Clinical Features And Gene Analysis In Chinese Patients With Isolate Early-Onset Parkinsonism

Background:Parkinson's disease(PD) is a neurodegenerative disorder and usually affect people in mid and late life.The prevalence of PD is estimated at 1%in people over 60 years of age.It is rare before age 50 years.Aproximately 5 to 10%of cases have an onset below age 50,they are generally referred as early-onset parkinsonism.The symptom of EOP is similar to idiopathic PD,the abroad study disclosed,however there are several characteristics that seem to cluster together in early-onset presentations of the disease.For example,younger onset age(onset age after 50 years),a longer disease duration,a slower disease progression,more patients with EOP having earlier motor complications, less cognitive decline and a good response to small doses of levodopa.But the big sample studies about analysis of the clinical characteristics of patients with EOP are fewer on domestic.EOP is commonly familial aggregation and closely correlation with parkin gene mutation,The frequency of parkin gene mutation is estimated at 1.33%～66.7%among EOP and 1.75%～21%among isolated EOP on domestic and abroad studies.On domestic,Guo Jifeng applied semiquantitative PCR to detect parkin gene mutation in the isolate EOP from mainland and reported that the frequency was 6.6%.LI Jing using the Denaturing high pressure liquid chromatography to screen the parkin gene mutation also in isolate case and reported that the frequency is 8.5%.Although the spectrum of parkin mutation is extensive,the mutation can be divied into two type of mutation——small sequence changes and exon rearrangement.The latter are,in the heterozygous state,only identifiable by the nucleic acid quantification technology.Thus,the mutation rate is also dependent on the screening methods employed.At present the real-time PCR method is becoming the new gold standard method for nucleic acid quantification.For accurately and overall detection the parkin gene mutation,we applied the real-time PCR and DNA direct sequencing to screened the mutation in parkin gene among ethnic Chinese patients with EOP.Objective:To learn the clinical characteristics and the mutation characteristics of parkin gene in ethnic Chinese patients with EOP.Methods:The clinical characteristics of 156 EOP patients collected by our group were reviewered retrospectively,which patients were coming from clinic service and hospitalization on xiangya hospital from November in 1997 to December in 2008.The clinical data included gender,onset age,disease duration,clinical symptoms,signs and the effect to madopar and cognitive.Patient evaluations included the Unified Parkinson's Disease Rating Scale,Webster and the Hoehn and Yahr stage.A total of 156 isolated ethnic Chinese patients with EOP screened for mutation in all exons of parkin by DNA direct sequencing and SYBR GreenⅠReal-time PCR.Based on the results,we discussed the PARK2 phenotype-genotype relationship.Results:107 male and 49 female patients were investigated in this study.The onset of EOP ranged from 13 to 50 years with the average of 40.23±7.40 years old.The course of disease persisted from 1 to 23 with the average of 4.79±3.78 years.The cases in this study had the following characteristics:1,initial symptom progressed slowly and showed asymmetry symptoms(76.9%);2,The observed initial symptoms in patients with EOP,the resting tremor(48.7%) is most frequent and the bradykinesia(39.7%) followed;3,The observed cardinal symptoms in patients with EOP,the rest tremor,bradykinesia,rigidity,gait abnormal and the symptoms benefit from sleep were present in 91.7%,96.8%,94.2%,89.1%and 50%,respectively;4,Brain CT and MRI were often normal;5,Response to levodopa was good.A total of 156 isolated EOP patients were screened for mutation in the parkin gene using real-time PCR combinded with DNA direct sequencing.We identified parkin mutations in 19 patients.A single heterozygous mutation,compound mutation and homozygous mutation were found in 15,1 and 2 patients.1 patient can't identify the mutation state.Seventeen parkin gene rearrangement mutation(12 exon deletions and 5 exon duplications) and three small sequence mutation (IVS9+18C＞T,c.202-203delAG and c.813delT) were identified.The c.813de1T is novel mutation.23 of 38 homologous chromosomes(19 patients) were affected.Between exon 1 and 7 of the parkin gene on the 20 of 23 homologous chromosomes were affected in some extent.The parkin case and without parkin mutation case show no different on initial symptom,cardinal symptoms and disease condition.But our patient withparkin disease showed a significantly earlier age at onset(P＞0.05) and longer disease duration(P＞0.05) than those without parkin mutation.Conclusions:1,The symptom of isolated EOP is similar to idiopathic PD,however there are several characteristics that seem to cluster together in early-onset presentations of the disease.For exmple,younger onset age,rigidity-akinesia dominance,the symptom is modified on morning and aggravation on the evening,an low rate of dystonia,good response to levodopa.2,The frequencyof parkin gene mutation was 12.18%among on ethnic Chinese patients with isolated EOP.Rearrangement mutation may be predominant type.The exon deletion is main mutation style. Between exon 1 and 7 of the parkin gene are mutational hot spots.3,There were no significant group differences in clinical features of parkin cases and other patients.But our patient with parkin disease showed a significantly earlier age at onset(P＞0.05),longer disease duration(P＞0.05)and slower progression than those without parkin mutation.