GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort

Simona Petrucci^{1

2}, Monia Ginevrino^{3

4}, Ilaria Trezzi^{5

6}, Edoardo Monfrini^{5

6}, Lucia Ricciardi⁷, Alberto Albanese⁸, Micol Avenali^{9

10}, Paolo Barone¹¹, Anna Rita Bentivoglio^{3

12}, Vincenzo Bonifati¹³, Francesco Bove^{3

12}, Laura Bonanni¹⁴, Livia Brusa¹⁵, Cristina Cereda⁹, Giovanni Cossu¹⁶, Chiara Criscuolo¹⁷, Giovanna Dati¹¹, Anna De Rosa¹⁷, Roberto Eleopra¹⁸, Giovanni Fabbrini^{1

19

20}, Laura Fadda²¹, Manuela Garbellini^{5

6}, Brigida Minafra⁹, Marco Onofrj¹⁴, Claudio Pacchetti⁹, Ilaria Palmieri^{9

22}, Maria Teresa Pellecchia¹¹, Martina Petracca^{3

12}, Marina Picillo¹¹, Antonio Pisani²³, Annamaria Vallelunga¹¹, Roberta Zangaglia⁹, Alessio Di Fonzo^{5

6}, Francesca Morgante^{7

24}, Enza Maria Valente^{9

22}; ITA-GENE-PD Study Group

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
² Department of Clinical and Molecular Medicine, S. Andrea University Hospital, Rome, Italy.
³ Agostino Gemelli IRCCS University Hospital Foundation, Rome, Italy.
⁴ Institute of Genomic Medicine, Catholic University, Rome, Italy.
⁵ Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.
⁶ Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
⁷ Neurosciences Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, United Kingdom.
⁸ Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
⁹ IRCCS Mondino Foundation, Pavia, Italy.
¹⁰ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
¹¹ Center for Neurodegenerative Diseases, Department of Medicine, Surgery and Dentistry "ScuolaMedicaSalernitana," University of Salerno, Baronissi, SA, Italy.
¹² Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.
¹³ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹⁴ Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.
¹⁵ Parkinson Center, Neurology Complex Operative Unit, Sant'Eugenio Hospital, Rome, Italy.
¹⁶ Brotzu Hospital, Neurology, Cagliari, Italy.
¹⁷ Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy.
¹⁸ Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹⁹ Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
²⁰ IRCCS Neuromed, Pozzilli (Isernia), Italy.
²¹ Department of Neurology, University Hospital of Cagliari, Cagliari, Italy.
²² Department of Molecular Medicine, University of Pavia, Pavia, Italy.
²³ Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy.
²⁴ Department of Experimental and Clinical Medicine, University of Messina, Messina, Italy.

PMID: 32658388
DOI: 10.1002/mds.28195

GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort

Simona Petrucci et al. Mov Disord. 2020 Nov.

. 2020 Nov;35(11):2106-2111.

doi: 10.1002/mds.28195. Epub 2020 Jul 13.

Authors

Collaborators

Affiliations

¹ Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.
² Department of Clinical and Molecular Medicine, S. Andrea University Hospital, Rome, Italy.
³ Agostino Gemelli IRCCS University Hospital Foundation, Rome, Italy.
⁴ Institute of Genomic Medicine, Catholic University, Rome, Italy.
⁵ Foundation IRCCS Ca'Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.
⁶ Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
⁷ Neurosciences Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, United Kingdom.
⁸ Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
⁹ IRCCS Mondino Foundation, Pavia, Italy.
¹⁰ Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.
¹¹ Center for Neurodegenerative Diseases, Department of Medicine, Surgery and Dentistry "ScuolaMedicaSalernitana," University of Salerno, Baronissi, SA, Italy.
¹² Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.
¹³ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹⁴ Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.
¹⁵ Parkinson Center, Neurology Complex Operative Unit, Sant'Eugenio Hospital, Rome, Italy.
¹⁶ Brotzu Hospital, Neurology, Cagliari, Italy.
¹⁷ Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy.
¹⁸ Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
¹⁹ Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
²⁰ IRCCS Neuromed, Pozzilli (Isernia), Italy.
²¹ Department of Neurology, University Hospital of Cagliari, Cagliari, Italy.
²² Department of Molecular Medicine, University of Pavia, Pavia, Italy.
²³ Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy.
²⁴ Department of Experimental and Clinical Medicine, University of Messina, Messina, Italy.

PMID: 32658388
DOI: 10.1002/mds.28195

Abstract

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear.

Objectives: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time.

Methods: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed.

Results: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest β-glucocerebrosidase activity.

Keywords: GBA; Parkinson's disease; dementia; genotype-phenotype correlates; impulsive-compulsive behavior.

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References

1. Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. New Engl J Med 2009;361:1651-1661.
1. Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurology 2015;72:201-208.
1. Brockmann K, Srulijes K, Pflederer S, et al. GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord 2015;30:407-411.
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1. Gan-Or Z, Amshalom I, Kilarski LL, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology 2015;84:880-887.

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GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort

Collaborators

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GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort

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Medical