146 research outputs found
ABCA4 Locus as a Model for Complex Genetics in Monogenic Diseases. ABCA4 lookus kui monogeensete haiguste kompleksse geneetika mudel
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Further Evidence for an Association of ABCR Alleles with Age-Related Macular Degeneration
No full textAge-related macular degeneration (AMD) accounts for >50% of the registered visual disability among North American and Western European populations and has been associated both with environmental factors, such as smoking, and with genetic factors. Previously we have reported disease-associated variants in the ABCR (also called ABCA4) gene in a subset of patients affected with this complex disorder. We have now tested our original hypothesis, that ABCR is a dominant susceptibility locus for AMD, by screening 1,218 unrelated AMD patients of North American and Western European origin and 1,258 comparison individuals from 15 centers in North America and Europe for the two most frequent AMD-associated variants found in ABCR. These two sequence changes, G1961E and D2177N, were found in one allele of ABCR in 40 patients (∼3.4%), and in 13 control subjects (∼0.95%). Fisher’s two-sided exact test confirmed that these two variants are associated with AMD at a statistically significant level (P<.0001). The risk of AMD is elevated approximately threefold in D2177N carriers and approximately fivefold in G1961E carriers. The identification of a gene that confers risk of AMD is an important step in unraveling this complex disorder
Functional Analysis of Retinal Flecks in Stargardt Disease
No full textTo evaluate visual function of flecked areas in a series of patients with Stargardt disease (STGD) and compare them with adjacent non flecked areas
Multimodal analysis of the Preferred Retinal Location and the Transition Zone in patients with Stargardt Disease
No full textPurpose: 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. The location and stability of the PRL along with the associated FAF pattern and visual sensitivities were determined and compared to the underlying retinal structure. Results: The mean visual sensitivity of the PRLs for the 52 eyes was 10.76 +/- 3.70 dB. For the majority of eyes, PRLs were associated with intact ellipsoid zone (EZ) bands and qualitatively normal FAF patterns. In 17 eyes (32.7%) the eccentric PRL was located at the edge of the MA. In 35 eyes (67.3%) it was located at varying distances from the border of the MA with a TZ between the PRL and the MA. The TZ was associated with decreased sensitivity values (5.92 +/- 4.69 dB) compared to PRLs (p<0.05), with absence/disruption of the EZ band and abnormal FAF patterns (hyper or hypo-autofluorescence). Conclusions: In STGD1 eccentric PRLs are located away from the border of MA and associated with intact EZ bands and normal FAF. The TZ is characterized by structural and functional abnormalities. The results of multimodal imaging of the PRL and TZ suggest a possible sequence of retinal and functional changes with disease progression that may help in the planning of future therapies; RPE dysfunction appears to be the primary event leading to photoreceptor degeneration and then to RPE loss
Autosoom-retsessiivne Stargardti tõbi: fenotüübiline heterogeensus ja genotüübi-fenotüübi seosed
No full textVäitekirja elektrooniline versioon ei sisalda publikatsiooneStargardti tõbi (STGD1) on kõige sagedasem pärilik võrkkesta kollatähni düstroofia põhjustades progresseeruvat nägemislangust sageli juba lapseeast. Haigust põhjustavad mutatsioonid ABCA4 geenis, mille tulemusena ladestuvad võrkkesta toksilised jääkproduktid põhjustades fotoretseptorite kadu. Praeguseks on teada üle 1000 haigustekkelise mutatsiooni ABCA4 geenis, mille tõttu on haiguse kliiniline pilt (fenotüüp) väga mitmekesine.
Meie uuringu peamisteks eesmärkideks olid STGD1 puhuste võrkkesta struktuurimuutuste analüüs ja leida võimalikke seoseid haiguse fenotüüpide ja (ABCA4) mutatsioonide vahel.
Doktoritöös leidsime, et vastupidiselt senise arusaama kohaselt esineb varases haiguse faasis noortel STGD1 haigetel lisaks fotoretseptorite kihi õhenemisele välise piirimembraani oluline paksenemine võrreldes kontrollgrupiga. Tõenäoliselt iseloomustab leid võrkkesta gliiarakkude mööduvat hüpertroofiat, olles STGD1 varajaseks kliiniliseks markeriks, mis omab kliinilist potentsiaali diagnoosimaks haigust varases faasis. Teiseks analüüsisime STGD1 korral harva esinevat fenotüüpi, mida nimetatakse kollatähni tsentri (fovea) tühimikuks (ingl.k. optical gap; foveal cavitation). Tegemist on foveas paiknevate fotoretseptorite kaoga, mille tulemusena moodustub võrkkesta väliskihtidesse struktuurne tühimik. Võrkkesta kuvamisuuringute analüüsil näitasime, kuidas fenotüüp dünaamiliselt kujuneb ja kaob ning lõime selle baasil arengustaadiumid. Vastupidiselt siiani juhtivale arusaamale, et STGD1 puhul esineb primaarselt võrkkesta pigmentepiteelirakkude (RPE) kõhetumine näitasime kuvamisuuringutel, et fovea tühimiku korral toimub esmaselt just fotoretseptorite kadu, millele järgneb RPE atroofia. Ühtlasi leidsime genotüübi-fenotüübi analüüsil, et STGD1 haigetel esineb statistiliselt tugev seos ABCA4 geenis paikneva p. G1961E mutatsiooni ja fovea tühimiku vahel. Kolmandaks näitasime, et STGD1 võib fenotüübilt sarnaneda hüdroksüklorokviin (Plaquenil) võrkkesta toksiliste muutusega. Moodustub nn „foveat säilitava“ fenotüübi variant, mille tulemusena on kollatähni teravanägemise punktis võrkkest suhteliselt hästi säilinud ning patsiendid on avastamise hetkel enamasti sümptomite vabad.
Fenotüüpide detailne iseloomustamine, dünaamika hindamine ja genotüübi-fenotüübi seoste kirjeldamine võiks paremini aidata planeerida ja analüüsida ravimi, geeniteraapia ja tüvirakuteraapia uuringuid ja nende tulemusi STGD1 kontekstisStargardt disease (STGD1) is the most common form of inherited macular dystrophy causing progressive visual loss often from childhood. The disease is caused by mutations in the ABCA4 gene resulting in progressive accumulation of toxic visual cycle byproducts in the retina leading to photoreceptor loss. More than 1000 disease-causing ABCA4 mutations have been described resulting in remarkable diverse clinical (phenotypic) expression of the disease.
The main aims of our study were to analyze STGD1-associated retinal structural changes as well as phenotypic expression via multimodal imaging and to detect possible genotype-phenotype associations.
In the thesis studies we determined that in addition to thinning of photoreceptor-associated (ellipsoid zone) layer, there is a statistically significant thickening of external limiting membrane in young STGD1 patients compared to age-matched controls. The finding describes probably transient hypertrophy of retinal glial cells and could clinically be an important early stage disease marker, holding a diagnostic potential in early diagnosis of the STGD1.
We also analyzed STGD1 patients with foveal cavitation (optical gap) phenotype. It is a rare manifestation of the STGD1 characterized by focal loss of photoreceptors in the fovea leaving a sub-foveal optically empty space detectable with spectral- domain optical coherent tomography (SD-OCT). With multimodal imaging we showed how the phenotype develops and dynamically behaves, based on which we described developmental stages of this phenotype. In contrast to the common understanding, that the first cells being affected in STGD1 are the retinal pigment epithelial (RPE) cells, we showed that, in foveal cavitation, the first cells which disappear are photoreceptors followed by atrophy of the RPE cells. We also detected a strong association between foveal cavitation phenotype and p.G1961E mutation in STGD1.
We also showed that STGD1 could phenocopy hydroxychloroquine (Plaquenil) maculopathy. The specific foveal sparing phenotype has quite unique conformation on SD-OCT, where foveal area is relatively well spared preserving a very good visual acuity.
Detailed phenotypic descriptions and dynamic assessment via multimodal imaging as well as detecting new genotype-phenotype associations potentially improves the planning of pharmacological, gene- and stem cell-based treatment studies of STGD1
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