Učestalost i specifičnost ispoljavanja Parkinsonove bolesti kod homozigotnih i heterozigotnih nosilaca mutacije gena za glukocerebrozidazu

Abstract

Uvod: Nedavno je otkriveno da nosioci mutacija u genu za glukocerebrozidazu (GBA), kako u homozigotnom stanju, kod pacijenata koji imaju Gošeovu bolest (GB), tako i kod heterozigotnih nosilaca ove mutacije, imaju veću šansu da obole od Parkinsonove bolesti (PB). Prema literaturnim podacima, klinička slika Parkinsonove bolesti kod nosilaca mutacije u GBA genu, slična je fenotipu sporadične forme. Ciljevi: Utvrđivanje učestalosti GBA mutacija u grupi pacijenata sa PB u Srbiji i karakterizacija genotipa. Određivanje specifičnosti kliničkog ispoljavanja PB kod heterozigotnih i homozigotnih nosilaca GBA mutacija i utvrđivanje genotipsko-fenotipske korelacije. Utvrđivanje neuroimidžing karakteristika PB pacijenata sa GBA mutacijama, zdravih nosilaca GBA mutacija i pacijenata sa GB. Materijal i metode: Analiza egzona 8-11 GBA gena obavljena je kod 644 PB pacijenta i 368 zdravih kontrola. Pored toga, pregledano je 18 pacijenata sa GB i njihovih 14 srodnika prvog stepena koji su obavezni nosioci GBA mutacija. Nakon određivanja GBA statusa i prisustva PB kod ovih ispitanika, formirane su grupe za dalju analizu. Dizajn po tipu studije preseka korišćen je za računanje odnosa šansi prisustva GBA mutacije u ispitivanim grupama, kao i za utvrđivanje osnovnih kliničkih karakeristika PB kod nosilaca GBA mutacija. Dizajn po tipu studije slučajeva i kontrola korišćen je za utvrđivanje nemotornih karakteristika kao i imidžing razlika kod PB udružene sa GBA mutacijama u poređenju sa sporadičnom PB (bez mutacija u GBA genu, sPB). Ekstenzivna testiranja za procenu kognitivnih, bihejvioralnih, motornih i nemotornih karakteristika uključile su: Unified Parkinson Disease Rating Scale (UPDRS), Hoehn i Yahr stadijum PB, Mini Mental State Examination (MMSE), Hamiltonovu skalu depresivnosti, Hamiltonovu skalu anksioznosti, Bekovu skalu za depresiju, skalu apatije, upitnik nemotornih simptoma, Adenbruksovo kognitivno ispitivanje i Bostonski test nominacije. Pregled mozga je obavljen na aparatu za magnetnu rezonanciju (MR) jačine 1,5 T. Na snimcima je određivano ukupno opterećenje hiperintenznim lezijama bele mase, zapremina sive mase mozga pomoću morfometrije zasnovane na vokselu i analiza puteva bele mase metodom difuzionog tenzorskog imidžinga. Transkranijalna sonografija mozga (TKS) korišćena je za analizu struktura srednje linije moždanog stabla. Kod zdravih nosilaca GBA mutacije, bez jasnih znakova PB, urađen je DaT-SPECT u cilju utvrđivanja premotorne faze PB...

INTRODUCTION: It was found recently that homozygous carriers of mutations in the gene encoding for glucocerebrosidase (GBA)- Gaucher’s disease (GD) patients, and heterozygous carriers of GBA mutations, are in greater risk to develop Parkinson’s disease (PD). According to literature, clinical presentation of such PD is similar to that in sporadic PD. Goals: To estimate GBA mutation frequency among PD patients in Serbia and to determine GBA genotype. To determine clinical presentation of PD patienets who are heterozygous or homozygous carriers od GBA mutations and to determine genotype-phenotype correlation. To determine neuroimaging characteristics PD patients with GBA mutations, GD patients and healthy carriers of GBA mutations. MATERIAL AND METHODS: Sequencing of exons 8-11 of GBA gene was performed on 644 PD patients and 368 healthy controls. Also, 18 GD patients and 14 of their first degree relatives, who are obligate carriers of GBA mutation, were included. After determining GBA status and the presence of PD signs, adequate groups were formed for further analysis. Cross-sectional study was used to determine odds ratio for presence of GBA mutations among PD patients and their basic clinical characteristics comparing to healthy controls. Case control study design was used for analysis of non-motor characteristics and imaging differences in between PD groups with and without GBA mutations. Motor, non-motor, cognitive and behavioral characteristics were assessed using Unified Parkinson Disease Rating Scale, Hoehn and Yahr scale, Mini Mental State Examination, Hamilton depression scale, Hamilton anxiety scale, Beck depression inventory, Apathy scale, Non-motor symptoms questionnaire, Addenbrooks cognitive examination and Boston naming test. MRI analysis was obtained with 1.5 T. Images were used for analysis of the white matter hyperintense lesions load, grey matter volume using voxel-based morphometry (VBM) and assessment of white matter tracts with diffusion tensor imaging (DTI). Transcranial sonography (TCS) was used for analysis of the brainstem midline structures. DaT-SPECT was performed in healthy GBA carriers without definite parkinsonism in order to detect premotor phase of PD. RESULTS: GBA mutations are more frequent among PD patients (6.52%) than among controls (1.36%) (OR=5.07; CI=1.99-12.92; p=0.00017). Seventeen different changes were detected in exons 8-11 of GBA gene in homozygous, heterozygous or compound heterozygous state, including mutations, recombinant allels, polymorphisms and silent variants. N370S, D409H and RecNciI were the three most frequent and together represented ¾ of all detected mutatations (72%)...