Neurologists rarely perform genetic testing for Parkinson's disease. Evidence suggests that many patients with major genetic variants go undiagnosed

2021 ◽  
Author(s):  
Moataz Dowaidar

This review addresses the past and current states of genetic testing for Parkinson's disease based on the available data. In short, neurologists rarely perform genetic testing for Parkinson's disease, and evidence suggests that many patients with major genetic variants go undiagnosed. For patients, caregivers, and families, we looked into the various clinical and personal applications of genetic information. Consumer interest and demand for genetic testing in general, and for Parkinson's disease in particular, is increasing. Furthermore, researchers now have a better understanding of the genetic phenotypes of Parkinson's disease; there is more access to free or low-cost genetic testing and counseling; and patients with specific PD genetic variants can now participate in interventional clinical trials. All of these developments highlight the importance of expanding genetic testing for Parkinson's disease. By addressing perceived barriers and providing practical information and resources, we hope to increase clinician comfort and confidence, allowing them to offer more PD genetic testing in their practices. We can provide tailored information specific to the patient by entering the realm of personalized medicine, which, as other specialties have done, may result in improvements in clinical practice, care, and outcomes. Expanding PD genetic testing, on the other hand, will necessitate the collaboration of a group of medical experts and key stakeholders, particularly genetic counselors, who are already experts at guiding patients through complex genetic information and, more importantly, in the context of their psychological states.

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Muhammad Aslam ◽  
Nirosiya Kandasamy ◽  
Anwar Ullah ◽  
Nagarajan Paramasivam ◽  
Mehmet Ali Öztürk ◽  
...  

AbstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.


2016 ◽  
Vol 365 ◽  
pp. 175-180 ◽  
Author(s):  
Erica Cassani ◽  
Roberto Cilia ◽  
Janeth Laguna ◽  
Michela Barichella ◽  
Manuela Contin ◽  
...  

Author(s):  
Domenico Buongiorno ◽  
Gianpaolo Francesco Trotta ◽  
Ilaria Bortone ◽  
Nicola Di Gioia ◽  
Felice Avitto ◽  
...  

2019 ◽  
Vol 75 ◽  
pp. 224.e9-224.e15 ◽  
Author(s):  
Jinyoung Youn ◽  
Chung Lee ◽  
Eungseok Oh ◽  
Jinse Park ◽  
Ji Sun Kim ◽  
...  

2021 ◽  
Vol 44 (1) ◽  
pp. 87-108
Author(s):  
Gabriel E. Vázquez-Vélez ◽  
Huda Y. Zoghbi

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by degeneration of the substantia nigra pars compacta and by accumulation of α-synuclein in Lewy bodies. PD is caused by a combination of environmental factors and genetic variants. These variants range from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk. Here, we review what is known about the genetics of PD. We also describe how PD genetics have solidified the role of endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology. Finally, we highlight how all three pathways are affected by α-synuclein and how this knowledge may be harnessed for the development of disease-modifying therapeutics.


2015 ◽  
Vol 1 ◽  
pp. 205520761559299 ◽  
Author(s):  
E Ray Dorsey ◽  
Kristin C Darwin ◽  
Samara Mohammed ◽  
Sean Donohue ◽  
Alyssa Tethal ◽  
...  

2020 ◽  
Vol 10 (11) ◽  
pp. 783
Author(s):  
Yih-Ru Wu ◽  
Chih-Hsin Lin ◽  
Chih-Ying Chao ◽  
Chia-Wen Chang ◽  
Chiung-Mei Chen ◽  
...  

Sequence variants in vacuolar protein sorting 35 (VPS35) have been reported to be associated with Parkinson’s disease (PD). To investigate if the genetic variants in VPS35 contribute to Taiwanese PD, VPS35 cDNA fragments from 62 patients with PD were sequenced. A cohort of PD (n = 560) and ethnically matched controls (n = 506) were further examined for the identified mutation. The effects of the mutation on cation-independent mannose-6-phosphate receptor (CI-MPR) sorting and mitochondrial morphology were further examined in 293T cells expressing the mutant VPS35. Here, a novel heterozygous A320V in the VPS35 gene was identified in two late-onset PD (LOPD) patients, which was absent in 506 normal controls. Expression of the A320V mutant in 293T cells demonstrated increased colocalization of VPS35 with CI-MPR and decreased CI-MPR and lysosomal-associated membrane protein 2 (LAMP2) levels. Decreased CI-MPR manifested in missorting of cathepsin D and decreased proteolysis of α-synuclein. A320V mutation also increased mitochondrial E3 ubiquitin protein ligase 1 (MUL1) and thus led to mitofusin 2 (MFN2) degradation. The results suggest that the expression of VPS35 A320V leads to disrupted CI-MPR sorting and impaired mitochondrial morphology, which may partly explain its action in PD.


2020 ◽  
Vol 80 ◽  
pp. 138-141 ◽  
Author(s):  
Letizia Straniero ◽  
Valeria Rimoldi ◽  
Giada Melistaccio ◽  
Alessio Di Fonzo ◽  
Gianni Pezzoli ◽  
...  

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