<scp><i>GBA</i>‐Related</scp> Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

Petrucci, Simona; Ginevrino, Monia; Trezzi, Ilaria; Monfrini, Edoardo; Ricciardi, Lucia; Albanese, Alberto; Avenali, Micol; Barone, Paolo; Bentivoglio, Anna Rita; Bonifati, Vincenzo; Bove, Francesco; Bonanni, Laura; Brusa, Livia; Cereda, Cristina; Cossu, Giovanni; Criscuolo, Chiara; Dati, Giovanna; Rosa, Anna De; Eleopra, Roberto; Fabbrini, Giovanni; Fadda, Lucia; Garbellini, Manuela; Minafra, Brigida; Onofrj, Marco; Pacchetti, Claudio; Palmieri, Ilaria; Pellecchia, Maria Teresa; Petracca, Martina; Picillo, Marina; Pisani, Antonio; Vallelunga, Annamaria; Zangaglia, Roberta; Fonzo, Alessio Di; Morgante, Francesca; Valente, Enza Maria

doi:10.1002/mds.28195

Cited by 86 publications

(130 citation statements)

References 33 publications

(91 reference statements)

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“…These findings have been replicated consistently over a the following years in other PD cohorts worldwide, the latest large clinical genome-wide association study in 4093 PD patients (Iwaki et al, 2019). Interestingly, variants that are classified as severe mutations (GBA severe ) have been associated with a more aggressive clinical phenotype suggesting a relevant effect depending on GBA mutation severity (Cilia et al, 2016;Thaler et al, 2018;Petrucci et al, 2020).…”

Section: Gba-associated Pd Presents With Non-motor Characteristicsmentioning

confidence: 99%

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Brockmann

2020

Front. Cell Dev. Biol.

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Section: Gba-associated Pd Presents With Non-motor Characteristicsmentioning

confidence: 99%

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

Brockmann

2020

Front. Cell Dev. Biol.

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“…[3][4][5][6] GBA-PD on average presents at a younger age with a higher prevalence of non-motor symptoms, however with a high variability between individual patients. 7,8 GCase is involved in intralysosomal metabolism of glycosphingolipids (GSLs), a class of lipids, essential for membrane and other cellular functions. 9 It hydrolyses the glycosphingolipid glucosylcerebroside (GluCer) into glucose and ceramide.…”

Section: Introductionmentioning

confidence: 99%

A randomized single and multiple ascending dose study in healthy volunteers of LTI‐291, a centrally penetrant glucocerebrosidase activator

Heijer

Kruithof

Amerongen

et al. 2021

Brit J Clinical Pharma

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A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers.Methods: In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level).Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level).Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.Results: LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. C max , AUC 0-24 and AUC 0-inf increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.Conclusions: These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.The authors confirm that the Principal Investigator for this paper is Geert Jan Groeneveld and that he had direct clinical responsibility for participants.

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“…The characteristic clinical phenotype of GBA monogenic PD is similar to those of sporadic PD, but the onset is earlier and the course is more severe (Brockmann et al, 2015;Ryan et al, 2019). Furthermore, PD patients with GBA mutations usually have an earlier and more frequent occurrence of NMS (Petrucci et al, 2020). It is worth noting that the NMS in PD patients carrying GBA mutations seems to be more prominent than iPD (Sidransky et al, 2009).…”

Section: Earlymentioning

confidence: 79%

Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

Liu

2020

Front. Aging Neurosci.

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Parkinson's disease (PD) is the second most common neurodegenerative disease in the elder population, pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While the precise mechanisms underlying the pathogenesis of PD remain unknown, various genetic factors have been proved to be associated with PD. To date, at least 23 loci and 19 disease-causing genes for PD have been identified. Although monogenic (often familial) cases account for less than 5% of all PD patients, exploring the phenotypes of monogenic PD can help us understand the disease pathogenesis and progression. Primary motor symptoms are important for PD diagnosis but only detectable at a relatively late stage. Despite typical motor symptoms, various non-motor symptoms (NMS) including sensory complaints, mental disorders, autonomic dysfunction, and sleep disturbances also have negative impacts on the quality of life in PD patients and pose major challenges for disease management. NMS is common in all stages of the PD course. NMS can occur long before the onset of PD motor symptoms or can present in the middle or late stage of the disease accompanied by motor symptoms. Therefore, the profiling and characterization of NMS in monogenic PD may help the diagnosis and differential diagnosis of PD, which thereby can execute early intervention to delay the disease progression. In this review, we summarize the characteristics, clinical phenotypes, especially the NMS of monogenic PD patients carrying mutations of SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and GBA. The clinical implications of this linkage between NMS and PD-related genes are also discussed.

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GBA‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

Cited by 86 publications

References 33 publications

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

GBA-Associated Synucleinopathies: Prime Candidates for Alpha-Synuclein Targeting Compounds

A randomized single and multiple ascending dose study in healthy volunteers of LTI‐291, a centrally penetrant glucocerebrosidase activator

Profiling Non-motor Symptoms in Monogenic Parkinson’s Disease

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