Background: GBA1 mutation is the most significant genetic risk factor for Parkinson's disease (PD). It encodes glucocerebrosidase (GCase), whose dysfunction - seen in Gaucher disease - leads to the accumulation of glucosylceramide and its derivate glucosylsphingosine (GlcSph). However, it remains unclear whether GCase and GlcSph are relevant in PD patients carrying no or monoallelic GBA1 variants, and what their clinical impact might be.
Objective: Investigating the relationships between GBA1 mutations, GCase, GlcSph, and clinical features in a large PD cohort.
Methods: We performed a cross-sectional study of PD patients screened for GBA1 mutations, GCase activity, and GlcSph via dried blood spot tests. Patients were classified as heterozygous mutation carriers (GBA1-PD) or non-carriers (nonGBA1-PD). Collected data included motor and non-motor parameters. Molecular and clinical differences were compared between GBA1-PD and nonGBA1-PD. Distinctive clinical features were further investigated through multivariate models to test their correlations with biochemical data.
Results: The cohort included 611 subjects (225 GBA1-PD, 386 nonGBA1-PD). GBA1-PD presented earlier onset, lower cognitive scores, higher incidence of mood disturbances and more advanced stage. Motor assessment revealed a higher frequency and severity of dyskinesias, independently from disease duration and LEDD. GlcSph levels showed an independent correlation with dyskinesia severity and time at onset in GBA1-PD patients, which was independent of sex, LEDD, UPDRS-III, disease duration and GBA1 mutation class.
Conclusions: This study reveals an association between GlcSph and dyskinesias in GBA1-PD, that should prompt further investigation to assess the GlcSph role as a possible biomarker and target to tackle dyskinesias in GBA1-PD.
Keywords: Dyskinesias; Glucocerebrosidase; Glucosylsphingosine; Motor fluctuations; Parkinson's disease.
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