目的分析脑腱黄瘤病的临床特点及CYP27A1基因复合杂合突变家系,旨在提高对该病的认识。方法对我中心2018年收治确诊的1例合并腭肌阵挛的脑腱黄瘤病患者临床资料,以及文献检索的25例中国籍患者的组织病理学及基因学特点进行分析。结果患...目的分析脑腱黄瘤病的临床特点及CYP27A1基因复合杂合突变家系,旨在提高对该病的认识。方法对我中心2018年收治确诊的1例合并腭肌阵挛的脑腱黄瘤病患者临床资料,以及文献检索的25例中国籍患者的组织病理学及基因学特点进行分析。结果患者为20岁女性,总病程12年,白内障12年,行走不稳、构音不清1年,癫痫发作6个月,饮水呛咳5个月。简易精神状态检查(Mini-Mental State Examination,MMSE)评分21分;蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)评分18分。查体:左侧跟腱增粗,高弓足;构音不清;双侧腭肌持续阵挛;辨距不良;双侧掌颏反射阳性,双侧肱二头肌腱反射、膝腱反射亢进,双侧踝阵挛阳性。双侧Babinski征、Chaddock征阳性。头颅MRI显示:双侧脑室旁、双侧底节区、双侧小脑半球对称斑片状T1WI等、低信号,T2WI高信号;DWI呈低信号为主的混杂信号;FLAIR呈高信号;增强扫描未见异常强化;MRS显示病灶区域NNA峰减低,总胆固醇升高。跟腱活检玻璃样变的纤维组织。基因检测发现CYP27A1基因复合杂合变异,分别为5号外显子c.1016C>T(p.Thr339Met)及7号内含子c.1263+1G>A(IVS7-5),美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异评级均为致病性,均为国外已报道位点。结合文献复习该病平均发病年龄为(21.38±12.87)岁,平均确诊时间为(12.58±11.5)年。首发症状以跟腱肿物最多,神经系统表现有小脑性共济失调、锥体束征、癫痫发作、认知障碍、周围神经病变。头颅MRI异常表现多在小脑半球、齿状核、内囊及脑干等。多数可查到CYP27A1基因致病变异,最常见于2号外显子,其次为5号、1号、6号,包括复合杂合突变、纯合突变、缺失突变等。结论脑腱黄瘤病临床罕见,临床表现复杂多样,诊断依靠病理检查及基因检测。展开更多
目的总结肝癌与固醇-27羟化酶(CYP27A1)的关联性研究近况及发展趋势,探讨CYP27A1在肝癌中的治疗作用。方法使用Go PubMed工具搜集文献资料,展开计量分析;基于The Human Protein Atlas数据库获取CYP27A1蛋白在正常肝组织及肝癌组织中的...目的总结肝癌与固醇-27羟化酶(CYP27A1)的关联性研究近况及发展趋势,探讨CYP27A1在肝癌中的治疗作用。方法使用Go PubMed工具搜集文献资料,展开计量分析;基于The Human Protein Atlas数据库获取CYP27A1蛋白在正常肝组织及肝癌组织中的免疫组化表达情况,并依据The Cancer Genome Atlas内RNA-Seq数据集整理绘制CYP27A1高低表达情况在肝癌患者中的生存曲线。结果文献计量分析结果显示,PubMed中共收录相关文献13篇,整理后共得出20个高频研究关键词及主要作者信息、12个顶级期刊收录情况、1份研究地域分布图;免疫组化结果显示,与正常肝组织比较,肝癌组织中的CYP27A1呈现明显的低表达趋势;生存分析结果显示,CYP27A1的高表达有助于改善肝癌患者的预后,提高生存质量。结论二者的关联性研究尚处于起步阶段,CYP27A1可能是肝癌的潜在治疗靶点。展开更多
BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive metabolic disease caused by mutations in CYP27 A1.It has a low incidence rate,insidious onset,and diverse clinical manifestations.It can be e...BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive metabolic disease caused by mutations in CYP27 A1.It has a low incidence rate,insidious onset,and diverse clinical manifestations.It can be easily misdiagnosed and can go unrecognized by clinicians,leading to delayed treatment and worsened patient outcomes.CASE SUMMARY A 38-year-old male was admitted to our hospital with a history of unabating unstable posture and difficulty in walking for more than 30 years.Subsequently based on the patient’s medical history,clinical symptoms,magnetic resonance imaging and gene sequencing results,he was finally diagnosed with CTX.Due to the low incidence rate of the disease,clinicians have insufficient knowledge of it,which makes the diagnosis process more tortuous and prolongs the diagnosis time.CONCLUSION Prompt diagnosis and treatment of CTX improve patient outcomes.展开更多
Bile acids(BAs) are amphipathic molecules important for metabolism of cholesterol,absorption of lipids and lipid soluble vitamins,bile flow,and regulation of gut microbiome.There are over 30 different BA species known...Bile acids(BAs) are amphipathic molecules important for metabolism of cholesterol,absorption of lipids and lipid soluble vitamins,bile flow,and regulation of gut microbiome.There are over 30 different BA species known to exist in humans and mice,which are endogenous modulators of at least 6 different membrane or nuclear receptors.This diversity of ligands and receptors play important roles in health and disease;however,the full functions of each individual BA in vivo remain unclear.We generated a mouse model lacking the initiating enzymes,CYP7 A1 and CYP27 A1,in the two main pathways of BA synthesis.Because females are more susceptible to BA related diseases,such as intrahepatic cholestasis of pregnancy,we expanded this model into female mice.The null mice of Cyp7 a1 and Cyp27 a1 were crossbred to create double knockout(DKO) mice.BA concentrations in female DKO mice had reductions in serum(63%),liver(83%),gallbladder(94%),and small intestine(85%),as compared to WT mice.Despite low BA levels,DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation,synthesis,conjugation,and transport.Additionally,through treatment with a synthetic FXR agonist,GW4064,female DKO mice responded to FXR activation similarly to WT mice.展开更多
BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to consi...BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to considerable diagnostic and treatment delay.CASE SUMMARY A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions,hallucinations,and behavioral disturbance is reported.The patient presented with cholestasis,cataract,Achilles tendon xanthoma,and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood.After the characteristic CTX findings on imaging were obtained,a pathological examination of the Achilles tendon xanthoma was refined.Replacement therapy was then initiated after the diagnosis was clarified by genetic analysis.During hospitalization in the psychiatric ward,the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis.After the patient’s history of CTX was identified,the patient was diagnosed with organic schizophrenia-like disorder,and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication.CONCLUSION Psychiatrists should be aware of CTX,its psychiatric manifestations,and clinical features and avoid misdiagnosis of CTX for timely intervention.展开更多
目的探讨槲皮素对高脂膳食诱导的载脂蛋白E敲除(apolipoprotein E knockout,ApoE KO)小鼠动脉粥样硬化(atherosclerosis,AS)的保护效应及其对巨噬细胞胆固醇稳态的调控作用机制。方法雌性成年ApoE KO小鼠45只随机分为3组:普通饲料组、...目的探讨槲皮素对高脂膳食诱导的载脂蛋白E敲除(apolipoprotein E knockout,ApoE KO)小鼠动脉粥样硬化(atherosclerosis,AS)的保护效应及其对巨噬细胞胆固醇稳态的调控作用机制。方法雌性成年ApoE KO小鼠45只随机分为3组:普通饲料组、高脂饲料组、高脂饲料+槲皮素组,持续喂养16周。检测血脂水平、主动脉斑块形成情况及胆固醇稳态调控相关基因表达水平。建立RAW264.7巨噬细胞泡沫化模型并进行槲皮素干预,检测巨噬细胞胆固醇蓄积情况及胆固醇稳态调控相关蛋白表达水平。结果槲皮素可有效改善ApoE KO小鼠AS斑块损伤并降低其血脂水平;通过上调巨噬细胞CYP27A1表达,抑制CD36介导的胆固醇摄取,并增加LXRα-ABCA1/G1信号通路介导的胆固醇输出,有效降低巨噬细胞泡沫化水平。结论槲皮素可通过CYP27A1/LXRα信号通路调控巨噬细胞胆固醇稳态,发挥AS保护作用。展开更多
BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a treatable autosomal recessive inherited metabolic disorder.It results from a deficiency of sterol 27-hydroxylase(CYP27A1),which is a mitochondrial cytochrome P450 enz...BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a treatable autosomal recessive inherited metabolic disorder.It results from a deficiency of sterol 27-hydroxylase(CYP27A1),which is a mitochondrial cytochrome P450 enzyme that catalyzes the hydroxylation of cholesterol and modulates cholesterol homeostasis.Patients with CYP27A1 deficiency show symptoms related to excessive accumulation of cholesterol and cholestanol in lipophilic tissues such as the brain,eyes,tendons,and vessels,resulting in juvenile cataracts,tendon xanthoma,chronic diarrhea,cognitive impairment,ataxia,spastic paraplegia,and peripheral neuropathy.CTX is underdiagnosed as knowledge of the disorder is mainly based on case reports.CASE SUMMARY A Chinese family with CTX consisting of one patient and four heterozygous carriers was studied.The patient is a 47-year-old male,who mainly had psychiatric signs but without some cardinal features of CTX such as cataracts,cerebellar ataxia,pyramidal signs and chronic diarrhea.There was a significant increase in the concentration of free fatty acid compared to normal range.Doppler ultrasound of the urinary system showed multiple left kidney stones,a right kidney cyst,and a hypoechoic area in the bladder,which could move with body position.Sagittal and axial magnetic resonance imaging(MRI)of the right ankle joint showed apparent enlargement of the right Achilles tendon and upper medial malleolus flexor tendon,abnormal thickening of the plantar fat,and a small amount of exudation around the fascia in front of the Achilles tendon.Cerebral MRI suggested white matter(WM)demyelination and slight cerebral atrophy.The diagnosis was confirmed by targeted sequencing,which identified compound heterozygous mutations in exon 2 and intron 7 of the CYP27A1 gene(c.435G>T,c.1263+1G>A).Treatment for 3 wk with a combination of lipid-lowering and antipsychotic therapy improved his psychiatric symptoms and normalized the levels of serum free fatty acid.Sediments in the bladder disappeared after therapy.CONCLUSION CYP27A1 genetic analysis should be the definitive method for CTX diagnosis.This case suggests that urinary system diseases may be neglected in CTX patients.The clinical,biological,radiological,and genetic characteristics of CTX are summarized to promote early diagnosis and treatment of this disease.展开更多
文摘目的分析脑腱黄瘤病的临床特点及CYP27A1基因复合杂合突变家系,旨在提高对该病的认识。方法对我中心2018年收治确诊的1例合并腭肌阵挛的脑腱黄瘤病患者临床资料,以及文献检索的25例中国籍患者的组织病理学及基因学特点进行分析。结果患者为20岁女性,总病程12年,白内障12年,行走不稳、构音不清1年,癫痫发作6个月,饮水呛咳5个月。简易精神状态检查(Mini-Mental State Examination,MMSE)评分21分;蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)评分18分。查体:左侧跟腱增粗,高弓足;构音不清;双侧腭肌持续阵挛;辨距不良;双侧掌颏反射阳性,双侧肱二头肌腱反射、膝腱反射亢进,双侧踝阵挛阳性。双侧Babinski征、Chaddock征阳性。头颅MRI显示:双侧脑室旁、双侧底节区、双侧小脑半球对称斑片状T1WI等、低信号,T2WI高信号;DWI呈低信号为主的混杂信号;FLAIR呈高信号;增强扫描未见异常强化;MRS显示病灶区域NNA峰减低,总胆固醇升高。跟腱活检玻璃样变的纤维组织。基因检测发现CYP27A1基因复合杂合变异,分别为5号外显子c.1016C>T(p.Thr339Met)及7号内含子c.1263+1G>A(IVS7-5),美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)变异评级均为致病性,均为国外已报道位点。结合文献复习该病平均发病年龄为(21.38±12.87)岁,平均确诊时间为(12.58±11.5)年。首发症状以跟腱肿物最多,神经系统表现有小脑性共济失调、锥体束征、癫痫发作、认知障碍、周围神经病变。头颅MRI异常表现多在小脑半球、齿状核、内囊及脑干等。多数可查到CYP27A1基因致病变异,最常见于2号外显子,其次为5号、1号、6号,包括复合杂合突变、纯合突变、缺失突变等。结论脑腱黄瘤病临床罕见,临床表现复杂多样,诊断依靠病理检查及基因检测。
文摘目的总结肝癌与固醇-27羟化酶(CYP27A1)的关联性研究近况及发展趋势,探讨CYP27A1在肝癌中的治疗作用。方法使用Go PubMed工具搜集文献资料,展开计量分析;基于The Human Protein Atlas数据库获取CYP27A1蛋白在正常肝组织及肝癌组织中的免疫组化表达情况,并依据The Cancer Genome Atlas内RNA-Seq数据集整理绘制CYP27A1高低表达情况在肝癌患者中的生存曲线。结果文献计量分析结果显示,PubMed中共收录相关文献13篇,整理后共得出20个高频研究关键词及主要作者信息、12个顶级期刊收录情况、1份研究地域分布图;免疫组化结果显示,与正常肝组织比较,肝癌组织中的CYP27A1呈现明显的低表达趋势;生存分析结果显示,CYP27A1的高表达有助于改善肝癌患者的预后,提高生存质量。结论二者的关联性研究尚处于起步阶段,CYP27A1可能是肝癌的潜在治疗靶点。
文摘BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive metabolic disease caused by mutations in CYP27 A1.It has a low incidence rate,insidious onset,and diverse clinical manifestations.It can be easily misdiagnosed and can go unrecognized by clinicians,leading to delayed treatment and worsened patient outcomes.CASE SUMMARY A 38-year-old male was admitted to our hospital with a history of unabating unstable posture and difficulty in walking for more than 30 years.Subsequently based on the patient’s medical history,clinical symptoms,magnetic resonance imaging and gene sequencing results,he was finally diagnosed with CTX.Due to the low incidence rate of the disease,clinicians have insufficient knowledge of it,which makes the diagnosis process more tortuous and prolongs the diagnosis time.CONCLUSION Prompt diagnosis and treatment of CTX improve patient outcomes.
基金supported by the National Institutes of Health(NIHR01GM104037,NIH-R21ES029258,NIH-T32ES007148,VA-BX002741,NIH-F31DK122725,RCLR graduate student award fund,USA)。
文摘Bile acids(BAs) are amphipathic molecules important for metabolism of cholesterol,absorption of lipids and lipid soluble vitamins,bile flow,and regulation of gut microbiome.There are over 30 different BA species known to exist in humans and mice,which are endogenous modulators of at least 6 different membrane or nuclear receptors.This diversity of ligands and receptors play important roles in health and disease;however,the full functions of each individual BA in vivo remain unclear.We generated a mouse model lacking the initiating enzymes,CYP7 A1 and CYP27 A1,in the two main pathways of BA synthesis.Because females are more susceptible to BA related diseases,such as intrahepatic cholestasis of pregnancy,we expanded this model into female mice.The null mice of Cyp7 a1 and Cyp27 a1 were crossbred to create double knockout(DKO) mice.BA concentrations in female DKO mice had reductions in serum(63%),liver(83%),gallbladder(94%),and small intestine(85%),as compared to WT mice.Despite low BA levels,DKO mice had a similar expression pattern to that of WT mice for genes involved in BA regulation,synthesis,conjugation,and transport.Additionally,through treatment with a synthetic FXR agonist,GW4064,female DKO mice responded to FXR activation similarly to WT mice.
基金National Natural Science Foundation of China,No.82172061the Key Research and Development Plan in Jiangsu,No.BE2022677and the 16th Batch of Six Talent Peak Projects in Jiangsu,No.WSN-166.
文摘BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1.Psychiatric manifestations in CTX are rare and nonspecific,and they often lead to considerable diagnostic and treatment delay.CASE SUMMARY A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions,hallucinations,and behavioral disturbance is reported.The patient presented with cholestasis,cataract,Achilles tendon xanthoma,and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood.After the characteristic CTX findings on imaging were obtained,a pathological examination of the Achilles tendon xanthoma was refined.Replacement therapy was then initiated after the diagnosis was clarified by genetic analysis.During hospitalization in the psychiatric ward,the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis.After the patient’s history of CTX was identified,the patient was diagnosed with organic schizophrenia-like disorder,and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication.CONCLUSION Psychiatrists should be aware of CTX,its psychiatric manifestations,and clinical features and avoid misdiagnosis of CTX for timely intervention.
基金Supported by Zhejiang Province Medical Science and Technology Project,No.2020RC061 and No.2019ZD021Jinhua Bureau of Science and Technology Project,No.2020-3-004.
文摘BACKGROUND Cerebrotendinous xanthomatosis(CTX)is a treatable autosomal recessive inherited metabolic disorder.It results from a deficiency of sterol 27-hydroxylase(CYP27A1),which is a mitochondrial cytochrome P450 enzyme that catalyzes the hydroxylation of cholesterol and modulates cholesterol homeostasis.Patients with CYP27A1 deficiency show symptoms related to excessive accumulation of cholesterol and cholestanol in lipophilic tissues such as the brain,eyes,tendons,and vessels,resulting in juvenile cataracts,tendon xanthoma,chronic diarrhea,cognitive impairment,ataxia,spastic paraplegia,and peripheral neuropathy.CTX is underdiagnosed as knowledge of the disorder is mainly based on case reports.CASE SUMMARY A Chinese family with CTX consisting of one patient and four heterozygous carriers was studied.The patient is a 47-year-old male,who mainly had psychiatric signs but without some cardinal features of CTX such as cataracts,cerebellar ataxia,pyramidal signs and chronic diarrhea.There was a significant increase in the concentration of free fatty acid compared to normal range.Doppler ultrasound of the urinary system showed multiple left kidney stones,a right kidney cyst,and a hypoechoic area in the bladder,which could move with body position.Sagittal and axial magnetic resonance imaging(MRI)of the right ankle joint showed apparent enlargement of the right Achilles tendon and upper medial malleolus flexor tendon,abnormal thickening of the plantar fat,and a small amount of exudation around the fascia in front of the Achilles tendon.Cerebral MRI suggested white matter(WM)demyelination and slight cerebral atrophy.The diagnosis was confirmed by targeted sequencing,which identified compound heterozygous mutations in exon 2 and intron 7 of the CYP27A1 gene(c.435G>T,c.1263+1G>A).Treatment for 3 wk with a combination of lipid-lowering and antipsychotic therapy improved his psychiatric symptoms and normalized the levels of serum free fatty acid.Sediments in the bladder disappeared after therapy.CONCLUSION CYP27A1 genetic analysis should be the definitive method for CTX diagnosis.This case suggests that urinary system diseases may be neglected in CTX patients.The clinical,biological,radiological,and genetic characteristics of CTX are summarized to promote early diagnosis and treatment of this disease.
