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

By Elisa Menozzi, MD, PhD, Sara Lucas Del Pozo, MD, Jane Macnaughtan, PhD, Roxana Mezabrovschi, BSc, Sofia Koletsi, MSc, Pierfrancesco Mitrotti, MD, Luca Gallo, Rosaria Calabrese, MSc, Marco Toffoli, MD, Nadine Loefflad, MSc, Franco Valzania, Francesco Cavallieri, Valentina Fiorvanti, Selen Yalkic, MSc, Naomi Limbachiya, Fabio Blandini, MD, Micol Avenali, MD, PhD, Anthony Schapira, PhD

Published December 11, 2024

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Description

**Background** Variants in the *GBA1* gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype-phenotype correlations exist but with conflicting data, particularly in the cognitive domain. **Objectives** Comparing clinical phenotypes in a multicentre, international cohort incorporating GBA-PD and idiopathic PD (iPD) patients. **Methods** Patients underwent a comprehensive assessment of motor and non-motor functions. Two-group (GBA-PD vs iPD) and multiple-group comparisons (iPD, risk, mild, and severe variant GBA-PD) were performed. **Results** Three hundred fifteen PD patients were recruited: 186 iPD, 39 severe GBA-PD, 24 mild GBA-PD, 56 risk GBA-PD, and 10 patients carrying variants of unknown significance. Groups were matched for sex, disease duration and medications. Mild and severe GBA-PD were younger and developed PD earlier. Severe GBA-PD had worse depression, cognitive impairment and hyposmia, and a trend for higher rates of motor complications. **Conclusions** Only severe variant GBA-PD have a distinctive, more severe clinical profile.

Identifier (DOI)

10.1038/s41531-025-01063-3

Tags

Original Research

Team

Team Schapira

Program

Collaborative Research Network

Theme

Neuro-Immune Interactions

Meet the Authors

Elisa Menozzi, MD, PhD

Key Personnel: Team Schapira,

University College London
Sara Lucas Del Pozo, MD

Key Personnel: Team Schapira,

University College London
Jane Macnaughtan, PhD

Collaborating PI: Team Schapira,

University College London
Roxana Mezabrovschi, BSc

Key Personnel: Team Schapira,

University College London
Sofia Koletsi, MSc

Project Manager: Team Schapira,

University College London
Pierfrancesco Mitrotti, MD

Key Personnel: Team Schapira,

University of Pavia
Luca Gallo

External Collaborator
Rosaria Calabrese, MSc

Key Personnel: Team Schapira,

Fondazione Istituto Neurologico Nazionale Casimiro Mondino
Marco Toffoli, MD

Key Personnel: Team Schapira,

University College London
Nadine Loefflad, MSc

Key Personnel: Team Schapira,

University College London
Franco Valzania

External Collaborator
Francesco Cavallieri

External Collaborator
Valentina Fiorvanti

External Collaborator
Selen Yalkic, MSc

Key Personnel: Team Schapira,

University College London
Naomi Limbachiya

External Collaborator
Fabio Blandini, MD

Co-PI (Core Leadership): Team Schapira,

IRCCS Ca' Granda Ospedale Maggiore Policlinico
Micol Avenali, MD, PhD

Key Personnel: Team Schapira,

Fondazione Istituto Neurologico Nazionale Casimiro Mondino
Anthony Schapira, PhD

Lead PI (Core Leadership): Team Schapira,

University College London