David Crosiers1, Aline Verstraeten2, Eline Wauters2, Sebastiaan Engelborghs3, Karin Peeters2, Maria Mattheijssens2, Peter P De Deyn3, Jessie Theuns2, Christine Van Broeckhoven2, Patrick Cras4. 1. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium. Electronic address: david.crosiers@uza.be. 2. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 3. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Hospital Network Antwerp, Middelheim, Antwerp, Belgium. 4. Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
Abstract
OBJECTIVE: To investigate the frequency of glucocerebrosidase (GBA) mutations in a Flanders-Belgian Parkinson's disease (PD) patient cohort and to assess genotype-phenotype correlations. METHODS: We performed an in-depth sequencing of all coding exons of GBA in 266 clinically well-characterized PD patients and 536 healthy control individuals. RESULTS: We identified rare, heterozygous GBA mutations in 12 PD patients (4.5%) and in 2 healthy control individuals (0.37%), confirming the genetic association of GBA mutations with PD in the Flanders-Belgian population (p<0.001). The patient carriers had a more severe Unified Parkinson's Disease Rating Scale (UPDRS) motor score than non-carriers. Also, GBA mutation status was a significant, independent predictor for the presence of dementia (OR=12.43, 95% CI: 2.27-68.14. p=0.004). Genetic association of PD with the common p.E326K and p.T369M variants in GBA was absent. CONCLUSION: In our Flanders-Belgian cohort, carrier status of a heterozygous GBA mutation was a strong genetic risk factor for PD. The GBA mutation frequency of 4.5% is comparable to previously reported data in other European PD patient cohorts. Furthermore, our clinical data suggest a more severe motor phenotype and a strong predisposition to dementia in GBA mutation carriers.
OBJECTIVE: To investigate the frequency of glucocerebrosidase (GBA) mutations in a Flanders-Belgian Parkinson's disease (PD) patient cohort and to assess genotype-phenotype correlations. METHODS: We performed an in-depth sequencing of all coding exons of GBA in 266 clinically well-characterized PDpatients and 536 healthy control individuals. RESULTS: We identified rare, heterozygous GBA mutations in 12 PDpatients (4.5%) and in 2 healthy control individuals (0.37%), confirming the genetic association of GBA mutations with PD in the Flanders-Belgian population (p<0.001). The patient carriers had a more severe Unified Parkinson's Disease Rating Scale (UPDRS) motor score than non-carriers. Also, GBA mutation status was a significant, independent predictor for the presence of dementia (OR=12.43, 95% CI: 2.27-68.14. p=0.004). Genetic association of PD with the common p.E326K and p.T369M variants in GBA was absent. CONCLUSION: In our Flanders-Belgian cohort, carrier status of a heterozygous GBA mutation was a strong genetic risk factor for PD. The GBA mutation frequency of 4.5% is comparable to previously reported data in other European PDpatient cohorts. Furthermore, our clinical data suggest a more severe motor phenotype and a strong predisposition to dementia in GBA mutation carriers.
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Authors: Shaun Martin; Stefanie Smolders; Peter Vangheluwe; Christine Van Broeckhoven; Chris Van den Haute; Bavo Heeman; Sarah van Veen; David Crosiers; Igor Beletchi; Aline Verstraeten; Helena Gossye; Géraldine Gelders; Philippe Pals; Norin Nabil Hamouda; Sebastiaan Engelborghs; Jean-Jacques Martin; Jan Eggermont; Peter Paul De Deyn; Patrick Cras; Veerle Baekelandt Journal: Acta Neuropathol Date: 2020-03-14 Impact factor: 17.088