Autosomal-recessive Stargardt disease: phenotypic heterogeneity and genotype-phenotype associations
Date
2017-05-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Stargardti 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 kontekstis
Stargardt 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.
Stargardt 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.
Description
Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
pärilikud haigused, võrkkestahaigused, kollatähni degeneratsioon, autosoomne retsessiivne pärilikkus, mutatsioonid, fenotüüp, hereditary diseases, retinal diseases, macular degeneration, autosomal recessive heredity, mutations, phenotype