A30P And A53T Mutations Of The SNCA Gene In α-synucleinopathies

Objective:Several neurodegenerative disorders share with idiopathicParkinson's disease (IPD)the features of bradykinesia,rigidity,hypokinetic speech,and unsteady gait.As these disorders bear clinical similarity to IPD,they have beentermed Parkinson-plus syndromes.These disorders have clinical and neuropathologicfeatures that are different from those of IPD.Furthermore,some Parkinson-plussyndromes are classified into alpha-synucleinopathy and tauopathy according to themain pathologic changes.The predominant pathologic change inalpha-synucleinopathies isα-synuclein(AS)abnormal aggregation in central nervoussystem.In the present study,detailed clinical investigations and neuroimagingexaminations were performed to explore the clinical features of Parkisnon PlusSyndromes.As the AS plays a key role in pathogenesis of alpha-synucleinopathies,the most common pathogenic mutations in AS gene-A30P and A53T mutations weredetected in the patients with MSA and DLB to determine whether genetic factorscould contribute to mechanism of sporadic alpha-synucleinopathes.Methods:73 IPD patients,68 MSA patients,10 DLB patients,15 PSP patientsand 6 CBD patients from neurology department of Tianjin general hospital wereincruited between January 1,2004 and April 30,2009.All patients were given detailedinvestigation,physical examination,mini-mental status examination and brainCT/MRI examination.Iron deposition in central nervous system was evaluatedamong 21 PD patients with SWI technique.41 patients were performed the 18F-FDGPET imaging.MSA and DLB patients who recruited from March 1 st,2007 to May31 st,2008 were extracted peripheral blood to detect the A30P and A53T mutations inSNCA gene with using polymerase chain reation-restriction fragment lengthpolymorphism(PCR-RFLP).Statistical analysis was performed with SPSS 11.0software.ANOVA was used to compare the measurement data.x~2 test was used tocompare the enumeration data.Results:l.Clinical features:The main clinical features including onset age,unilateral onset,orthostatic hypotension,bladder dysfunction,sleep dysfunction, cerebellar symptoms,cognitive impairment,rest tremor,postural tremor,rigidity,bradykinesia,postural instability,dystonia,alien limb phenomena,hallucination,eyemovement dysfunction,personality change,fall and levodopa response differedsignificantly among the groups(p(?)0.001).The onset age in MSA group waslowest(57.75±7.652 years),while was highest in DLB group(69.40±5.337 years).Allthe patients with PD and CBD were unilateral onset.All the patients with DLB andPSP were bilateral onset on the contrary.The patients with MSA rarely wereunilateral onset(2.9%).The incidence of orthostatic hypotension was highest in MSAgroup(50.0%).The patients with DLB and CBD had no orthostatic hypotension.The incidence of bladder dysfunction was highest in MSA group(67.6%),which was26.7% and 16.7% in PSP and CBD groups respectively.The patients with DLB hadno bladder dysfunction.The incidence of possible REM sleep disorder were high ineach group with the highest incidence in PSP group(93.3%)and the lowest incidencein PD group(41.1%).The incidence of cerebellar symptoms was highest in MSAgroup(61.8%)compared to PD,DLB and CBD groups in which there was no casewith cerebellar symptoms.All the DLB patients had cognitive impairment.Theincidence of cognitive impairment was high in PSP and CBD group either(66.7% and83.3% respectively).The patients with MSA had no cognitive impairment.All the PDpatients had rest tremor.20.0% DLB patients had rest tremor.The patients with PSPand CBD had no rest tremor.All the DLB patients had postural tremor which wascommon in MSA group(86.8%)and rare in PSP group.Rigidity was seen in all PD,DLB and PSP patients.The incidence of rigidity was close between MSA group andCBD group(69.1% and 66.7% respectively).Bradykinesia was seen in all PD,DLBand PSP patients.The incidence of bradykinesia was close between MSA group andCBD group either(67.6% and 66.7% respectively).Dystonia and alien limbphenomena were only seen in CBD patients which incidence was both 66.7%.Hallucination was seen in all DLB patients and rare PSP patients(13.3%),whilewasn't seen in PD,MSA and CBD patients.Eye movement dysfunction was seen inmajority of PSP patients(66.7%)and minority of CBD patients(16.7%).All the CBDpatients had personality change,while majority of the DLB and PSP patients(90.0%and 93.3% respectively)and minority of the PD and MSA patients(13.7% and 14.7% respectively)had.Fall was most prominent in PSP group(93.3%)and rarest in PDgroup(9.6%).The response to levodopa was best in PD group(100.0%),good in DLBgroup(70.0%)and worst in PSP group(6.7%).2.Brain MRI examination:59 MSApatients were given brain MRI examination.Olivopontocerebellar atrophy was seenin 48 patients(81.4%),putaminal hypointensities on T2-weighted images were seen in4 patients(6.8%)and the"hot cross bun"signal in pons was seen in 30patients(50.8%).Hummingbird-like change was seen in midsagittal view of MRI inthree PSP patients (20.0%).All six CBD patients presented asymmetric corticalatrophy especially in frontoparietal areas,and one of them also presented putaminalhypointensities on T2-weighted image.3.Decreased signal intensities were detectedin substantia nigra and basal ganglia areas in IPD patients' SWI.4.Brain 18F-FDGPET imaging:Among 17 MSA patients who were performed 18F-FDG PET imaging,MSA-P patients usually presented low 18F-FDG intake in the subcortical nuclei suchas basal ganglia,while MSA-C patients usually presented low 18F-FDG intake in thecerebellar cortex,low 18F-FDG intake in bilateral occipital lobes and posteriorparietal areas was seen in DLB patients.The PSP patients presented low 18F-FDGintake in bilateral frontal lobes,subcortical structures such as striatum and midbrain.CBD patients presented asymmetric low 18F-FDG intake in frontoparietal area andsubcortical nuclei such as thalamus and putamen,which was more prominent in thecontralateral side to the involved limb.4.Detection of A30P and A53T mutations inSNCA gene:A30P and A53T mutations weren't detected in SNCA gene among thepatients with MSA and DLB.Conclusion:1.Each Parkinsonism plus syndrome has its specific clinical featureswhich attribute to rule it out from either IPD or other Parkinsonism plus syndromes.2.Brain cMRI examination,SWI technique and 18F-PET scan can help to diagnoseand differentiate Parkinsonism plus syndromes.3.A30P and A53T mutations weren'tdetected among Chinese DLB and MSA patients.Race and different etiology andpathogenesis among DLB,MSA and IPD contribute to this negative outcome.