Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Menozzi, Elisa; Schapira, Anthony H.V.

doi:10.3389/fneur.2021.694764

Cited by 44 publications

(46 citation statements)

References 83 publications

(120 reference statements)

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“…Therefore, the clinical features of NMSs in GBA ‐PD patients seem to be influenced by the severity of GBA variants. Importantly, our clinical data support the view that complex variants are similar to severe variants, which is consistent with a recent review [41].…”

Section: Discussionsupporting

confidence: 92%

Prevalence and genotype–phenotype correlations of GBA‐related Parkinson disease in a large Chinese cohort

Ren

Zhang

et al. 2022

Euro J of Neurology

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Background and purpose Variants in the glucocerebrosidase (GBA) gene are recognized as a common and important genetic risk factor for Parkinson disease (PD). However, the impact of variant severity on the clinical phenotype of PD in the Chinese population remains unclear. Thus, the present study aimed to determine the frequency of GBA‐related PD (GBA‐PD) and the relationship of GBA variant severity with clinical characteristics in a large Chinese cohort. Methods Long‐range polymerase chain reaction and next generation sequencing were performed for the entire GBA gene. GBA variant severity was classified into five classes: mild, severe, risk, complex, and unknown. Results Among the total 737 PD patients, 47 GBA variants were detected in 79 (10.72%) patients, and the most common GBA variants were R163Q, L444P, and R120W. Complete demographic and clinical data were obtained for 673 patients, which revealed that 18.50% of early onset PD patients had GBA variants. Compared with patients without GBA variants, GBA‐PD patients experienced PD onset an average of 4 years earlier and had more severe motor and nonmotor symptoms. Patients carrying severe and complex variants had a higher burden of nonmotor symptoms, especially depression, and more mood/cognitive and gastrointestinal symptoms than patients carrying mild variants. Conclusions GBA‐PD is highly prevalent in the Chinese population. The severity of GBA variants underlies distinct phenotypic spectrums, with PD patients carrying severe and complex variants seeming to have similar phenotypes. PD patient stratification by GBA variant severity should become a prerequisite for selecting specific treatments.

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Section: Discussionsupporting

confidence: 92%

Prevalence and genotype–phenotype correlations of GBA‐related Parkinson disease in a large Chinese cohort

Ren

Zhang

et al. 2022

Euro J of Neurology

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“…The involvement of GBA P/LP variants in familial PD and their penetrance is complex 19 – 22 , and our results showing P/LP variants in GBA to be the main reportable findings in our PD patients are in line with previous studies of PD patients of European ancestry 5 , 7 as well as international studies 23 .…”

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confidence: 93%

A multicenter study of genetic testing for Parkinson’s disease in the clinical setting

Kovanda

Rački

Bergant

et al. 2022

npj Parkinsons Dis.

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Parkinson’s disease (PD) guidelines lack clear criteria for genetic evaluation. We assessed the yield and rationale of genetic testing for PD in a routine clinical setting on a multicenter cohort of 149 early-onset and familial patients by exome sequencing and semi-quantitative multiplex ligation-dependent probe amplification of evidence-based PD-associated gene panel. We show that genetic testing for PD should be considered for both early-onset and familial patients alike, and a clinical yield of about 10% in the Caucasian population can be expected.

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“… 37 This has been hypothesised to relate to lysosomal dysfunction and the more rapid accumulation of pathogenic alpha-synuclein species in patients with carrying GBA variants. 38 However, there are also reports that GBA mutations are associated with earlier disease onset while cluster 3 has the most GBA mutations and a higher than average age at diagnosis and cluster 2 has the least GBA mutations and the lowest average age at diagnosis. 10 This highlights that there is still heterogeneity of disease onset within the clusters and that GBA mutation carriers are only a small proportion (~12%) of even the cluster with the highest carrier rate.…”

Section: Discussionmentioning

confidence: 99%

Genetics of validated Parkinson’s disease subtypes in the Oxford Discovery and Tracking Parkinson’s cohorts

Lawton

Tan

Ben‐Shlomo

et al. 2022

J Neurol Neurosurg Psychiatry

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ObjectivesTo explore the genetics of four Parkinson’s disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables.MethodsWe looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer’s disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype.ResultsA severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6.ConclusionsWe have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease.

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Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

Cited by 44 publications

References 83 publications

Prevalence and genotype–phenotype correlations of GBA‐related Parkinson disease in a large Chinese cohort

Prevalence and genotype–phenotype correlations of GBA‐related Parkinson disease in a large Chinese cohort

A multicenter study of genetic testing for Parkinson’s disease in the clinical setting

Genetics of validated Parkinson’s disease subtypes in the Oxford Discovery and Tracking Parkinson’s cohorts

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