Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known ...Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.展开更多
Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited dis...Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.展开更多
BACKGROUND Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions.In young children with a history of fasting preceding these metabolic derangements,inborn errors of metabolism should be pri...BACKGROUND Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions.In young children with a history of fasting preceding these metabolic derangements,inborn errors of metabolism should be primarily considered.However,the Warburg effect,a rare metabolic complication,can also manifest in children with hematologic malignancies.Only a few reports of this condition in children have been published in the literature.AIM To identify the clinical course,treatment strategies,and outcomes of childhood hematologic malignancies with type B lactic acidosis.METHODS We performed a comprehensive search of the PubMed,Scopus,and Cochrane databases without any time restriction but limited to English language articles.The databases were last accessed on July 1st,2023.RESULTS A total of 20 publications were included in the analysis,all of which were case reports or case series.No higher quality evidence was available.Among children with hematologic malignancies and Warburg effect,there were 14 cases of acute lymphoblastic leukemia and 6 cases of non-Hodgkin’s lymphoma including our illustrative case.Lactic acidosis occurred in 55%of newly diagnosed cases and 45%of relapsed cases.The mean age was 10.3±4.5 years,and 80%of cases were male.The mean serum lactate was 16.9±12.6 mmol/L,and 43.8%of the cases had concomitant hypoglycemia.Lactic acidosis initially subsided in 80%of patients receiving chemotherapy compared to 60%in the contrast group.The mortality rate of newly diagnosed cases was 45.5%,while the relapsed cases represented a 100%mortality rate.All 8 patients reported before 2001 died from disease-related complications.However,patients described in reports published between 2003 and 2023 had a 54.5%rate of complete remission.CONCLUSION This complication has historically led to fatal outcome;however,patients who received chemotherapy showed a more favorable response.Therefore,it is crucial to promptly initiate specific treatment in this context.展开更多
Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IE...Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area.展开更多
Inborn errors of metabolism（IEMs） are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understand...Inborn errors of metabolism（IEMs） are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.展开更多
The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens...The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.展开更多
In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune di...In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune disease.Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases,such as arthritis,systemic lupus erythematosus(SLE),and Sjogren’s syndrome(SjS).Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms.Here,we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency,highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.展开更多
BACKGROUND Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase(AMACR)gene mutation.The disease is usually found in children with mi...BACKGROUND Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase(AMACR)gene mutation.The disease is usually found in children with mild to severe liver disease,cholestasis and poor fat-soluble vitamin absorption.At present,there is no report of inborn errors of bile acid synthesis type 4 in adults with liver disease and poor fat-soluble vitamin absorption.CASE SUMMARY A 71-year-old man was hospitalized in our department for recurrent liver dysfunction.The clinical manifestations were chronic liver disease and yellow skin and sclera.Serum transaminase,bilirubin and bile acid were abnormally increased;and fat-soluble vitamins decreased.Liver cirrhosis and ascites were diagnosed by computed tomography.The patient had poor coagulation function and ascites and did not undergo liver puncture.Genetic testing showed AMACR gene missense mutation.The patient was diagnosed with inborn error of bile acid synthesis type 4.He was treated with ursodeoxycholic acid,liver protection and vitamin supplementation,and jaundice of the skin and sclera was reduced.The indicators of liver function and the quality of life were significantly improved.CONCLUSION When adults have recurrent liver function abnormalities,physicians should be alert to genetic diseases and provide timely treatment.展开更多
免疫出生错误(inborn errors of immunity,IEI)是由遗传因素导致免疫结构或功能障碍所致的一类疾病,可累及固有免疫和适应性免疫。2022年IEI新分类包含485种IEI,分为十大类疾病。近年来随着分子生物学的快速发展,许多IEI的具体发病机制...免疫出生错误(inborn errors of immunity,IEI)是由遗传因素导致免疫结构或功能障碍所致的一类疾病,可累及固有免疫和适应性免疫。2022年IEI新分类包含485种IEI,分为十大类疾病。近年来随着分子生物学的快速发展,许多IEI的具体发病机制得以揭示,使得基因治疗在该类疾病的临床前和临床研究成为可能。该文综述基因治疗在IEI中的研究和应用,以进一步提高临床医生对IEI诊治的认知。展开更多
目的:分析新生儿重症监护室(neonatal intensive care unit,NICU)中遗传代谢病(或称先天性代谢缺陷,inborn errors of metabolism,IEM)高危新生儿的病因谱及发病特征。方法:联合应用液相色谱-串联质谱(liquid chromatography-tandem mas...目的:分析新生儿重症监护室(neonatal intensive care unit,NICU)中遗传代谢病(或称先天性代谢缺陷,inborn errors of metabolism,IEM)高危新生儿的病因谱及发病特征。方法:联合应用液相色谱-串联质谱(liquid chromatography-tandem mass spectrometry,LC-MS/MS)和气相色谱-质谱(gas chromatography-mass spectrometry,GC-MS)技术,对2007年9月—2012年8月复旦大学附属儿科医院收治的859例IEM高危新生儿进行血尿代谢标志物的检测和分析,并对确诊为IEM患儿的病因和临床表现进行分析。结果:859例IEM高危新生儿中共诊断IEM22例(2.7%),其中氨基酸代谢病11例(50%),以枫糖尿病(7例)多见;有机酸代谢病11例(50%),以甲基丙二酸血症(8例)多见。22例IEM患儿的临床表现各不相同,多在出生后一个短暂的"正常"期后起病,以拒食、呕吐、惊厥发作等消化系统或神经系统症状为主。结论:高危新生儿IEM病因谱复杂多样,以甲基丙二酸血症和枫糖尿病最多见,临床应重视早期联合运用LC-MS/MS和GC-MS技术对NICU中IEM高危新生儿进行IEM检测,以便早期诊断和干预。展开更多
文摘Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.
文摘Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect interme-diary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spec-trometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.
文摘BACKGROUND Type B lactic acidosis and hypoglycemia can occur in various pediatric conditions.In young children with a history of fasting preceding these metabolic derangements,inborn errors of metabolism should be primarily considered.However,the Warburg effect,a rare metabolic complication,can also manifest in children with hematologic malignancies.Only a few reports of this condition in children have been published in the literature.AIM To identify the clinical course,treatment strategies,and outcomes of childhood hematologic malignancies with type B lactic acidosis.METHODS We performed a comprehensive search of the PubMed,Scopus,and Cochrane databases without any time restriction but limited to English language articles.The databases were last accessed on July 1st,2023.RESULTS A total of 20 publications were included in the analysis,all of which were case reports or case series.No higher quality evidence was available.Among children with hematologic malignancies and Warburg effect,there were 14 cases of acute lymphoblastic leukemia and 6 cases of non-Hodgkin’s lymphoma including our illustrative case.Lactic acidosis occurred in 55%of newly diagnosed cases and 45%of relapsed cases.The mean age was 10.3±4.5 years,and 80%of cases were male.The mean serum lactate was 16.9±12.6 mmol/L,and 43.8%of the cases had concomitant hypoglycemia.Lactic acidosis initially subsided in 80%of patients receiving chemotherapy compared to 60%in the contrast group.The mortality rate of newly diagnosed cases was 45.5%,while the relapsed cases represented a 100%mortality rate.All 8 patients reported before 2001 died from disease-related complications.However,patients described in reports published between 2003 and 2023 had a 54.5%rate of complete remission.CONCLUSION This complication has historically led to fatal outcome;however,patients who received chemotherapy showed a more favorable response.Therefore,it is crucial to promptly initiate specific treatment in this context.
文摘Background Data of classical inborn errors of metabolism （IEM） of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area.
文摘Inborn errors of metabolism（IEMs） are a large group of inherited disorders characterized by disruption of metabolic pathways due to deficient enzymes, cofactors, or transporters. The rapid advances in the understanding of the molecular pathophysiology of many IEMs, have led to significant progress in the development of many new treatments. The institution and continued expansion of newborn screening provide the opportunity for early treatment, leading to reduced morbidity and mortality. This review provides an overview of the diverse therapeutic approaches and recent advances in the treatment of IEMs that focus on the basic principles of reducing substrate accumulation, replacing or enhancing absent or reduced enzyme or cofactor, and supplementing product deficiency. In addition, the challenges and obstacles of current treatment modalities and future treatment perspectives are reviewed and discussed.
文摘The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.
基金funding by the DZIF TTU 07.806_00(German Centre for Infection Research)the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under Germany’s Excellence Strategy–EXC 2155“RESIST”–Project ID 39087428+1 种基金the German Federal Ministry of Education and Research(BMBF,01GM1910E)the Rosemarie-Germscheid Foundation.
文摘In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune disease.Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases,such as arthritis,systemic lupus erythematosus(SLE),and Sjogren’s syndrome(SjS).Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms.Here,we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency,highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.
文摘BACKGROUND Inborn error of bile acid synthesis type 4 is a peroxisomal disease with impaired bile acid synthesis caused by a-methylacyl-CoA racemase(AMACR)gene mutation.The disease is usually found in children with mild to severe liver disease,cholestasis and poor fat-soluble vitamin absorption.At present,there is no report of inborn errors of bile acid synthesis type 4 in adults with liver disease and poor fat-soluble vitamin absorption.CASE SUMMARY A 71-year-old man was hospitalized in our department for recurrent liver dysfunction.The clinical manifestations were chronic liver disease and yellow skin and sclera.Serum transaminase,bilirubin and bile acid were abnormally increased;and fat-soluble vitamins decreased.Liver cirrhosis and ascites were diagnosed by computed tomography.The patient had poor coagulation function and ascites and did not undergo liver puncture.Genetic testing showed AMACR gene missense mutation.The patient was diagnosed with inborn error of bile acid synthesis type 4.He was treated with ursodeoxycholic acid,liver protection and vitamin supplementation,and jaundice of the skin and sclera was reduced.The indicators of liver function and the quality of life were significantly improved.CONCLUSION When adults have recurrent liver function abnormalities,physicians should be alert to genetic diseases and provide timely treatment.
文摘免疫出生错误(inborn errors of immunity,IEI)是由遗传因素导致免疫结构或功能障碍所致的一类疾病,可累及固有免疫和适应性免疫。2022年IEI新分类包含485种IEI,分为十大类疾病。近年来随着分子生物学的快速发展,许多IEI的具体发病机制得以揭示,使得基因治疗在该类疾病的临床前和临床研究成为可能。该文综述基因治疗在IEI中的研究和应用,以进一步提高临床医生对IEI诊治的认知。
基金supported by Shanghai Rising-Star Program (No.09QA1404700)Shanghai Health Bureau (No.2007145)+1 种基金Chinese Hi-Tech Research and Development Program (No.2007AA02Z447)Shanghai Government Foundations (No.2008ZD001)
文摘目的:分析新生儿重症监护室(neonatal intensive care unit,NICU)中遗传代谢病(或称先天性代谢缺陷,inborn errors of metabolism,IEM)高危新生儿的病因谱及发病特征。方法:联合应用液相色谱-串联质谱(liquid chromatography-tandem mass spectrometry,LC-MS/MS)和气相色谱-质谱(gas chromatography-mass spectrometry,GC-MS)技术,对2007年9月—2012年8月复旦大学附属儿科医院收治的859例IEM高危新生儿进行血尿代谢标志物的检测和分析,并对确诊为IEM患儿的病因和临床表现进行分析。结果:859例IEM高危新生儿中共诊断IEM22例(2.7%),其中氨基酸代谢病11例(50%),以枫糖尿病(7例)多见;有机酸代谢病11例(50%),以甲基丙二酸血症(8例)多见。22例IEM患儿的临床表现各不相同,多在出生后一个短暂的"正常"期后起病,以拒食、呕吐、惊厥发作等消化系统或神经系统症状为主。结论:高危新生儿IEM病因谱复杂多样,以甲基丙二酸血症和枫糖尿病最多见,临床应重视早期联合运用LC-MS/MS和GC-MS技术对NICU中IEM高危新生儿进行IEM检测,以便早期诊断和干预。
