Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes...Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes range from benign recurrent intrahepatic cholestasis(BRIC), associated with recurrent cholestatic attacks, to progressive FIC(PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency(PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency(PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.展开更多
Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver di...Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.展开更多
Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for es...Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].展开更多
Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student...Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.展开更多
BACKGROUND Genetic factors play an important role in neonatal hyperbilirubinemia(NH)caused by genetic diseases.AIM To explore the characteristics of genetic mutations associated with NH and analyze the correlation wit...BACKGROUND Genetic factors play an important role in neonatal hyperbilirubinemia(NH)caused by genetic diseases.AIM To explore the characteristics of genetic mutations associated with NH and analyze the correlation with genetic diseases.METHODS This was a retrospective cohort study.One hundred and five newborn patients diagnosed with NH caused by genetic diseases were enrolled in this study between September 2020 and June 2023 at the Second Affiliated Hospital of Xiamen Medical College.A 24-gene panel was used for gene sequencing to analyze gene mutations in patients.The data were analyzed via Statistical Package for the Social Sciences 20.0 software.RESULTS Seventeen frequently mutated genes were found in the 105 patients.Uridine 5'-diphospho-glucuronosyltransferase 1A1(UGT1A1)variants were identified among the 68 cases of neonatal Gilbert syndrome.In patients with sodium taurocholate cotransporting polypeptide deficiency,the primary mutation identified was Na+/taurocholate cotransporting polypeptide Ntcp(SLC10A1).Adenosine triphosphatase 7B(ATP7B)mutations primarily occur in patients with hepatolenticular degeneration(Wilson's disease).In addition,we found that UGT1A1 and glucose-6-phosphate dehydrogenase mutations were more common in the high-risk group than in the low-risk group,whereas mutations in SLC10A1,ATP7B,and heterozygous 851del4 mutation were more common in the low-risk group.CONCLUSION Genetic mutations are associated with NH and significantly increase the risk of disease in affected newborns.展开更多
Liver transplantation is hindered by organ shortage. The potential way to relieve this issue is to expand the donor pool via extending the donor criteria and make full use of all available grafts. The concept of “no-...Liver transplantation is hindered by organ shortage. The potential way to relieve this issue is to expand the donor pool via extending the donor criteria and make full use of all available grafts. The concept of “no-donor” liver transplantation allows grafts to be recovered from other liver recipients. This review summarizes the current clinical practice of “no-donor” liver transplantation, focusing on the experiences of Chinese transplant teams. Domino liver transplantation was introduced by Furtado in 1995 and implemented later in 2013 in China, and novel donor indications including some essential-to-treat inherited metabolic liver-based diseases have emerged. The concept of cross-auxiliary domino liver transplantation brings a further expansion of the domino liver graft pool, and the first pair of liver transplantation performed “rigorously without donation” was accomplished in our center in 2018. Our experience with this original transplantation procedure is hereby reviewed. In order to further promote and make successful “no-donor” liver transplantation, close co-operation between researchers, surgeons, physicians, organ procurement organizations, as well as ethical committees is required.展开更多
Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photo...Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.展开更多
Background and Aims:Inherited metabolic liver diseases(IMLDs)have complex etiologies and vary widely in clinical presentation,with a significant overall incidence.With the advancements in diagnostic and treatment tech...Background and Aims:Inherited metabolic liver diseases(IMLDs)have complex etiologies and vary widely in clinical presentation,with a significant overall incidence.With the advancements in diagnostic and treatment technologies,an increasing number of children with inherited metabolic dis-eases are surviving into adolescence and adulthood.These advancements have improved our understanding of the IMLD disease spectrum and clinical outcomes.This study aimed to analyze changes in the disease spectrum and epidemio-logical characteristics of inherited metabolic liver diseases(IMLD)over the past 20 years in two specialized liver dis-ease hospitals in northern China.Methods:A retrospective analysis was conducted on IMLD cases diagnosed between January 1,2002,and December 31,2023,at two liver dis-ease specialty hospitals in Beijing.Data were obtained from inpatient and outpatient hospital information systems,with diagnoses based on national and international IMLD diag-nosis and treatment guidelines.Results:A total of 2,103 IMLD patients were analyzed,including 1,213 adults and 890 children.IMLD accounted for 4.58‰of hospitalized liver dis-ease patients during this period.The most common IMLD was Wilson’s disease,comprising 68%of all IMLD cases.The number of diagnosed IMLD types increased from 15 to 32 across two 11-year periods(2002–2012 and 2013–2023).Among pediatric patients,glycogen storage disease and Alagille syndrome were more prevalent in those under one year of age,while Wilson’s disease was prevalent across all age groups.In adult IMLD patients,Wilson’s disease,poly-cystic liver disease,and hereditary hyperbilirubinemia were more frequently observed.Conclusions:Over the past 20 years,both the number of diagnosed IMLD cases and disease diversity have significantly increased,with Wilson’s disease remaining the most prevalent IMLD.These findings provide valuable insights for the long-term management of IMLD pa-tients and the allocation of healthcare resources.展开更多
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a m...Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."展开更多
Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing h...Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing has been applied and achieved significant progress in treating inherited genetic disorders that remain incurable by conventional therapy.Here,we present a review of various programmable genome editing systems with their principles,advantages,and limitations.We introduce their recent applications for treating inherited diseases in the clinic,including sickle cell disease(SCD),β-thalassemia,Leber congenital amaurosis(LCA),heterozygous familial hypercholesterolemia(HeFH),etc.We also discuss the paradigm of ex vivo and in vivo editing and highlight the promise of somatic editing and the challenge of germline editing.Finally,we propose future directions in delivery,cutting,and repairing to improve the scope of clinical applications.展开更多
Dear Editor,Alpha-thalassemia(α-tha) is an inherited hemolytic disease with an increasing prevalence worldwide that is caused by a complete or partial absence of α-globin chain synthesis due to α-globin chain synth...Dear Editor,Alpha-thalassemia(α-tha) is an inherited hemolytic disease with an increasing prevalence worldwide that is caused by a complete or partial absence of α-globin chain synthesis due to α-globin chain synthesis disorders(Farashi and Harteveld,2018).Mild α-tha is generally considered untreatable,whereas transfusion-dependent and severe forms require lifelong transfusions,which can lead to chronic iron overload necessitating chelation therapy(Horvei et al.,2021;Baird et al.,2022).展开更多
Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissue...Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissues.Here,we report a patient with photosensitive dermatitis and acute icteric hepatitis caused by EPP,whose clinical and biochemical results successfully improved following 2-month treatment with glucose load,ursodeoxycholic acid capsules,and cholestyramine powder.This case provides a reference for a combination therapy strategy for patients with liver and skin injury caused by EPP.展开更多
Background:Medical literature on the prevalence of genetic liver disease is lacking.In this study,we investigated the inhospital healthcare and economic burden from genetic causes of non-alcoholic chronic liver diseas...Background:Medical literature on the prevalence of genetic liver disease is lacking.In this study,we investigated the inhospital healthcare and economic burden from genetic causes of non-alcoholic chronic liver disease(NACLD)and nonalcoholic liver cirrhosis(NALC)in the USA.Methods:Data were abstracted from the National Inpatient Sample database between 2002 and 2014 using ICD9 codes for patients discharged with NACLD and NALC secondary to genetic diseases including alpha-1 antitrypsin deficiency(A1ATd),cystic fibrosis(CF),Wilson disease(WD),hereditary hemochromatosis(HHC),glycogen storage disease,and disorders of aromatic amino-acid metabolism(DAAAM).Results:Throughout the study period,there were 19,332 discharges for NACLD associated with the six genetic diseases including 14,368 for NALC.There were$1.09 billion in hospital charges,790 in-hospital deaths,and 955 liver transplants performed.Overall,A1ATd was associated with 8,983(62.52%)hospitalizations for NALC followed by WD,CF,and HHC.The highest in-hospital mortality was seen with HHC.The greatest frequency of liver transplants was seen with DAAAM.Conclusion:The number of hospitalizations for genetic liver diseases continues to increase.With increased funding and directed research efforts,we can aim to improvemedical treatments and the quality of life for patients at risk for liver deterioration.展开更多
Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological p...Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.展开更多
文摘Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes range from benign recurrent intrahepatic cholestasis(BRIC), associated with recurrent cholestatic attacks, to progressive FIC(PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency(PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency(PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.
基金Supported by Shanghai Science and Technology Development Foundation(Outstanding Academic Leader),No.23XD1423100National Natural Science Foundation,No.82241221 and No.92059205。
文摘Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.
基金Supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology,Macular Society(UK),Fight for Sight(UK),Onassis Foundation,Leventis Foundation,The Wellcome Trust(099173/Z/12/Z)Moorfields Eye Hospital Special Trustees,Moorfields Eye Charity,Retina UK,and the Foundation Fighting Blindness(USA).
文摘Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].
基金supported by National Natural Science Foundation of China [No.82171073]。
文摘Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.
基金Supported by The Xiamen Municipal Science and Technology Bureau Project,No.3502Z20209177.
文摘BACKGROUND Genetic factors play an important role in neonatal hyperbilirubinemia(NH)caused by genetic diseases.AIM To explore the characteristics of genetic mutations associated with NH and analyze the correlation with genetic diseases.METHODS This was a retrospective cohort study.One hundred and five newborn patients diagnosed with NH caused by genetic diseases were enrolled in this study between September 2020 and June 2023 at the Second Affiliated Hospital of Xiamen Medical College.A 24-gene panel was used for gene sequencing to analyze gene mutations in patients.The data were analyzed via Statistical Package for the Social Sciences 20.0 software.RESULTS Seventeen frequently mutated genes were found in the 105 patients.Uridine 5'-diphospho-glucuronosyltransferase 1A1(UGT1A1)variants were identified among the 68 cases of neonatal Gilbert syndrome.In patients with sodium taurocholate cotransporting polypeptide deficiency,the primary mutation identified was Na+/taurocholate cotransporting polypeptide Ntcp(SLC10A1).Adenosine triphosphatase 7B(ATP7B)mutations primarily occur in patients with hepatolenticular degeneration(Wilson's disease).In addition,we found that UGT1A1 and glucose-6-phosphate dehydrogenase mutations were more common in the high-risk group than in the low-risk group,whereas mutations in SLC10A1,ATP7B,and heterozygous 851del4 mutation were more common in the low-risk group.CONCLUSION Genetic mutations are associated with NH and significantly increase the risk of disease in affected newborns.
基金supported by grants from Capital’s Funds for Health Improvement and Research (2024–1–2022)Beijing Nat-ural Science Foundation (7244318)。
文摘Liver transplantation is hindered by organ shortage. The potential way to relieve this issue is to expand the donor pool via extending the donor criteria and make full use of all available grafts. The concept of “no-donor” liver transplantation allows grafts to be recovered from other liver recipients. This review summarizes the current clinical practice of “no-donor” liver transplantation, focusing on the experiences of Chinese transplant teams. Domino liver transplantation was introduced by Furtado in 1995 and implemented later in 2013 in China, and novel donor indications including some essential-to-treat inherited metabolic liver-based diseases have emerged. The concept of cross-auxiliary domino liver transplantation brings a further expansion of the domino liver graft pool, and the first pair of liver transplantation performed “rigorously without donation” was accomplished in our center in 2018. Our experience with this original transplantation procedure is hereby reviewed. In order to further promote and make successful “no-donor” liver transplantation, close co-operation between researchers, surgeons, physicians, organ procurement organizations, as well as ethical committees is required.
基金supported by Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.20200730009 (to YX)the National Natural Science Foundation of China,No.82074169 (to XM)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,No.2021A1515012473 (to XM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045 (to XM)Aier Eye Hospital Group,No.AF2019001 (to ST,KFS,YX,XM)。
文摘Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.
基金supported by Capital Health Development Re-search Project(2022-1-2182)Beijing Hospitals Authority’s Ascent Plan(DFL20241701)high-level public health technical talents of the Beijing Municipal Health Commission(Academic Leader-02-14).
文摘Background and Aims:Inherited metabolic liver diseases(IMLDs)have complex etiologies and vary widely in clinical presentation,with a significant overall incidence.With the advancements in diagnostic and treatment technologies,an increasing number of children with inherited metabolic dis-eases are surviving into adolescence and adulthood.These advancements have improved our understanding of the IMLD disease spectrum and clinical outcomes.This study aimed to analyze changes in the disease spectrum and epidemio-logical characteristics of inherited metabolic liver diseases(IMLD)over the past 20 years in two specialized liver dis-ease hospitals in northern China.Methods:A retrospective analysis was conducted on IMLD cases diagnosed between January 1,2002,and December 31,2023,at two liver dis-ease specialty hospitals in Beijing.Data were obtained from inpatient and outpatient hospital information systems,with diagnoses based on national and international IMLD diag-nosis and treatment guidelines.Results:A total of 2,103 IMLD patients were analyzed,including 1,213 adults and 890 children.IMLD accounted for 4.58‰of hospitalized liver dis-ease patients during this period.The most common IMLD was Wilson’s disease,comprising 68%of all IMLD cases.The number of diagnosed IMLD types increased from 15 to 32 across two 11-year periods(2002–2012 and 2013–2023).Among pediatric patients,glycogen storage disease and Alagille syndrome were more prevalent in those under one year of age,while Wilson’s disease was prevalent across all age groups.In adult IMLD patients,Wilson’s disease,poly-cystic liver disease,and hereditary hyperbilirubinemia were more frequently observed.Conclusions:Over the past 20 years,both the number of diagnosed IMLD cases and disease diversity have significantly increased,with Wilson’s disease remaining the most prevalent IMLD.These findings provide valuable insights for the long-term management of IMLD pa-tients and the allocation of healthcare resources.
基金Supported, in part, by grants from NIH (R01 AA021978, P30 DK120531, and R21 ES031531, USA)。
文摘Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."
基金supported by the Genome Tagging Project and grants from the National Natural Science Foundation of China(31821004,32030029,31730062,and 3210060158)CAS Special Research Assistant Program.
文摘Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing has been applied and achieved significant progress in treating inherited genetic disorders that remain incurable by conventional therapy.Here,we present a review of various programmable genome editing systems with their principles,advantages,and limitations.We introduce their recent applications for treating inherited diseases in the clinic,including sickle cell disease(SCD),β-thalassemia,Leber congenital amaurosis(LCA),heterozygous familial hypercholesterolemia(HeFH),etc.We also discuss the paradigm of ex vivo and in vivo editing and highlight the promise of somatic editing and the challenge of germline editing.Finally,we propose future directions in delivery,cutting,and repairing to improve the scope of clinical applications.
基金supported by the National Key R&D Program of China (2019YFA0109900,2019YFA0109901,2019YFA0802800 and 2019YFA0110803 to Y.W.)grants from the Shanghai Municipal Commission for Science and Technology (19PJ1403500 to Y.W.)+1 种基金the National Natural Science Foundation of China (82270125 to Y.W.,82060029 to Y.L.)the Scientific Research of Bo Shi Ke Yan (XJ2020025 to D.L.) from Anhui Medical University and the Anhui Province Fund for Excellent Young Scholars (2024AH030022 to DL.)。
文摘Dear Editor,Alpha-thalassemia(α-tha) is an inherited hemolytic disease with an increasing prevalence worldwide that is caused by a complete or partial absence of α-globin chain synthesis due to α-globin chain synthesis disorders(Farashi and Harteveld,2018).Mild α-tha is generally considered untreatable,whereas transfusion-dependent and severe forms require lifelong transfusions,which can lead to chronic iron overload necessitating chelation therapy(Horvei et al.,2021;Baird et al.,2022).
基金the Guangdong Key Field R&D Plan of China(2019B020228001)the 5010 Project of Clinical Research in Sun Yat-sen University,China(No.2018024).
文摘Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissues.Here,we report a patient with photosensitive dermatitis and acute icteric hepatitis caused by EPP,whose clinical and biochemical results successfully improved following 2-month treatment with glucose load,ursodeoxycholic acid capsules,and cholestyramine powder.This case provides a reference for a combination therapy strategy for patients with liver and skin injury caused by EPP.
文摘Background:Medical literature on the prevalence of genetic liver disease is lacking.In this study,we investigated the inhospital healthcare and economic burden from genetic causes of non-alcoholic chronic liver disease(NACLD)and nonalcoholic liver cirrhosis(NALC)in the USA.Methods:Data were abstracted from the National Inpatient Sample database between 2002 and 2014 using ICD9 codes for patients discharged with NACLD and NALC secondary to genetic diseases including alpha-1 antitrypsin deficiency(A1ATd),cystic fibrosis(CF),Wilson disease(WD),hereditary hemochromatosis(HHC),glycogen storage disease,and disorders of aromatic amino-acid metabolism(DAAAM).Results:Throughout the study period,there were 19,332 discharges for NACLD associated with the six genetic diseases including 14,368 for NALC.There were$1.09 billion in hospital charges,790 in-hospital deaths,and 955 liver transplants performed.Overall,A1ATd was associated with 8,983(62.52%)hospitalizations for NALC followed by WD,CF,and HHC.The highest in-hospital mortality was seen with HHC.The greatest frequency of liver transplants was seen with DAAAM.Conclusion:The number of hospitalizations for genetic liver diseases continues to increase.With increased funding and directed research efforts,we can aim to improvemedical treatments and the quality of life for patients at risk for liver deterioration.
文摘Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.
