Wilson’s disease(WD)is an autosomal recessive inherited disorder of hepatic copper metabolism.WD can be present in different clinical conditions,with the most common ones being liver disease and neuropsychiatric dist...Wilson’s disease(WD)is an autosomal recessive inherited disorder of hepatic copper metabolism.WD can be present in different clinical conditions,with the most common ones being liver disease and neuropsychiatric disturbances.Most cases present symptoms at<40years of age.However,few reports exist in the literature on patients in whom the disease presented beyond this age.In this report,we present a case of late onset fulminant WD in a 58-year-old patient in whom the diagnosis was established clinically,by genetic analysis of the ATP7B gene disclosing rare mutations(G1099S and c.1707+3ins T)as well as by high hepatic copper content.We also reviewed the relevant literature.The diagnosis of WD with late onset presentation is easily overlooked.The diagnostic features and the geneticbackground in patients with late onset WD are not different from those in patients with early onset WD,except for the age.Effective treatments for this disorder that can be fatal are available and will prevent or reverse many manifestations if the disease is discovered early.展开更多
In a recent genome-wide association study, the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer＇s disease in Caucasians. Here, we investigated this association in a large North...In a recent genome-wide association study, the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer＇s disease in Caucasians. Here, we investigated this association in a large Northern Han Chinese cohort consisting of 599 sporadic late-onset Alzheimer＇s disease patients and 598 healthy controls matched for sex and age in a Northern Han Chinese population from Qingdao, China. Genotyping by the polymerase chain reaction-ligase detection reaction revealed that there were significant differences in the genotype （P = 0.017） and allele （P = 0.007） frequencies of the rs2072064 polymorphism between late-onset Alzheimer＇s disease patients and controls. The A allele of this polymorphism was significantly associated with a reduced risk of late-onset Alzheimer＇s disease （odds ratio （OR） = 0.792, 95% confidence interval （CI） = 0.670-0.937, P = 0.007）. When the data were stratified by the apolipoprotein E E4 status, there was a significant difference only among apolipoprotein E E4 non-carriers （genotypic P = 0.001, allelic P = 0.001）. Furthermore, the association between rs2072064 and late-onset Alzheimer＇s disease remained significant by logistic regression analysis after adjustment for age, gender, and the apolipoprotein E E4 carrier status （dominant model： OR = 0.787, 95% CI = 0.619-1.000, P = 0.050; recessive model： OR = 0.655, 95% CI = 0.448-0.959, P= 0.030; additive model： OR = 0.792, 95% CI = 0.661-0.950, P = 0.012）. These findings suggest that SLC26A4 is a susceptibility gene for late-onset Alzheimer＇s disease in a Northern Han Chinese population from the Qingdao area.展开更多
The apolipoprotein E gene ε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer＇s disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype ap...The apolipoprotein E gene ε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer＇s disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype apolipoprotein E gene polymorphisms. Genomic DNA from mouth swab specimens was extracted using magnetic nanoparticles, and genotyping was performed by real-time PCR using TaqMan-BHQ probes. Genotyping accuracy was validated by DNA se- quencing. Our results demonstrate 100% correlation to DNA sequencing, indicating reliability of our protocol. Thus, the method we have developed for apolipoprotein E genotyping is accurate and reliable, and also suitable for genotyping large samples, which may help determine the role of the apolipoprotein E ε4 allele in neural regeneration in late-onset Alzheimer＇s disease cases.展开更多
Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel m...Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel missense mutation,APP E674Q(also named“Shanghai APP”),was detected in a Chinese index patient with typical late-onset AD(LOAD)who developed memory decline in his mid-70s.The results from neuroimaging were consistent with AD,where widespread amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-secretase cleavage site and the well-studied Swedish APP mutation(KM670/671NL),which was predicted to be pathogenic in silico.Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1.The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ.Furthermore,we applied an adeno-associated virus(AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice.AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain,implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation.Collectively,we report a strong amyloidogenic effect of the E674Q substitution in AD.To our knowledge,E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.展开更多
Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individu...Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individuals that are diagnosed with early-onset Alzheimer’s disease. It is understood that these individuals see faster effects of the disease and die considerably sooner, but it is not understood why. This review compares the early-onset (EOAD) and late-onset (LOAD) types to try and determine some of the most blaring differences between the two. The genetic basis linking EOAD and LOAD has been the apolipoprotein E gene (APOE) to indicate metabolic alteration with the ε4 allele specifically. The topographical atrophy disparities between EOAD and LOAD supported the more noticeable cognitive differences between the two Alzheimer’s disease categories. The faster and wider spread atrophy of EOAD patients correlates with the difficulty they experience with attention, language, visuo-spatial, and executive functions. Finally, brain metabolism differs between both AD subtypes as well, where EOAD indicates the wide spread damage and metabolic breakdown across more diverse regions of the brain.展开更多
In 2002,the National Kidney Foundation Kidney Disease Outcomes Quality Initiative(NKF KDOQI)instituted new guidelines that established a novel chronic kidney disease(CKD)staging paradigm.This set of guidelines,since u...In 2002,the National Kidney Foundation Kidney Disease Outcomes Quality Initiative(NKF KDOQI)instituted new guidelines that established a novel chronic kidney disease(CKD)staging paradigm.This set of guidelines,since updated,is now very widely accepted around the world.Nevertheless,the authoritative United States Preventative Task Force had in August 2012acknowledged that we know surprisingly little about whether screening adults with no signs or symptoms of CKD improve health outcomes and that we deserve better information on CKD.More recently,the American Society of Nephrology and the American College of Physicians,two very well respected United States professional physician organizations were strongly at odds coming out with exactly opposite recommendations regarding the need or otherwise for"CKD screening"among the asymptomatic population.In this review,we revisit the various angles and perspectives of these conflicting arguments,raise unanswered questionsregarding the validity and veracity of the NKF KDOQI CKD staging model,and raise even more questions about the soundness of its evidence-base.We show clinical evidence,from a Mayo Clinic Health System Renal Unit in Northwestern Wisconsin,United States,of the pitfalls of the current CKD staging model,show the inexactitude and unpredictable vagaries of current CKD prediction models and call for a more cautious and guarded application of CKD staging paradigms in clinical practice.The impacts of acute kidney injury on CKD initiation and CKD propagation and progression,the effects of such phenomenon as the syndrome of late onset renal failure from angiotensin blockade and the syndrome of rapid onset end stage renal disease on CKD initiation,CKD propagation and CKD progression to end stage renal disease all demand further study and analysis.Yet more research on CKD staging,CKD prognostication and CKD predictions are warranted.Finally and most importantly,cognizant of the very serious limitations and drawbacks of the NKF K/DOQI CKD staging model,the need to individualize CKD care,both in terms of patient care and prognostication,cannot be overemphasized.展开更多
目的评估睾酮替代治疗(TRT)对迟发性性腺功能减退(LOH)患者前列腺病变的影响。方法计算机检索中国知网(CNKI)、万方、PubMed、Embase、Cochrane library、Web of science等数据库,搜索建库至2021年6月发表的TRT对LOH患者前列腺相关疾病...目的评估睾酮替代治疗(TRT)对迟发性性腺功能减退(LOH)患者前列腺病变的影响。方法计算机检索中国知网(CNKI)、万方、PubMed、Embase、Cochrane library、Web of science等数据库,搜索建库至2021年6月发表的TRT对LOH患者前列腺相关疾病影响的随机对照试验(RCT)。由2名研究者按照纳入与排除标准确定最终纳入文献,获取纳入文献的资料并进行质量评价后,采用RevMan5.3软件进行Meta分析。结果共纳入10篇RCT,共1981例患者。Meta分析结果显示,无论干预时程≥12个月或<12个月,睾酮剂型为睾酮、十一酸睾酮或庚酸睾酮,给药方式为肌注、经皮或口服,剂量为≥100mg或<100mg,睾酮组与对照组前列腺癌、前列腺活检、前列腺结节比较,差异无统计学意义(P>0.05);干预时程<12个月、睾酮剂型为睾酮,以及给药方式为经皮,睾酮组与对照组前列腺特异性抗原水平的变化比较,差异具有统计学意义(P<0.001)。结论TRT会导致前列腺特异性抗原水平的升高,但无法证明会增加LOH患者前列腺病变的发生、发展风险。展开更多
Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,espe...Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding regions.The aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant carriers.Methods:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 controls.Variants at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test.We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD patients.Results:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with PD.Genotype phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous dysfunctions.Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype,which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.展开更多
文摘Wilson’s disease(WD)is an autosomal recessive inherited disorder of hepatic copper metabolism.WD can be present in different clinical conditions,with the most common ones being liver disease and neuropsychiatric disturbances.Most cases present symptoms at<40years of age.However,few reports exist in the literature on patients in whom the disease presented beyond this age.In this report,we present a case of late onset fulminant WD in a 58-year-old patient in whom the diagnosis was established clinically,by genetic analysis of the ATP7B gene disclosing rare mutations(G1099S and c.1707+3ins T)as well as by high hepatic copper content.We also reviewed the relevant literature.The diagnosis of WD with late onset presentation is easily overlooked.The diagnostic features and the geneticbackground in patients with late onset WD are not different from those in patients with early onset WD,except for the age.Effective treatments for this disorder that can be fatal are available and will prevent or reverse many manifestations if the disease is discovered early.
文摘In a recent genome-wide association study, the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer＇s disease in Caucasians. Here, we investigated this association in a large Northern Han Chinese cohort consisting of 599 sporadic late-onset Alzheimer＇s disease patients and 598 healthy controls matched for sex and age in a Northern Han Chinese population from Qingdao, China. Genotyping by the polymerase chain reaction-ligase detection reaction revealed that there were significant differences in the genotype （P = 0.017） and allele （P = 0.007） frequencies of the rs2072064 polymorphism between late-onset Alzheimer＇s disease patients and controls. The A allele of this polymorphism was significantly associated with a reduced risk of late-onset Alzheimer＇s disease （odds ratio （OR） = 0.792, 95% confidence interval （CI） = 0.670-0.937, P = 0.007）. When the data were stratified by the apolipoprotein E E4 status, there was a significant difference only among apolipoprotein E E4 non-carriers （genotypic P = 0.001, allelic P = 0.001）. Furthermore, the association between rs2072064 and late-onset Alzheimer＇s disease remained significant by logistic regression analysis after adjustment for age, gender, and the apolipoprotein E E4 carrier status （dominant model： OR = 0.787, 95% CI = 0.619-1.000, P = 0.050; recessive model： OR = 0.655, 95% CI = 0.448-0.959, P= 0.030; additive model： OR = 0.792, 95% CI = 0.661-0.950, P = 0.012）. These findings suggest that SLC26A4 is a susceptibility gene for late-onset Alzheimer＇s disease in a Northern Han Chinese population from the Qingdao area.
基金supported by two grants from Science,Industry,Trade and Information Technology Commission of Shenzhen Municipality in China,grant No.201002063,JC20110518075 7A
文摘The apolipoprotein E gene ε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer＇s disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype apolipoprotein E gene polymorphisms. Genomic DNA from mouth swab specimens was extracted using magnetic nanoparticles, and genotyping was performed by real-time PCR using TaqMan-BHQ probes. Genotyping accuracy was validated by DNA se- quencing. Our results demonstrate 100% correlation to DNA sequencing, indicating reliability of our protocol. Thus, the method we have developed for apolipoprotein E genotyping is accurate and reliable, and also suitable for genotyping large samples, which may help determine the role of the apolipoprotein E ε4 allele in neural regeneration in late-onset Alzheimer＇s disease cases.
基金supported by grants from the Ministry of Science and Technology of the People's Republic of China(No.2021ZD020180)the Natural Science Foundation of China(No.81971068,81922021,81773635,82073765).
文摘Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel missense mutation,APP E674Q(also named“Shanghai APP”),was detected in a Chinese index patient with typical late-onset AD(LOAD)who developed memory decline in his mid-70s.The results from neuroimaging were consistent with AD,where widespread amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-secretase cleavage site and the well-studied Swedish APP mutation(KM670/671NL),which was predicted to be pathogenic in silico.Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1.The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ.Furthermore,we applied an adeno-associated virus(AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice.AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain,implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation.Collectively,we report a strong amyloidogenic effect of the E674Q substitution in AD.To our knowledge,E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.
文摘Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individuals that are diagnosed with early-onset Alzheimer’s disease. It is understood that these individuals see faster effects of the disease and die considerably sooner, but it is not understood why. This review compares the early-onset (EOAD) and late-onset (LOAD) types to try and determine some of the most blaring differences between the two. The genetic basis linking EOAD and LOAD has been the apolipoprotein E gene (APOE) to indicate metabolic alteration with the ε4 allele specifically. The topographical atrophy disparities between EOAD and LOAD supported the more noticeable cognitive differences between the two Alzheimer’s disease categories. The faster and wider spread atrophy of EOAD patients correlates with the difficulty they experience with attention, language, visuo-spatial, and executive functions. Finally, brain metabolism differs between both AD subtypes as well, where EOAD indicates the wide spread damage and metabolic breakdown across more diverse regions of the brain.
文摘In 2002,the National Kidney Foundation Kidney Disease Outcomes Quality Initiative(NKF KDOQI)instituted new guidelines that established a novel chronic kidney disease(CKD)staging paradigm.This set of guidelines,since updated,is now very widely accepted around the world.Nevertheless,the authoritative United States Preventative Task Force had in August 2012acknowledged that we know surprisingly little about whether screening adults with no signs or symptoms of CKD improve health outcomes and that we deserve better information on CKD.More recently,the American Society of Nephrology and the American College of Physicians,two very well respected United States professional physician organizations were strongly at odds coming out with exactly opposite recommendations regarding the need or otherwise for"CKD screening"among the asymptomatic population.In this review,we revisit the various angles and perspectives of these conflicting arguments,raise unanswered questionsregarding the validity and veracity of the NKF KDOQI CKD staging model,and raise even more questions about the soundness of its evidence-base.We show clinical evidence,from a Mayo Clinic Health System Renal Unit in Northwestern Wisconsin,United States,of the pitfalls of the current CKD staging model,show the inexactitude and unpredictable vagaries of current CKD prediction models and call for a more cautious and guarded application of CKD staging paradigms in clinical practice.The impacts of acute kidney injury on CKD initiation and CKD propagation and progression,the effects of such phenomenon as the syndrome of late onset renal failure from angiotensin blockade and the syndrome of rapid onset end stage renal disease on CKD initiation,CKD propagation and CKD progression to end stage renal disease all demand further study and analysis.Yet more research on CKD staging,CKD prognostication and CKD predictions are warranted.Finally and most importantly,cognizant of the very serious limitations and drawbacks of the NKF K/DOQI CKD staging model,the need to individualize CKD care,both in terms of patient care and prognostication,cannot be overemphasized.
文摘目的评估睾酮替代治疗(TRT)对迟发性性腺功能减退(LOH)患者前列腺病变的影响。方法计算机检索中国知网(CNKI)、万方、PubMed、Embase、Cochrane library、Web of science等数据库,搜索建库至2021年6月发表的TRT对LOH患者前列腺相关疾病影响的随机对照试验(RCT)。由2名研究者按照纳入与排除标准确定最终纳入文献,获取纳入文献的资料并进行质量评价后,采用RevMan5.3软件进行Meta分析。结果共纳入10篇RCT,共1981例患者。Meta分析结果显示,无论干预时程≥12个月或<12个月,睾酮剂型为睾酮、十一酸睾酮或庚酸睾酮,给药方式为肌注、经皮或口服,剂量为≥100mg或<100mg,睾酮组与对照组前列腺癌、前列腺活检、前列腺结节比较,差异无统计学意义(P>0.05);干预时程<12个月、睾酮剂型为睾酮,以及给药方式为经皮,睾酮组与对照组前列腺特异性抗原水平的变化比较,差异具有统计学意义(P<0.001)。结论TRT会导致前列腺特异性抗原水平的升高,但无法证明会增加LOH患者前列腺病变的发生、发展风险。
基金This study was supported by the National Key Research and Development Program of China(2016YFC1306000,2017YFC0909100,2018YFC1312000,and 2016YFC1306501)to GJ.F,T.B.S and Y.X.X,the Central Public-Interest Scientific Institution Basal Research Fund of Chinese Academy of Medical Sciences(2018-12 M-HL-025)+3 种基金to GJ.F,the National Natural Science Foundation of China(81873785,81974202)to GJ.F and T.B.S,and Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030)to GJ.F,the innovative team program from Department of Sci-ence&Technology of Hunan Province(2019RS1010)to GJ.F,and the Innovation-driven Team Project from Central South University(2020CX016)to GJ.F.
文摘Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding regions.The aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant carriers.Methods:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 controls.Variants at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test.We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD patients.Results:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with PD.Genotype phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous dysfunctions.Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype,which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.
