GBA Mutations Are Associated With Earlier Onset and Male Sex in Dementia With Lewy Bodies

Gámez-Valero, Ana; Prada-Dacasa, Patricia; Santos, Cristina; Adame-Castillo, Cristina; Campdelacreu, Jaume; Rizzoli, René; Gascón‐Bayarri, Jordi; Ispierto, Lourdes; Álvarez, Ramiro; Ariza, Aurelio; Beyer, Katrin

doi:10.1002/mds.26593

Cited by 36 publications

(45 citation statements)

References 33 publications

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“…These demographic and clinical characteristics in our german DLB cohort are in line with findings from two small DLB cohorts of Ashkenazi Jews ancestry and Spanish origin, in which GBA1 promoted a younger onset and higher prevalence of RBD …”

Section: Discussionsupporting

confidence: 90%

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

et al. 2019

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Background Patients with dementia with Lewy bodies reveal a variable pathology including alpha‐synuclein, amyloid‐beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha‐synuclein. Objective Whether GBA1 mutations are associated with a CSF alpha‐synuclein profile in dementia with Lewy bodies. Methods Screening of the GBA1 gene and single‐nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha‐synuclein, amyloid‐beta1‐42, total‐Tau, phospho‐Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross‐sectionally. Results Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha‐synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype. Conclusion Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha‐synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha‐synuclein–lowering compounds. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 90%

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

et al. 2019

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“…Dementia and visual hallucinations are conditions that typically occur in advanced stages, and are possibly related to the presence of Lewy bodies in cortical areas. In fact, autopsies of GBA mutation-carriers revealed a more widespread Lewy body pathology in the neocortex than that of non-carriers [6] and an increased rate of GBA mutations in Parkinson’s disease with dementia and Lewy body disease [37]. On the basis of our results we therefore hypothesize that deleterious GBA variants may lead to a major alteration to the molecular mechanisms involved in α-synuclein clearance.…”

Section: Discussionsupporting

confidence: 52%

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

et al. 2016

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The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

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“…Male sex may increase the risk of developing PD among patients with Gaucher disease type 1 (62), although larger samples need to be studied. One recent study (63) found that, among those with dementia with Lewy bodies (DLB) both with and without GBA1 mutations, men were overwhelmingly represented in GBA-associated DLB, by a male:female ratio of 9:1; the ratio in DLB subjects without GBA1 mutations was 1.1:1. Also, whereas the sex distribution for many inherited parkinsonisms, including LRRK2 and parkin, does not demonstrate the typical increased frequency in men (56, 64), screens of GBA1 samples suggest that GBA-PD may have a more typical 60:40 male:female predominance (61).…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric characteristics of GBA-associated Parkinson disease

Swan

Doan

Ortega

et al. 2016

Journal of the Neurological Sciences

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Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13–11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.

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GBA Mutations Are Associated With Earlier Onset and Male Sex in Dementia With Lewy Bodies

Abstract: GBA mutations are also an important risk factor for DLB development in the Spanish population, are associated with earlier disease onset, and are more prevalent in men. © 2015 International Parkinson and Movement Disorder Society.

Cited by 36 publications

References 33 publications

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

Neuropsychiatric characteristics of GBA-associated Parkinson disease

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