Dejavniki, ki vplivajo na klinično sliko bolnikov s patogeno različico p.G90D gena za rodopsin

Krašovec, Tjaša (author), Kobal, Nina (author), Fakin, Ana (mentor), Hawlina, Marko (comentor)

Izhodišče: Patogene različice v genu za rodopsin (RHO) največkrat povzročajo različne oblike pigmentne retinopatije (RP), ki je napredujoča degeneracija mrežnice, redkeje pa kongenitalno stacionarno nočno slepoto (CSNB). Do sedaj je bilo predpostavljeno, da posamezna različica povzroča bodisi eno ali drugo klinično sliko (npr. p.G90D CSNB), z redkimi izjemami (npr. p.E113K). V nekaterih raziskavah so pokazali, da lahko jemanje vitamina A upočasni napredovanje RP, vendar zdravljenje z vitaminom A ni sprejeto v klinični praksi. Namen: Ugotoviti ali lahko različica p.G90D poleg CSNB povzroča tudi druge klinične slike in ali obstajajo dejavniki, ki so s tem povezani. Metode: V prospektivni raziskavi smo pregledali vse znane bolnike s potrjeno patogeno različico p.G90D v RHO in vse njihove družinske člane, ki so poročali o nočni slepoti, skupaj 19 bolnikov iz treh družin (13 moških in 6 žensk; mediana 41 let, razpon 8 – 71). Opravili so razširjen oftalmološki pregled, ki je vključeval preiskave vidne funkcije (vključno z elektroretinografijo) in slikovne preiskave (avtofluorescenco očesnega ozadja in optično koherentno tomografijo). Bolniki so izpolnili vprašalnik o pridruženih boleznih in življenjskemu slogu; iz vzorca venske krvi smo določili serumsko koncentracijo vitamina A. Patogena različica p.G90D je bila potrjena z uporabo sekvenciranja nove generacije ali Sangerjevega sekvenciranja. Rezultati: Bolniki so imeli bodisi nočno slepoto brez strukturne okvare (NBWD) (26 %) klasično RP (48 %), pericentralno RP (5 %) ali sektorsko RP (21 %). Bolniki z NBWD so bili mlajši od ostalih, vendar razlika ni bila statistično značilna. Pridužene bolezni so navajali izključno bolniki s klasično in sektorsko RP (v 75 % in v 56 %), ki pa so bili tudi starejši. Med bolniki starimi 40 let ali več, so imeli tisti z blažjo klinično sliko (NBWD, sektorska RP) statistično značilno višjo koncentracijo vitamina A kot tisti z večjo strukturno okvaro (klasična RP, pericentralna RP) (mediana 3,0 vs. 2,0 μmol/L, Mann-Whitneyev test, p < 0,05). Zaključki: V nasprotju z dosedanjimi raziskavami patogena različica p.G90D poleg disfunkcije paličnic (CSNB oz. NBWD) povzroča tudi različne oblike distrofije mrežnice (klasična RP, pericentralna RP in sektorska RP). Taka fenotipska raznolikost je posebnost med ostalimi več kot 200 različicami v RHO, ki zanje ni značilna. Serumski vitamin A je možen modifikator bolezni vendar je za potrditev potrebna raziskave na večih bolnikih in z daljšim sledenjem.

• Language: Slovenian
• Keywords: oftalmologija
• Work type: Research project (high school)
• Typology: 2.12 - Final Research Report
• Organization: MF - Faculty of Medicine
• Place of publishing: Ljubljana
• Publisher: [T. Krašovec, N. Kobal]
• Year: 2021
• Number of pages: 93 str.
• PID: 20.500.12556/RUL-143963
• UDC: 617.7
• COBISS.SI-ID: 136402691

Note

Univerzitetna Prešernova nagrada

• Publication date in RUL: 24.01.2023

Secondary language

• Language: English

Abstract

Background: Pathogenic variants in the rhodopsin gene (RHO) most commonly cause various forms of retinitis pigmentosa (RP), which is a progressive retinal degeneration, and less commonly congenital stationary blindness (CSNB). Until now, it has been assumed that a single variant produces either one or the other clinical outcome (e.g. p.G90D CSNB), with rare exceptions (e.g. pE113K). Some studies have shown that taking vitamin A can slow the progression of RP, but vitamin A treatment is not accepted in clinical practice. Aim: To determine whether the p.G90D causes other clinical pictures in addition to CSNB and identify potential modifying factors associated with this. Methods: A prospective study included all known patients harboring p.G90D in RHO and all their family members who reported night blindness, a total of 19 patients from three families (13 male and 6 female; median age 41 years, range 8 – 71). They underwent an extended ophthalmologic examination which included examinations of visual function (including electroretinography) and imaging (fundus autofluorescence and optical coherence tomography). Patients completed a questionnare on associated diseases and lifestyle. Serum vitamin A concentration was determined from a venous blood sample. The pathogenic variant p.G90D was confirmed using next-generation sequencing or Sanger sequencing. Results: Patients had either night blindness without degeneration (NBWD) (26%), classic RP (48%), pericentral RP (5%) or sectoral RP (21%). Patients with NBWD were younger than the others, however the diffrence was not significant. Systemic diseases were reported exlusievely by patients with classic and sectoral RP (75 % and 56 %), who were also oldest. In a subgroup of patients aged 40 years or more, patients with a milder clinical signs (NBWD, sectoral RP) had significantly higher vitamin A concentration than patients with greater structural impairment (classic RP, pericentral RP) (median 3.0 vs 2.0 μmol/L, Mann-Whitney test, p < 0.05). Conclusions: Contrary to the previous report, p.G90D also causes various forms of retinal dystrophy (classic RP, sector RP and pericentral RP) in addition to rod dysfunction (CSNB or NBWD). Such phenotypic variability is unusual even among more than 200 variants in RHO, which is not characteristic of them. Serum vitamin A concentration is a possible disease modifier, however studies on larger cohorts and longer follow-up are needed to confirm this.

• Keywords: ophthalmology, rhodopsin, retinitis pigmentosa, retinal degeneration, genetics, vitamin A, membrane proteins, night vision, night blindness