The SPID-GBA study

Straniero, Letizia; Asselta, Rosanna; Bonvegna, Salvatore; Rimoldi, Valeria; Melistaccio, Giada; Soldà, Giulia; Aureli, Massimo; Porta, Matteo Giovanni Della; Lucca, Ugo; Fonzo, Alessio Di; Zecchinelli, Anna; Pezzoli, Gianni; Cilia, Roberto; Duga, Stefano

doi:10.1212/nxg.0000000000000523

Cited by 42 publications

(32 citation statements)

References 34 publications

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“…When stratified by variant, in one study, PD carriers of severe or biallelic variants showed worse cognitive function compared with noncarriers, whereas mild or risk variants did not ( 30 ). However, other studies found that risk variants (p.E326K) were associated with similar cognitive deterioration ( 26 , 48 ), or faster progression to dementia compared with pathogenic GBA variants ( 49 , 50 ), as opposed to what is expected on the basis of the impact on GCase activity.…”

Section: Genotype–phenotype Correlation With Clinical Profile In Gba -Parkinson Diseasementioning

confidence: 87%

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

Menozzi

Schapira

2021

Front. Neurol.

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Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

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Section: Genotype–phenotype Correlation With Clinical Profile In Gba -Parkinson Diseasementioning

confidence: 87%

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

Menozzi

Schapira

2021

Front. Neurol.

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“…Heterozygous GBA mutations are currently recognized as the most frequent genetic risk factor for PD [ 182 , 183 ], with a three-fold higher risk of developing PD dementia (PDD) and Dementia with Lewy Bodies (DLB) [ 184 , 185 , 186 , 187 ]. It is estimated that 5–10% of PD patients are carriers of GBA mutations worldwide (Odds Ratio: 3–4.7 for mild mutations, 14.6–19.3 for severe mutations [ 187 ]) [ 182 , 184 ], with even higher prevalence rates in specific ancestries [ 188 ]. Four missense GBA variations (p.E326K, p.T369M, p.N370S, and p.L444P) account for almost 82% of all mutant alleles found in PD [ 189 ].…”

Section: Autosomal Dominant Genes With Variable Penetrancementioning

confidence: 99%

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

et al. 2022

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Understanding the pathophysiology and genetic background of Parkinson’s disease (PD) increases the likelihood of developing effective disease-modifying therapeutic strategies. In particular, the discovery of genetic variants causing or increasing the risk for PD has contributed to refining the clinical, biological, and molecular classification of the disease and has offered new insights into sporadic forms. It is even more evident that specific genetic mutations can show different responses to pharmacological and device-aided therapies. To date, several agents acting on multiple PD-causing pathogenic pathways have been tested as disease-modifying strategies, with disappointing results. This may be caused by the recruitment of PD populations whose underlying molecular pathophysiology is heterogeneous. We believe that an effective model of personalized medicine must be prioritized in the near future. Here, we review the current therapeutic options under clinical and preclinical development for PD and discuss the key pending questions and challenges to face for successful clinical trials. Furthermore, we provide some insights into the role of genetics in guiding the decision-making process on symptomatic and device-aided therapies for PD in daily clinical practice.

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“…Genetic alterations and mutations in familial PD forms, such as SNCA, Parkin, LRRK2, DJ-1, PINK-1, and UCHL-1, only account for approximately 10% of idiopathic PD patients. Age of onset and clinical symptoms are variable, as example convincingly demonstrated in Glucocerebrosidase (GBA) mutation carriers [ 104 , 105 , 106 , 107 , 108 ]. Neuroprotection trials are again under way in these GBA mutation carrying PD patients.…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

Müller

Mueller

Riederer

2021

Cells

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Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration.

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The SPID-GBA study

Cited by 42 publications

References 34 publications

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

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

Precision Medicine in Parkinson’s Disease: From Genetic Risk Signals to Personalized Therapy

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

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