Severe GBA1 variants drive the GBA1-PD clinical phenotype: implications for counselling and clinical trials

Elisa Menozzi^{1

2}, Sara Lucas Del Pozo^{1

2}, Jane Macnaughtan^{2

3}, Roxana Mezabrovschi^{1

2}, Sofia Koletsi^{1

2}, Pierfrancesco Mitrotti^{4

5}, Luca Gallo⁴, Rosaria Calabrese⁵, Marco Toffoli^{1

2}, Nadine Loefflad^{1

2}, Franco Valzania⁶, Francesco Cavallieri⁶, Valentina Fioravanti⁶, Selen Yalkic^{1

2}, Naomi Limbachiya^{1

2}, Fabio Blandini^#^{4

7}, Micol Avenali^#^{4

5}, Anthony Hv Schapira^#^{8

9}

Affiliations

¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL), London, UK.
² Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
³ Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.
⁴ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁵ IRCCS Mondino Foundation, Pavia, Italy.
⁶ Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
⁷ Ca' Granda IRCCS Foundation, Ospedale Maggiore Policlinico, Milan, Italy.
⁸ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL), London, UK. a.schapira@ucl.ac.uk.
⁹ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. a.schapira@ucl.ac.uk.

^# Contributed equally.

PMID: 41034226
PMCID: PMC12488979
DOI: 10.1038/s41531-025-01063-3

Severe GBA1 variants drive the GBA1-PD clinical phenotype: implications for counselling and clinical trials

Elisa Menozzi et al. NPJ Parkinsons Dis. 2025.

. 2025 Oct 1;11(1):281.

doi: 10.1038/s41531-025-01063-3.

Authors

Affiliations

¹ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL), London, UK.
² Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
³ Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, UK.
⁴ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁵ IRCCS Mondino Foundation, Pavia, Italy.
⁶ Neurology Unit, Neuromotor and Rehabilitation Department, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
⁷ Ca' Granda IRCCS Foundation, Ospedale Maggiore Policlinico, Milan, Italy.
⁸ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London (UCL), London, UK. a.schapira@ucl.ac.uk.
⁹ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. a.schapira@ucl.ac.uk.

^# Contributed equally.

PMID: 41034226
PMCID: PMC12488979
DOI: 10.1038/s41531-025-01063-3

Abstract

Variants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype-phenotype correlations exist but with conflicting data. Here, we compared the clinical phenotype of 183 idiopathic PD (iPD) patients, 39 severe GBA1-PD, 24 mild GBA1-PD, and 55 risk GBA1-PD. Compared to iPD, we observed that only severe GBA1-PD patients had a distinctive, more several clinical profile, characterised by worse depression, hyposmia, cognitive dysfunction, and possibly constipation.

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Conflict of interest statement

Competing interests: E.M., S.L.D.P., J.M., S.K., P.M., L.G., R.C., M.T., N.Lo., F.V., F.C., V.F., N.Li., F.B. and M.A. have no conflicts to disclose. R.M. and S.Y. are supported by a Royal Free Charity fellowship. A.H.V.S. has provided paid consultancy to Capsida, Neurocrine and Auxilius, is the Chief Investigator of the ambroxol phase III study and a Principal Investigator of the MOVES-PD study.

References

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1. Westenberger, A. et al. Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson’s disease study. Brain147, 2652–2667 (2024). - PMC - PubMed
1. Skrahina, V. et al. The Rostock International Parkinson’s Disease (ROPAD) Study: Protocol and Initial Findings. Mov. Disord.36, 1005–1010 (2021). - PMC - PubMed
1. Pal, G. et al. Parkinson disease and subthalamic nucleus deep brain stimulation: cognitive effects in GBA mutation carriers. Ann. Neurol.91, 424–435 (2022). - PMC - PubMed
1. Menozzi, E., Toffoli, M. & Schapira, A. H. V. Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues. Pharm. Ther.246, 108419 (2023). - PubMed

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Severe GBA1 variants drive the GBA1-PD clinical phenotype: implications for counselling and clinical trials

Affiliations

Severe GBA1 variants drive the GBA1-PD clinical phenotype: implications for counselling and clinical trials

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources