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.

EM, SLDP, JM, SK, PM, LG, RC, MT, NL, FV, FC, VF, NL, FB and MA have no conflicts to disclose. RM and SY are supported by a Royal Free Charity fellowship. AHVS 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.

This research was funded in part by Aligning Science Across Parkinson s (Grant number: ASAP000420) through the Michael J. Fox Foundation for Parkinson s Research (MJFF) and by the EU Joint Programme Neurodegenerative Research (JPND: GBA PaCTS) through the MRC grant code MR/T046007/1. For the purpose of open access the author has applied a CC BY 4.0 public copyright license to all Author Accepted Manuscripts arising from this submission.

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London Queen Square Research Ethics Committee gave ethical approval for this work (Reference Number: 15/LO/1155). Ethics Committee of Pavia gave ethical approval for this work (code P20210009687). Ethics Committee of the Area Vasta Emilia Nord gave ethical approval for this work (code 2021/0092531).

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