The Analysis Of The Clinical Features And Serum Metabolic Biomarkers Of Prion Disease Patients In Henan Province

BackgroundsPrion disease are a group of rare,rapidly progressive,lethal,and infectious CNS degenerative diseases caused by the deposition of abnormal prion protein(PrP^SC).The main clinical manifestation was rapidly progressive dementia.As a rare disease,diagnostic clinical symptoms were often non-specific at early stage of the disease.Once onset,there was no any effective therap.Thus,increasing attentions had been paid on prion disease both in the field of clinical practice and public health globally.According to the origin of abnormal prion protein,prion disease can be classified as sporadic,genetic and infection-acquired types.The main clinical phenotypes are Creutzfeldt-Jakob disease?CJD?,Gerstmann-Straussler's syndrome?GSS?,fatal insomnia?FI?,Kuru disease.CJD can also be divided into four subtypes:sporadic CJD?sCJD?,variant CJD?vCJD?,genetic CJD?gCJD?and iatrogenic CJD?iCJD?,of which sCJD account for the vast majority.The diagnosis of prion disease in China was almost clinical diagnosis due to difficulty in obtaining brain tissue pathology.Currently the diagnosis was made mainly basing on clinical symptoms such as rapidly progressive dementia with auxiliary examinations including neuroimaging,electroencephalogram,cerebrospinal fluid examination.Due to low incidence,misdiagnosis was common in clinical practice.According to the data from China Center for Disease Control and Prevention,Henan province was a high-incidence area of prion disease in China.Besides many sporadic prion disease cases identified,several genetic prion disease cases or pedigrees have also been reported in Henan.It has been proved that the incidence and clinical manifestations of prion disease were greatly affected by the PRNP gene.Because of the different genetic background,the clinical and genetic features of prion disease patients in China are not very clear.The widely used diagnostic criteria have not been tested in Han Chinese prion disease patients.Clinical findings strongly implied that prion disease presented with great clinical heterogeneity,such as variable clinical manifestations,variable age of onset and disease durations.Although the pathogenesis of prion disease was not fully clear,oxidative stress and metabolic abnormalities have been found played a role in prion disease.This study retrospectively reviewed the cases of prion diseases diagnosed in Henan province in recent years.Thirty-five prion disease cases with detailed clinical,neuroimaging and auxiliary examinations informations were enrolled including 26sCJD cases and 9 cases of genetic prion disease.Because of the difference on clinical manifestations between sporadic prion disease and hereditary prion disease,we studied them separately.In the first part we summarized the clinical manifestations,neuroimaging and other auxiliary examinations of 26 sCJD cases in Henan province and discussed the diagnostic strategies in sCJD.In the second part we analyzed the clinical and genetic features of 9 genetic prion disease cases and explored the diagnostic pathway of genetic prion diseases under the unique genetic background of Chinese Han population.The third part aimed at the clinical heterogeneity of prion disease.We examined the serum biomarkers on oxidative stress and lipid metabolism to explore possible disease modifying factors of prion disease.Part I:Analysis of the clinical and auxiliary examinations in26 sporadic CJD patientsObjectiveTo summarize the clinical manifestations of 26 sporadic CJD?sCJD?patients and the contributions of brain magnetic resonance imaging?MR?,cerebrospinal fluid14-3-3 protein,electroencephalogram?EEG?in the diagnosis.The diagnostic difficulties and strategies were discussed.MethodsAll 26 sCJD patients received brain MR scan,CSF protein 14-3-3 detection,EEG and PRNP gene screening.The initial or onset symptoms,clinical manifestations,diagnostic process,treatment and prognosis were summarized.The characteristics and distributions of abnormal brain MR signals were analyzed.The positive rates of CSF 14-3-3 protein and EEG periodical sharp slow complex wave?PSWC?were calculated.Results1.The onset symptoms of sCJD patients in this study were mainly rapidly progressive dementia,visual impairment and cerebellar ataxia.A small portion of patients presented non-specific onset symptoms such as mental and emotional abnormalities and dizziness.No patient presented myoclonus at onset.Non-specific symptoms at onset easily lead to delayed diagnosis.2.At the time of diagnosis,the incidence of myoclonus and akinetic mutism of the core clinical symptoms were relatively low?<50%?,suggesting myoclonus and akinetic mutism were not sensitive in the early diagnosis of sCJD in China.3.For auxiliary examinations,the positive rate of the typical brain MR abnormalities was 96%.The positive rate of 14-3-3 protein in cerebrospinal fluid?CSF?was 64%.And the positive rate of typical PSWC on EEG was 50%.Brain MR was the most valuable examination in diagnosis.4.On brain MR,the DWI sequences showed the highest sensitivity?96%?.Two major lesion patterns were identified:isolated cortex involvement and cortex/basal ganglia involvement?each accounted for about 50%?.The newly defined"cortical pseudo-hypertrophy"on T2WI phase was positive in 27%of the patients.ConclusionThe onset symptoms were nonspecific in few sCJD patients.The sensitivity of some core clinical symptoms in the late stage was low.The clinical manifestations with cranial MR are critical to diagnosis.Part II Analysis of the clinical and genetic features in 9 patients of genetic prion diseaseObjectiveThe genetic background of human prion protein gene?PRNP?differ among ethic groups.The common mutation sites and clinical phenotypes were largely different.Clinical manifestations of Chinese genetic prion disease patients may be distinct.In this part,we analyzed the clinical and genetic features in 9 patients of genetic prion disease in Henan Province.MethodsNine genetic prion disease patients were all found to harbor pathogenic PRNP mutations by genetic sequencing.We conducted a retrospective review of the clinical features and other auxiliary examinations including brain MR,EEG,14-3-3 protein,polysomnography.These were compared with patients with sporadic prion disease.And finally we explored the diagnostic suggestions of genetic prion disease patients under the unique genetic background of Chinese Han population.Results1.The D178 N,E200K and V180 I mutations were found in patients with genetic prion disease in Henan,with D178 N being the most common.Four of the nine cases reported a positive family history.The clinical phenotypes were CJD and FFI,but no GSS found.2.Unlike the European and American populations,the clinical phenotypes of D178N-129M/M mutations in this group were CJD and FFI.In the Chinese Han population,it was not the 129 amino acid polymorphism that determined the clinical phenotype of D178 N mutation.3.We found for the first time that two D178 N patients presenting with typical CJD and FTD imaging features on brain MR,respectively.4.The positive rates of brain MR,electroencephalogram and CSF 14-3-3 protein were 33%,22% and 11% in this group of genetic prion disease,which were lower than that in the s CJD group.ConclusionThe hot spot mutation site of PRNP gene in Henan area was D178 N.The clinical phenotypes of D178 N mutation were largely different from that in European and American populations.Because of the atypical clinical manifestations and low positive rate of auxiliary examinations,genetic testing was strongly recommended.Part III The significance of serum metabolic biomarkers in prion diseaseObjectivePrion disease presented with significant clinical heterogeneity.Besides the genetic background,there may be other protective or risk factors involved.Abnormal oxidative stress and lipid metabolism were not only considered as important pathogenic mechanism,but also possible disease modifying factors.In this part,we examined the related serum biomarkers on oxidative stress and lipid metabolism in prion disease patients to explore possible disease modifying factors.MethodsWe enrolled 26 prion disease patients as the disease group and 29 age,sex matched healthy ones as control group.The serum metabolic markers were analyzed.All patients completed serum uric acid?UA?,total cholesterol?CHOL?,triglyceride?TG?,high-density lipoprotein?HDL?,low density lipoprotein?LDL?,apolipoprotein A1?Apo A1?examinations.The serum UA and lipid levels were compared between the prion disease group and the control group.The analysis of its impact on the age of onset and survival was conducted.ResultsThe serum UA and LDL/HDL levels in prion disease patients were significantly lower than that in controls?UA:207.3±72.4 ?mol/L VS 269.0±88.9?mol/L,P<0.01;LDL/HDL:1.9±0.8 VS 2.4±0.8,P<0.01?.Patients with lower uric acid levels had earlier age of onset.Serum UA and LDL/HDL were not correlated with the survival period.ConclusionsLow serum uric acid and LDL/HDL were susceptible and modifying factors for prion disease.Oxidative stress and abnormal lipid metabolism may be involved in the pathogenesis of prion disease.