Genetika a fenotypová charakteristika Parkinsonovy nemoci s časným začátkem

• Thesis title in Czech: Genetika a fenotypová charakteristika Parkinsonovy nemoci s časným začátkem
• Thesis title in English: Genetics and phenotypic characteristics of early-onset Parkinson’s disease
• Key words: alelické varianty, fenotyp, genotyp, mutace, PARK2, parkin, Parkinsonova nemoc s časným začátkem, polymorfismy
• English key words: allelic variants, early-onset Parkinson's disease, genotype, mutations, PARK2, parkin, phenotype, polymorphisms
• Academic year of topic announcement: 2013/2014
• Thesis type: dissertation
• Thesis language: čeština
• Department: Department of Neurology First Faculty of Medicine Charles University and General University Hospital in Prague (11-00600)
• Supervisor: prof. MUDr. Evžen Růžička, DrSc.
• Author: hidden - assigned and confirmed by the Study Dept.
• Date of registration: 12.06.2014
• Date of assignment: 12.06.2014
• Confirmed by Study dept. on: 12.06.2014
• Date and time of defence: 29.09.2014 15:15
• Venue of defence: Neurologická klinika 1. LF UK a VFN
• Date of electronic submission: 20.06.2014
• Date of proceeded defence: 29.09.2014
• Course: Defence of the dissertation (B90002)
• Opponents: prof. MUDr. Pavel Seeman, Ph.D.

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Preliminary scope of work

Úvod:Mutace genu parkin (PARK2), asociované s autozomálně recesivní Parkinsonovou nemocí s časným začátkem (EOPD), mají v různých populacích variabilní četnost. Cílem této práce je popsat fenotypovou charakteristiku českých pacientů s EOPD, zhodnotit vliv faktorů vnějšího prostředí na riziko onemocnění a určit frekvenci alelických variant parkinu ve skupině pacientů a kontrol.
Metodika:Celkem u 70 pacientů s EOPD (věk při vzniku nemoci ≤ 40 let) a 75 kontrol byla provedena fenotypová charakteristika a analýza alelických variant parkinu.
Výsledky:V souboru nemocných byly zachyceny tyto hlavní fenotypové rysy: absence kognitivního deficitu, častý výskyt dystonie, deprese a hyperhidrózy, výborná odpovídavost na dopaminergní léčbu, brzký rozvoj polékových dyskinezí a hybných fluktuací. Pacienti s mutacemi parkinu měli signifikantně nižší věk při vzniku onemocnění. Práce v zemědělství a expozice chemikáliím byly spojeny s vyšším rizikem EOPD, naopak pití kávy představovalo protektivní faktor. Mutace parkinu jsme identifikovali u pěti pacientů (7.1%): bodová mutace p.R334C byla přítomna u jednoho nemocného, čtyři pacienti měli exonové delece. Kromě jedné homozygotní delece exonu 4, se všechny nalezené mutace nacházely v heterozygotní konstituci. V kontrolní skupině mutace zachyceny nebyly. Polymorfismy p.S167N a p.D394N byly přítomny v podobném procentu mezi pacienty i kontrolami, polymorfismus p.V380L se vyskytoval s téměř dvakrát vyšší frekvencí v kontrolní skupině, kde jsme také zachytili novou alelickou variantu p.V380I.
Závěr:Klinická charakteristika pacientů odpovídá předchozím popisům fenotypu EOPD. Nízká prevalence mutací parkinu svědčí pro úlohu dalších genů v patogenezi onemocnění u slovanské populace.

Preliminary scope of work in English

Objective:Mutations in the parkin (PARK2) gene have been associated with autosomal recessive early-onset Parkinson’s disease (EOPD) with various frequencies in different populations. The aim of the study is to describe phenotypic characteristics of Czech EOPD patients, to evaluate the influence of environmental risk factors, and to determine the frequency of parkin allelic variants in patients and healthy controls.
Methods:A total of 70 EOPD patients (age at onset ≤ 40 years) and 75 controls were phenotyped and screened for the sequence variants and exon rearrangements in the parkin gene.
Results:The main features in the phenotype of the patients’ sample were: the absence of cognitive deficit, high occurrence of dystonia, depression, hyperhidrosis, an excellent response to dopaminergic therapy, early onset of dyskinesia and motor fluctuation. Patients with mutations in the parkin gene had significantly lower age at onset. The agricultural occupation and work with chemicals increased the risk of EOPD, however the coffee drinking appeared to be a protective factor. Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous deletion of the exon 4. No mutations were obtained in control subjects. A novel sequence variant p.V380I (c.1138G>A) was identified in one control. Polymorphisms p.S167N and p.D394N were seen in similar percentage in patients and controls, polymorphism p.V380L was almost twice as frequent in controls as in patients.
Conclusions:The clinical characteristics of patients correspond to previous descriptions of EOPD phenotype. Our study contributes to the growing body of evidence on the low frequency of the parkin mutations in the EOPD suggesting the potential role of other genes in the pathogenesis of the disease in Slavic population.