Abstract
There is great heterogeneity in both the clinical presentation and rate of disease progression among patients with Parkinson’s disease (PD). This can pose prognostic difficulties in a clinical setting, and a greater understanding of the risk factors that contribute to modify disease course is of clear importance for optimizing patient care and clinical trial design. Genetic variants in SNCA are an established risk factor for PD and are candidates to modify disease presentation and progression. This systematic review aimed to summarize all available primary research reporting the association of SNCA polymorphisms with features of PD. We systematically searched PubMed and Web of Science, from inception to 1 June 2020, for studies evaluating the association of common SNCA variants with age at onset (AAO) or any clinical feature attributed to PD in patients with idiopathic PD. Fifty-eight studies were included in the review that investigated the association between SNCA polymorphisms and a broad range of outcomes, including motor and cognitive impairment, sleep disorders, mental health, hyposmia, or AAO. The most reproducible findings were with the REP1 polymorphism or rs356219 and an earlier AAO, but no clear associations were identified with an SNCA polymorphism and any individual clinical outcome. The results of this comprehensive summary suggest that, while there is evidence that genetic variance in the SNCA region may have a small impact on clinical outcomes in PD, the mechanisms underlying the association of SNCA polymorphisms with PD risk may not be a major factor driving clinical heterogeneity in PD.
Highlights
There is great heterogeneity in both the clinical presentation and the rate of disease progression between patients with Parkinson’s disease (PD)[1,2]
We provide a comprehensive summary of available data regarding the association of SNCA polymorphisms and clinical outcomes or age at onset (AAO) in patients with idiopathic PD
58 studies were identified that analyzed the association of 51 different SNCA polymorphisms with a broad range of outcomes, most commonly addressing AAO or motor impairment that is the core feature of PD, and a broad range of non-motor symptoms, including cognitive impairment, sleep, mental health, and psychosis
Summary
There is great heterogeneity in both the clinical presentation and the rate of disease progression between patients with Parkinson’s disease (PD)[1,2]. A logical first step in seeking genetic modifiers for progression in PD is to examine well-established PD susceptibility genes These include SNCA, the gene encoding the α-synuclein protein that constitutes the major protein component of Lewy bodies (LBs)[4]. In familial cases of PD, specific mutations or copy number variations (CNVs) of SNCA have been shown to cause increased production of α-synuclein and this is correlated with increasing disease severity[6,7] Such mutations and CNVs of SNCA are rare in the general PD population, but candidate gene studies and genome-wide association studies (GWAS) have established the SNCA locus as a risk factor for idiopathic PD8,9 and as a promising candidate for disease modification
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