The Study Of Natural History And Level Of Alpha-Synuclein In Plasma And Analysis Of The SNCA Gene Polymorphism In Patients With Multiple System Atrophy

BackgroundMultiple system atrophy(MSA) is a rare late onset neurodegenerative disorder which presents with auromonic failure and a complicated motor syndrome including atypical parkinsonism and ataxia.The definite MSA requires profuse numbers of distinctive glial cytoplasmic inclusions formed by fibrillized alpha-synuclein.MSA was defined three categories by original criteria,striatonigral degeneration (SND),sporadic olivopontocerebellar atrophy(sOPCA) and Shy-Drager syndrome. The second consensus on diagnosis in2008defined two subtypes,MSA with predominant parkinsomism(MSA-P) and MSA with predominant cerebellar ataxia(MSA-C) by Gilman et al.Mean age at disease onset was60years.There was no significant difference between genders.According studies from the European MSA Study Group (EMSA-SG),68%of patients were classified as parkinsonian type(MSA-P) and32%as cerebellar type(MSA-C).In contrast, a predominance of MSA-C cases(83.8%) compared to MSA-P(16.2%) was noted in Japan.The etiopathogenesis of MSA is complex,and many genetic as well as environmental factors are involved.The normal function of alpha-synuclein has been quite elusive,but there is significant association with Parkinson disease, dementia with Lewy bodies,and multiple system atrophy.El-Agnaf et al documented that neuronal cells normally secrete alpha-synulein and this protein is detectable in CSF and plasma.Lee et al found that the alpha-synuclein level was significantly elevated in patients with PD and in those with MSA diagnosed by Quinn Criteria, and that the level was higher in patients with PD than in those with MSA.And little is known about the prevalence and the level of plasma alpha-synclein in patients with multiple system atrophy in China. Moreover,many studies about MSA were diagnosed according to the previous criteria.Thus,it is needed to recruit MSA patients diagnosed by the new criteria to enhance assessments of this disease. Scholz et al demonstrated that genetic variants within the SNCA locus are associated with increased risk for development of MSA in Caucasian individuals by a genome-wide association study in2009.And the most associated SNPs are rs11931074and rs3857059.In contrast, a recent South Korean study failed to identify an association with the previously identified risk variants among clinically diagnosed MSA patients.This observation suggests there is population heterogeneity at the SNCA locus. Until now, there are no relevant reports in mainland China.Thus, study of natural history of patients with MSA according to the new criteria and further study of level of alpha-synuclein in plasma and heterogeneity at the SNCA locus among patients with MSA in China are needed.Objective1、According to the new criteria for diagnosis of MSA,we analyzed the data of previously diagnosed MSA patients to understand the epidemiological characteristics among Chinese patients;2、We measured the plasma alpha-synuclein concentration in patients with MSA and controls to study the value of plasma alpha-synuclein in MSA;3、Our study was to identify the previously reported risk variants of SNCA gene in patients with MSA in China;Method1、We selected the data of previously diagnosed MSA patients, one hundred and seven subjects during February,2002to February2011in First Hospital, Second Hospital and Third Hospital affiliated Xiangya Medical School Central South University were studied retrospectively about clinical features according to the new diagnostic criteria for MSA;2、We enrolled64patients with MSA diagnosed according to the new diagnostic criteria and65healthy controls who are free of disease.After informed consent was obtained, a blood sample was drawn.And the plasma alpha-synuclein level was determined using enzyme-linked immunosorbent assay kit.3、we analyzed rs11931074and rs3857059of SNCA gene for82MSA and100normal control by PCR,6%polyacrylamide gel and DNA sequencing.Result1、We retrospectively reviewed the medical records and clinical features of107patients with suspected MSA who were then evaluated based on the new criteria on the diagnosis of MSA. Sixteen patients unfulfilled the criteria were excluded, and9patients were lost to follow up. And82patients met the new criteria, consisting of59males and23females(M:F=2.57:1).There were more MSA-C patients(65.85%) than MSA-P patients(34.15%).The mean age at onset was52.96±7.00(33～68) years. The initial symptoms of58patients were cerebellar ataxia or parkinsonism.14patients presented with autonomic dysfunction. Interestingly,10patients met the new criteria after follow-up with a chief complaint of fatigue but without motor or autonomic symptoms at onset.Sleep disturbance and sexual function were more frequent in MSA patients.In contrast, syncope, rest tremor and pyramidal signs were less in our study.In addition,disease duration showed positive correlations with the scores of UMSARS(Ⅰ、Ⅱ、Ⅳ).And the scores of Montreal Cognitive Assessment (MoCA)Beijing Version in MSA were significantly low compared with the patients with PD and controls. 2、The alpha-synuclein level in plasma was significantly elevated in patients with MSA compared with the level of controls,and there was significantly negative correlations between the level of alpha-synuclein and scores of UMSARS-II.No difference was found in plasma alpha-synuclein concentration between MSA-P and MSA-C.3、We failed to identify the differences of allele frequency and genotype frequency in rs11931074and rs3857059of SNCA gene between our patients with MSA and controls.Conclusions1、According to new diagnostic criteria for MSA in2008, we further perfect the epidemiological data in patients with MSA,the characteristics among Chinese MSA patients may be different from that of Europe and Japan.2、Plasma alpha-synuclein concentration in patients with MSA was measured for the first time in China.The study showed increased plasma alpha-synuclein levels in patients with MSA and provide clinical evidence of a role of plasma alpha-synuclein in the diagnosis and evaluation of MSA.3、There is no obvious association between SNP rs11931074and rs3857059on SNCA with multiple system atrophy in Chinese.They may not be the genetic risk factors of multiple system atrophy in Chinese.