Studija genetičke osnove Parkinsonove bolesti kod stanovništva Srbije

Abstract

Parkinsonova bolest je drugo najčešće neurodegenerativno oboljenje koje pogaĎa od 1% do 2% stanovništva starijeg od 65 godina i više od 4% stanovništva starijeg od 85 godina. Klinička prezentacija obuhvata četiri kardinalna znaka bolesti: bradikineziju, tremor u miru, rigor i posturalnu nestabilnost, kao i druge motorne i nemotorne simptome. Parkinsonova bolest se karakteriše kao multifaktorijalno oboljenje u čijem nastanku najverovatniju ulogu ima interakcija genetičkih i sredinskih faktora. Genetička osnova je veoma kompleksna i do danas je otkriveno preko 28 hromozomskih regiona koji su sa većom ili manjom sigurnošću povezani sa nastankom bolesti. Uzrok autozomno-dominantne forme bolesti najčešće su mutacije u LRRK2 genu, dok je VPS35 najskorije potvrĎen gen, asociran sa ovakvim načinom nasleĎivanja. Kod autozomno-recesivne forme su najčešće mutacije u Parkin genu, a najznačajniji faktor rizika za razvoj Parkinsonove bolesti su mutacije u GBA genu koje dovode do autozomno-recesivnog oboljenja, Gošeove bolesti. Cilj: Cilj ovog istraživanja je karakterizacija genetičke osnove Parkinsonove bolesti kod stanovništva Srbije i formiranje preporuka za genetičko testiranje bolesnika. U tom cilju je vršeno odreĎivanja učestalosti i spektra mutacija kod obolelih od Parkinsonove bolesti u genima LRRK2, Parkin, VPS35 i GBA, kao i utvrĎivanje potencijalnih korelacija genotipa sa fenotipom. Materijal i metode: U ovo istraživanje je uključeno ukupno 496 bolesnika (305 muškog i 191 ženskog pola) kojima je klinička dijagnoza Parkinsonove bolesti postavljena na Klinici za neurologiju, Kliničkog centra Srbije. Svi bolesnici su testirani na prisustvo mutacija u odabranim regionima LRRK2 i VPS35 gena metodom direktnog sekvenciranja. Detektovane promene koje do sada nisu opisane u literaturi su analizirane i kod 143 kontrolnih, neurološki zdravih subjekata, straijih od 50 godina...

Parkinson’s disease is the second most common neurodegenerative disorder that affects 1% to 2% of the population older than 65 years and over 4% of the population older than 85 years. Clinical presentation includes four cardinal signs of disease: bradykinesia, resting tremor, rigidity an postural instability, as well as other motor and non-motor symptoms. Parkinson’s disease is characterized as a multifactorial disorder with probable interaction of genetic and environmental factors. The genetic basis is very complex and more than 28 chromosomal regions, associated with the disease, are discovered so far. Mutations in the LRRK2 gene are the most common cause of autosomal dominant Parkinson’s disease, while the mutations in VPS35 gene are recently discovered as a new cause of dominantly inherited form of the disease. Autosomal recessive Parkinson’s disease is the most frequently linked to mutations in the Parkin gene. The strong risk factor for the development of Parkinson's disease are heterozygous mutations in the GBA gene. Homozygous and compound heterozygous mutations in GBA gene are cause of autosomal recessive Gaucher’s disease. Aim: The aim of this study was to determine genetic basis of Parkinson’s disease in Serbian population and to establish recommandations for genetic testing of patients with this disorder. It was planed to determine the frequency of mutations and the mutation spectrum in LRRK2, Parkin, VPS35 i GBA genes in Serbian patients with Parkinson’s disease and to examine correlations of genotype and phenotype. Material and methods: In this study were included 496 patients with Parkinson’s disease (305 male and 196 female) diagnosed in Neurology Clinic, Clinical Center of Serbia. The presence of mutations in selected exons of LRRK2 and VPS35 genes was analyzed by direct sequencing...