. Choroideremia. Retina Image Bank. March 29, 2013; Image Number 5375. © The American Society of Retina Specialists.Permission for use obtained from Director of Retina Image Bank and Members Section of the ASRS. This image was originally published in the Retina Image Bank.</ref> |300x300px|none]] == Fundus Autofluorescence == Fundus autofluorescence can show early loss of peripheral autofluorescence with subsequent centripetal loss.<ref>Jolly JK, Edwards TL, Moules J, Groppe M, Downes SM, MacLaren RE. A Qualitative and Quantitative Assessment of Fundus Autofluorescence Patterns in Patients With Choroideremia. ''Investigative ophthalmology & visual science. ''2016;57(10):4498-4503.</ref> The scalloped edges of demarcation are sharp and can clarify areas of the fundus that are affected and not apparent on fundus examination (See images below). Hypoautofluorescence in the nonatrophic areas may precede photoreceptor cell death, and the amount of hypoautofluorescence may help predict disease activity and help identify patients undergoing a more rapid degeneration. A speckled autofluorescence may be observed in an otherwise unaffected macula in both affected males and carriers.<ref name=":7" /><ref>Preising MN, Wegscheider E, Friedburg C, Poloschek CM, Wabbels BK, Lorenz B. Fundus autofluorescence in carriers of choroideremia and correlation with electrophysiologic and psychophysical data. ''Ophthalmology. ''2009;116(6):1201-1209.e1201-1202.</ref> {|style="margin: 0 auto;" |[[File:Normal choreremiacarrier makl 011215 12.jpg|thumb|This fundus autofluorescent image is of a female choroideremia carrrier. The lyonization found with this disease can be seen with the patchy distribution of atrophic areas.<ref>This image was originally published in the Retina Gallery. No author information was provided on the site. Permission for use obtained from Retina Gallery webmaster. [http://retinagallery.com/displayimage.php?album=994&pid=8237#top_display_media File 12/37].</ref>|298x298px|none]] |[[File:Choroideremia Figure 5.png|thumb|331x331px|This figure is a fundus photograph (A) and the associated fundus autofluorescence (C) of a patient with choroideremia. Note the better characterization of diseased and healthy retina on fundus autofluorescence that is not as apparent as on the fundus photograph. Image B was performed in retromode and image D is an NIR-AF image.<ref>Maurizio BP, Pierluigi I, Stelios K, Stefano V, Marialucia C, Ilaria Z, Francesco B. Retro-mode imaging and fundus autofluorescence with scanning laser ophthalmoscope of retinal dystrophies. This image is allowed to be used if properly cited, as per the [https://creativecommons.org/licenses/by/2.0/ Creative Commons Attribution License].© Parodi et al.; licensee BioMed Central Ltd. 2012.This [http://bmcophthalmol.biomedcentral.com/articles/10.1186/1471-2415-12-8 image] was originally published by BMC Ophthalmology. </ref>]] |} == Electroretinography == [http://eyewiki.org/Electroretinogram Electroretinography] is abnormal early in the course of the disease, with a reduced scotopic component before the photopic component.<ref>Zhou Q, Liu L, Xu F, et al. Genetic and phenotypic characteristics of three Mainland Chinese families with choroideremia. ''Molecular vision. ''2012;18:309-316.</ref><ref name=":16">Sieving PA, Niffenegger JH, Berson EL. Electroretinographic findings in selected pedigrees with choroideremia. ''American journal of ophthalmology. ''1986;101(3):361-367.</ref><ref name=":17">Renner AB, Kellner U, Cropp E, et al. Choroideremia: variability of clinical and electrophysiological characteristics and first report of a negative electroretinogram. ''Ophthalmology. ''2006;113(11):2066.e2061-2010.</ref> It becomes extinguished by midlife.<ref name=":17" /> Carriers generally have a normal ERG pattern but symptomatic carriers may develop minor changes, in particular a subnormal 30-Hz flicker response on full-field ERG or diffuse elevation of 650-nm dark-adapted thresholds.<ref name=":11" /><ref name=":14" /><ref name=":16" /> == Optical Coherence Tomography == Optical coherence tomography demonstrates preservation of the inner retinal layers throughout the disease process.<ref name=":7" /> Patients tend to have a small increase in central retinal thickness early in the course of disease when normal visual acuity is present, but eventually develop progressive subfoveal retinal thinning as visual acuity declines.<ref name=":7" /><ref name=":13" /> OCT can demonstrate a reduction in subfoveal choroidal thickness. As the disease progresses, patients often develop retinal tubulations in the outer nuclear layers and inner retinal microcysts. <ref name=":10" /><ref name=":12" /><ref name=":13" /> One study showed that 62.5 % of patients showed some degree of cystoid macular edema on OCT.<ref>Genead MA, Fishman GA. Cystic macular oedema on spectral-domain optical coherence tomography in choroideremia patients without cystic changes on fundus examination. ''Eye (London, England). ''2011;25(1):84-90.</ref> == Visual Field == Visual field loss is consistent with the location of chorioretinal degeneration. The earliest field change is a patchy loss of midperipheral vision.<ref name=":13" /> Progressive, patchy atrophy can lead to irregular scotomas and eventually to near complete loss of a central and peripheral vision.<ref name=":13" /> In advanced disease small islands of vision can remain in the fovea and light can be perceived in the far periphery.<ref>McCulloch C. Choroideremia: a clinical and pathologic review. ''Transactions of the American Ophthalmological Society. ''1969;67:142-195.</ref> ==[http://eyewiki.org/Optical_Coherence_Tomography_Angiography OCT Angiography]== [http://eyewiki.org/Optical_Coherence_Tomography_Angiography OCT angiography] is a noninvase, functional extension of OCT for visualizing retinal and choroidal microvasculature. Advanced cases of choroideremia can result in the distortion of the neurosensory retina, RPE and choriocapillaris, which can complicate the interpretation of both FA and OCT. Patel et al demonstrated the use of OCT angiography in the characterization and quantification of CNV in a patient with choroideremia.<ref>Patel RC, Gao SS, Zhang M, et al. OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF CHOROIDAL NEOVASCULARIZATION IN FOUR INHERITED RETINAL DYSTROPHIES. ''Retina (Philadelphia, Pa). ''2016;36(12):2339-2347.</ref> More research is necessary to clarify the role of this new technology in the management of choroideremia. == Differential diagnosis with defining features == * [[Gyrate atrophy]]: Choroidetemia in early stages may mimic gyrate atrophy of retina and choroid. Examination of fundus of family members, early presentation, and X-linked inheritance pattern are important features to clinically differentiate choroideremia from gyrate atrophy. Autosomal recessive, well demarcated scalloped areas of chorioretinal atrophy, nyctalopia in second to third decade, systemic hyperornithinemia, myopia and early cataracts<ref>Sergouniotis PI, Davidson AE, Lenassi E, Devery SR, Moore AT, Webster AR. Retinal structure, function, and molecular pathologic features in gyrate atrophy. ''Ophthalmology. ''2012;119(3):596-605.</ref> * [http://eyewiki.org/Retinitis_Pigmentosa Retinitis Pigmentosa]: Waxy disc pallor, peripheral RPE bone spicule like degeneration, retinal arteriolar attenuation<ref>Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. ''Lancet (London, England). ''2006;368(9549):1795-1809.</ref> * [http://eyewiki.aao.org/Pathologic_myopia_(myopic_degeneration) Myopic Degeneration]: Absence of nyctalopia, tessellated fundus, lacquer cracks, diffuse atrophy, patchy atrophy, posterior staphyloma, high axial length, macular atrophy, straightened and stretched vessels, high rates of choroidal neovascularization, temporal peripapillary atrophic crescent, hemorrhages and tilting of the optic disc<ref>Silva R. Myopic maculopathy: a review. ''Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. ''2012;228(4):197-213.</ref> * [http://eyewiki.org/Albinism Ocular albinism]: Infantile nystagmus, iris translucency, substantial hypopigmentation of ocular fundus, foveal hypoplasia, aberrant optic pathway projection associated with asymmetry of cortical responses on visual evoked potential testing<ref>Lewis RA. Ocular Albinism, X-Linked. In: Pagon RA, Adam MP, Ardinger HH, et al., eds.''GeneReviews(R)''. Seattle (WA): University of Washington, Seattle University of Washington, Seattle. All rights reserved.; 1993.</ref> * Usher syndrome type 1: Autosomal recessive, pigmentary retinopathy, congenital deafness, imbalance from vestibular dysfunction<ref>Eudy JD, Sumegi J. Molecular genetics of Usher syndrome. ''Cellular and molecular life sciences : CMLS. ''1999;56(3-4):258-267.</ref> * Thioridazine hydrochloride retinal toxicity: History of medication use, loss of night vision, decreased ERG amplitudes, accumulation of fine or coarse pigment clumps, geographic RPE and choriocapillary atrophy<ref>Borodoker N, Del Priore LV, De ACC, Yannuzzi LA. Retinopathy as a result of long-term use of thioridazine. ''Archives of ophthalmology (Chicago, Ill. : 1960). ''2002;120(7):994-995.</ref> *Bietti crystalline dystrophy: Autosomal recessive, corneal deposits, yellow-white crystalline retinal deposits, progressive atrophy of the RPE, loss of choriocapillaris, progressive nyctalopia, visual field constriction, legal blindness in the fifth or sixth decades of life<ref>Halford S, Liew G, Mackay DS, et al. Detailed phenotypic and genotypic characterization of bietti crystalline dystrophy. ''Ophthalmology. ''2014;121(6):1174-1184.</ref> {|style="margin: 0 auto;" |+ |[[File:Gyrate Atrophy.png|thumb|This is a fundus photograph of a patient with gyrate atrophy. Note the hyperpigmentation of the remaining RPE, in comparison to choroideremia.<ref>Vislisel, J. Gyrate Atrophy. This image was originally published in the Ophthalmic Atlas Images by [http://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/gyrate-atrophy.htm EyeRounds.org of The University of Iowa]. This image is licensed under the [/eyewiki.org/Creative_Commons_Attribution-NonCommercial-NoDerivs_3.0_Unported_License Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License]. © of EyeRounds.org of The University of Iowa. Permissions obtained from executive director and editor of Eyerounds.org. </ref>|218x218px]] |[[File:Retinitis pigmentosa.jpg|thumb|This is a fundus photograph of a patient with retinitis pigmentosa. Note the bone-spicule pigment clumping and optic nerve pallor that differentiates this disease from choroideremia.<ref>Hamel, Christian. Retinitis Pigmentosa. Orphanet Journal of Rare Diseases 2006 1:40 doi:10.1186/1750-1172-1-40.This is an Open Access article distributed under the terms of the [http://creativecommons.org/licenses/by/2.0 Creative Commons Attribution License], which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.© 2006 Hamel; licensee BioMed Central Ltd. </ref>|none|222x222px]] |[[File:Myopic degeneration.jpeg|thumb|This image is a fundus photograph of a patient with myopic degeneration. Note involvement of the center of the macula, which is affected sooner in myopic degeneration than in choroideremia.<ref>Gerardo Garcia-Aguirre, MD. Myopic Degeneration. Retina Image Bank. Oct 3, 2013; Image Number 10884. © The American Society of Retina Specialists. Permission for use obtained from Director of Retina Image Bank and Members Section of the ASRS. This image was originally published in the Retina Image Bank.</ref>|none|194x194px]] |[[File:Ocular albinism.jpeg|thumb|This is a fundus image of a patient with ocular albinism. Note the diffuse absence of pigmentation, in comparison to the scalloped, patchy loss of pigmentation in choroideremia.<ref>Homayoun Tabandeh, MD. [http://imagebank.asrs.org/file/14632/ocular-albinism Ocular Albinism]. Retina Image Bank. March 3, 2014; Image Number 14632. © The American Society of Retina Specialists. Permission for use obtained from Director of Retina Image Bank and Members Section of the ASRS. This image was originally published in the Retina Image Bank.</ref>|none|202x202px]] |} == Laboratory test == The diagnosis of choroideremia can be suggested by characteristic fundus findings and family history. It can be confirmed by direct genetic testing or through immunoblot analysis with anti-REP-1 antibody.<ref>MacDonald IM, Mah DY, Ho YK, Lewis RA, Seabra MC. A practical diagnostic test for choroideremia. ''Ophthalmology. ''1998;105(9):1637-1640.</ref> Confirmation is warranted due to phenotypic variation and clinical overlap with other conditions, with possible therapeutic and prognostic relevance if an alternative diagnosis is made.<ref>Lee TK, McTaggart KE, Sieving PA, et al. Clinical diagnoses that overlap with choroideremia. ''Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. ''2003;38(5):364-372; quiz 372.</ref> = Management = == Investigational Therapies == === Gene delivery through the Adeno-Associated Virus Subtype 2 Viral Vector === ====Basics==== Recent success in the treatment of Leber’s congenital amaurosis has brought hope to developing a successful therapy for choroideremia.<ref>Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. ''The New England journal of medicine. ''2008;358(21):2231-2239.</ref><ref>Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. ''The New England journal of medicine. ''2008;358(21):2240-2248.</ref><ref>Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. ''Human gene therapy. ''2008;19(10):979-990.</ref> Since choroideremia is a genetic disease and caused by a mutation of one gene, it is a promising candidate for successful gene therapy. <ref>Lukashev AN,Zamyatnin AA, Jr. Viral Vectors for Gene Therapy: Current State and Clinical Perspectives. ''Biochemistry Biokhimiia. ''2016;81(7):700-708.</ref> Recent investigational therapies have focused on replacing the defective gene via viral vectors. Adeno-associated virus subtype 2 (AAV2) has been of particular interest in ophthalmic research due to its affinity for primate photoreceptors and RPE.<ref name=":18" /> This subtype of adeno-associated viruses also has the advantage of being well characterized in a number of animal models.<ref name=":18">Tolmachova T, Tolmachov OE, Barnard AR, et al. Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo. ''Journal of molecular'' medicine (Berlin, Germany). ''2013;91(7):825-837.''</ref> The amount of genetic material that can be transmitted by a virus is limited by the packaging capacity of the vector, so the size of the gene to be replaced is important. The limit of AAV vectors is estimated to around 5kb for single stranded DNA, which is much greater than the approximate 1.9kb coding sequence of REP-1.<ref>Zinkernagel MS, MacLaren RE. Recent advances and future prospects in choroideremia. ''Clinical ophthalmology (Auckland, N.Z.). ''2015;9:2195-2200.</ref><ref>Bennett J, Maguire AM, Cideciyan AV, et al. Stable transgene expression in rod photoreceptors after recombinant adeno-associated virus-mediated gene transfer to monkey retina. ''Proceedings of the National Academy of Sciences of the United States of America. ''1999;96(17):9920-9925.</ref> Prior to the investigational treatment in humans, the replacement of the REP-1 gene was first investigated in mice. REP-1 replacement via the AAV2 vector was demonstrated to be feasible by Tamolchova et al.<ref name=":18" /> In addition, they demonstrated an improvement in ERG responses in mice following subretinal injections of the designed viral vector.<ref name=":18" /> In a recent, multicenter phase 1/2 clinical trial, six male patients were administered with AAV.REP1.<ref name=":0" /> The surgical techinques and results are discussed below. ==== Surgical technique ==== The viral vectors in this study were placed subretinally. The first step in the surgical procedure was to detach the target retina with the use of balanced salt solution injected through a 41G Teflon cannula. Once detached, a fixed volume (0.1mL) of 1×10<sup>10</sup> AAV2.REP1 genome particles was injected into the subretinal space in 5 of 6 patients. In the sixth patient, a dose of 6×10<sup>9</sup> was injected. The injection of viral particles resulted in extension of the detachment in all patients. The sixth patient was injected with a smaller dose of viral particles because of difficulty in creating a detachment in that patient and concern about stretching the papillomacular bundle. ==== Results ==== At six months, the mean change in ETDRS letters was +3.8 letters in the treated eyes in comparison to +1.5 letters in the control eyes. Statistical analysis was not published in this study due to small sample size. Patient 1 had a +21 letter improvement and patient 4 had a +11 letter improvement, with the other patients have a marginal loss in visual acuity. On microperimetry, a mean increase was noted in retinal sensitivity with respect to the dimmest stimulus seen, mean retinal sensitivity and total number of test points seen, in contrast to a reduction in all of these parameters in the patient's contralateral eye. In regards to safety, there was no observed immune response to the injected viral particles. Two patients had mild distortion of central vision which resolved by 6 months. All patients had sub-clinical progression of lens opacification, as expected following vitrectomy. No serious systemic or ocular adverse events were reported.<ref name=":0" /> At 3.5 years, the patients who had initial improvement in visual acuity maintained that visual acuity. <ref name=":21">Edwards TL, Jolly JK, Groppe M, et al. Visual Acuity after Retinal Gene Therapy for Choroideremia. ''The New England journal of'' medicine. ''2016;374(20):1996-1998.''</ref>Three other patients did not have a significant change in visual acuity and one patient had a decline in vision. <ref name=":21" />The patient who had a decline in vision was the patient injected with a lower total vector dose.<ref name=":21" /> These studies are promising because they show the feasibility and tolerability of gene therapy through a viral vector in humans with choroideremia. More studies will be needed to investigate further clarify the effectiveness and safety of this therapy. ====Current Viral Vector Studies==== Here is a global list of clinical trials into the treatment of choroideremia through viral vectors: * [https://clinicaltrials.gov/ct2/show/NCT02553135?term=choroideremia&rank=3 NCT02553135] * [https://clinicaltrials.gov/ct2/show/NCT02341807?term=choroideremia&rank=1 NCT02341807] * [https://clinicaltrials.gov/ct2/show/NCT02077361?term=choroideremia&rank=2 NCT02077361] * [https://clinicaltrials.gov/ct2/show/NCT02407678?term=choroideremia&rank=5 NCT02407678] * [https://clinicaltrials.gov/ct2/show/NCT01461213?term=NCT01461213&rank=1 NCT01461213] * [https://clinicaltrials.gov/ct2/show/NCT02671539?term=choroideremia&rank=4 NCT02671539] === Lutein === Lutein has been investigated as a supplement to reduce the progression of atrophy and vision loss in choroideremia. Lutein is a carotenoid that is present in high concentrations in the macula. It works as a filter protecting the macula from blue light and functions as a free radical scavenger and antioxidant.<ref>Lima VC, Rosen RB, Farah M. Macular pigment in retinal health and disease. ''International journal of retina and vitreous. ''2016;2:19.</ref> Supplementation with oral lutein (20 mg per day) has been investigated over a 6 month period. <ref name=":20" />Results demonstrated an increase in serum lutein and macular pigment levels, but absolute foveal sensitivity did not change, suggesting no short term benefit from supplementation.<ref name=":20" /> No studies looking into the long-term effectiveness of oral lutein supplementation have been conducted.<ref name=":20">Duncan JL, Aleman TS, Gardner LM, et al. Macular pigment and lutein supplementation in choroideremia. ''Experimental eye research.'' ''2002;74(3):371-381.''</ref> == Macular edema == Frank macular edema is not a typical feature of choroideremia, but its development may result in a sudden decline in central visual acuity. The pathogenic etiology of macular edema in patients with retinal dystrophies remains poorly understood. It may be treated with topical dorzolamide, which was demonstrated to be effective in a small study'''.'''<ref>Genead MA, McAnany JJ, Fishman GA. Topical dorzolamide for treatment of cystoid macular edema in patients with choroideremia. ''Retina (Philadelphia, Pa.). ''2012;32(4):826-833.</ref> This therapy is similar to the management of macular edema found in other retinal dystrophies such as retinitis pigmentosa.<ref>Huckfeldt RM,Comander J. Management of Cystoid Macular Edema in Retinitis Pigmentosa. ''Seminars in ophthalmology. ''2016:1-9.</ref><ref>Liew G, Moore AT, Webster AR, Michaelides M. Efficacy and prognostic factors of response to carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa. ''Investigative ophthalmology & visual science. ''2015;56(3):1531-1536.</ref> While the edema may be responsive to anti-VEGF agents as demonstrated in retinitis pigmentosa patients, it may be more appropriate to begin with topical carbonic anhydrase inhibitor therapy and if that fails then move to more invasive options.<ref>Yuzbasioglu E, Artunay O, Rasier R, Sengul A, Bahcecioglu H.Intravitreal bevacizumab (Avastin) injection in retinitis pigmentosa. ''Current eye research. ''2009;34(3):231-237.</ref><ref>Melo GB, Farah ME, Aggio FB. Intravitreal injection of bevacizumab for cystoid macular edema in retinitis pigmentosa. ''Actaophthalmologica Scandinavica. ''2007;85(4):461-463.</ref> ''' ''' == Cataract surgery == Surgeons may be appropriately concerned about performing cataract surgery in patients with choroideremia. Patients are placed at risk of phototoxicity from microscope illumination as well as at risk of postoperative pseudophakic macular edema. Few studies have been performed looking at outcomes of cataract surgery in this patient population. One study, a case series of 6 patients, demonstrated an improvement in visual acuity with cataract surgery without the development of postoperative macular edema.<ref name=":19">Edwards TL, Groppe M, MacLaren RE. Outcomes following cataract surgery in choroideremia. ''Eye (London, England). ''2015;29(4):460-464.</ref> Two patients did develop early capsular phimosis however, suggesting this may be a feature of the disease. <ref name=":19" /> When performing cataract surgery in patients with choroideremia, it is important to obtain appropriate informed consent and educating patients about the potential risks of the procedure and the unknowns of the post-operative course. = References =
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