INTRODUCTIONα-ketoadipate(α-KA),an intermediate in thecatabolism of L-lysine,hydroxylysine,and L-tryptophan,undergoes oxidative deearboxylation toform glutaryl-CoA and then dehydrogenates to formcrotonyl-CoA,the lat...INTRODUCTIONα-ketoadipate(α-KA),an intermediate in thecatabolism of L-lysine,hydroxylysine,and L-tryptophan,undergoes oxidative deearboxylation toform glutaryl-CoA and then dehydrogenates to formcrotonyl-CoA,the latter undergoes furtherdegradation and enters in TCA cycle,as shown inFigure 1.α-ketoadipic aciduria (Mckusick 245130)is a rare inborn error in the metabolism of α-KA展开更多
Methylmalonic aciduria（MMA） is a common inherited autosomal recessive disorder resulting from defects in the enzyme methylmalonyl CoA mutase（MCM,mut complementation group） or in the synthesis of the MCM cofactor a...Methylmalonic aciduria（MMA） is a common inherited autosomal recessive disorder resulting from defects in the enzyme methylmalonyl CoA mutase（MCM,mut complementation group） or in the synthesis of the MCM cofactor adenosylcobalamin（cbl complementation groups）.The defects in the mut complementation group accounts for the largest number of patients with isolated MMA.At least 200 mutations in the MUT gene on chromosome 6p12 have been identified in MMA patients until now.This study aimed to investigate the clinical characteristics of MMA and genomic variations in the MUT gene of Chinese patients.Genomic DNA was extracted from 18 patients who were diagnosed as having isolated MMA by gas chromatography/mass spectrometry（GC-MS）,and from some of their parents as well.Amplification and direct sequencing of the MUT coding regions（exon 2-13） and their adjacent intronic consensus splice sites were performed in order to identify the disease causing mutations.In this group,six novel mutations in the MUT gene,c.424AG（p.T142A）,c.786TG（p.S262R）,c.808GC（p.G270R）,c.1323_1324insA,c.1445-1GA and c.1676＋77AC were identified.p.T142A and p.G270R were respectively detected at a heterozygous level in one patient.Two previously reported mutations,c.682CT（p.R228X） and c.323GA（p.R108H） were also found in this study.In addition,six previously described single nucleotide polymorphism（SNP）,c.636AG（p.K212K）,c.1495GA（p.A499T）,c.1595AG（p.H532R）,c.1992GA（p.A664A）,c.2011GA（p.V671I） and c.1677-53AG were identified.In this study,we updated the spectrum of MUT mutations and identified the main MMA-causing mutations in Chinese MMA patients.展开更多
Objective To follow up study on α-ketoadipic aciduria , which is a rare inborn error of metabolism of L-ly sine, hydroxy-L-lysine, and L-tryptophan. Methods The case with α-ketoadipic aciduria was investigated ...Objective To follow up study on α-ketoadipic aciduria , which is a rare inborn error of metabolism of L-ly sine, hydroxy-L-lysine, and L-tryptophan. Methods The case with α-ketoadipic aciduria was investigated clinically and metabolites were detected by using gas chromatography-mass spectrometry techniques during a period of 15 years (9months～ 15years). Results The case had growth retardation at the onset but later grew normally. The urinary metabolites showed persisent abnormality compatible with α-ketoadipic aciduria. The concentrations of α-ketoadipate , α-aminoadipate and α-hy droxyadipate were 33mmol/mol creatinine, 92～266mmol/mol creatinine and 17～28mmol/mol creatinine , respectively. Glutarate also increased in their urine. Conclusion The study suggested the clinical course of a-ketoadipic aciduria is benign and the clinical manifestations are various. The follow-up study on this case with α-ketoadipic aciduria must be continued.展开更多
Methylmalonic aciduria （MMA） is an autosomal recessive disorder of cobalamin （cbl） metabolism. Cobalamin C （cblC） disease is the most common type of MMA and is characteristically concurrent with homocystinemia ...Methylmalonic aciduria （MMA） is an autosomal recessive disorder of cobalamin （cbl） metabolism. Cobalamin C （cblC） disease is the most common type of MMA and is characteristically concurrent with homocystinemia （HCY） due to impaired synthesis of two active forms of cbl, namely adenosylcobalamin （AdoCbl） and methylcobalamin （MeCbl）. The estimated worldwide incidence of MMA ranges between 1：48,000 and 1：250,000. Mutations of the MMA and HCY type C protein （MMACtfC） gene are responsible for cblC disease and were first identified by Lerner-Ellis et aL in 2006.By the year 2016, more than 82 different MMACHC gene mutations have been reported （http：// www.hgmd.cf.ac.uk/ac/index.php）. Among these mutations, c.609G〉A （p.W203X） was reported to be the most frequent cblC mutation in Chinese patients.展开更多
Background:Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.Methods:A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardi...Background:Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.Methods:A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein’s cardiac anomaly was performed.Results:The levels of ammonia,methylmalonic acid,free carnitine,and propionylcarnitine of the patient were improved.The patient survived surgery following institution of four metabolic treatment principles:1)restriction of toxic substrate;2)promotion of anabolism via administration of carbohydrate and lipid calories;3)administration of detoxifying levocarnitine and sodium benzoate;and 4)cobalamin enzymatic co-factor administration.The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe,cobalamin non-responsive disease:c.322C>T/c.1233del3(p.R108C/p.ΔI412).Conclusion:Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment.展开更多
Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisi...Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.展开更多
基金the grant from the J.A.M.W.Ogyaa Donation Foundation (JODF)National Science Foundation for High-Technology Research Center of Kanazawa Medical University (H98-3).
文摘INTRODUCTIONα-ketoadipate(α-KA),an intermediate in thecatabolism of L-lysine,hydroxylysine,and L-tryptophan,undergoes oxidative deearboxylation toform glutaryl-CoA and then dehydrogenates to formcrotonyl-CoA,the latter undergoes furtherdegradation and enters in TCA cycle,as shown inFigure 1.α-ketoadipic aciduria (Mckusick 245130)is a rare inborn error in the metabolism of α-KA
基金supported by grants from the National Basic Research Program of China(2005CB522507)the 11th Five-year Plan of National Science & Technology(2006BAI05A07)
文摘Methylmalonic aciduria（MMA） is a common inherited autosomal recessive disorder resulting from defects in the enzyme methylmalonyl CoA mutase（MCM,mut complementation group） or in the synthesis of the MCM cofactor adenosylcobalamin（cbl complementation groups）.The defects in the mut complementation group accounts for the largest number of patients with isolated MMA.At least 200 mutations in the MUT gene on chromosome 6p12 have been identified in MMA patients until now.This study aimed to investigate the clinical characteristics of MMA and genomic variations in the MUT gene of Chinese patients.Genomic DNA was extracted from 18 patients who were diagnosed as having isolated MMA by gas chromatography/mass spectrometry（GC-MS）,and from some of their parents as well.Amplification and direct sequencing of the MUT coding regions（exon 2-13） and their adjacent intronic consensus splice sites were performed in order to identify the disease causing mutations.In this group,six novel mutations in the MUT gene,c.424AG（p.T142A）,c.786TG（p.S262R）,c.808GC（p.G270R）,c.1323_1324insA,c.1445-1GA and c.1676＋77AC were identified.p.T142A and p.G270R were respectively detected at a heterozygous level in one patient.Two previously reported mutations,c.682CT（p.R228X） and c.323GA（p.R108H） were also found in this study.In addition,six previously described single nucleotide polymorphism（SNP）,c.636AG（p.K212K）,c.1495GA（p.A499T）,c.1595AG（p.H532R）,c.1992GA（p.A664A）,c.2011GA（p.V671I） and c.1677-53AG were identified.In this study,we updated the spectrum of MUT mutations and identified the main MMA-causing mutations in Chinese MMA patients.
文摘Objective To follow up study on α-ketoadipic aciduria , which is a rare inborn error of metabolism of L-ly sine, hydroxy-L-lysine, and L-tryptophan. Methods The case with α-ketoadipic aciduria was investigated clinically and metabolites were detected by using gas chromatography-mass spectrometry techniques during a period of 15 years (9months～ 15years). Results The case had growth retardation at the onset but later grew normally. The urinary metabolites showed persisent abnormality compatible with α-ketoadipic aciduria. The concentrations of α-ketoadipate , α-aminoadipate and α-hy droxyadipate were 33mmol/mol creatinine, 92～266mmol/mol creatinine and 17～28mmol/mol creatinine , respectively. Glutarate also increased in their urine. Conclusion The study suggested the clinical course of a-ketoadipic aciduria is benign and the clinical manifestations are various. The follow-up study on this case with α-ketoadipic aciduria must be continued.
文摘Methylmalonic aciduria （MMA） is an autosomal recessive disorder of cobalamin （cbl） metabolism. Cobalamin C （cblC） disease is the most common type of MMA and is characteristically concurrent with homocystinemia （HCY） due to impaired synthesis of two active forms of cbl, namely adenosylcobalamin （AdoCbl） and methylcobalamin （MeCbl）. The estimated worldwide incidence of MMA ranges between 1：48,000 and 1：250,000. Mutations of the MMA and HCY type C protein （MMACtfC） gene are responsible for cblC disease and were first identified by Lerner-Ellis et aL in 2006.By the year 2016, more than 82 different MMACHC gene mutations have been reported （http：// www.hgmd.cf.ac.uk/ac/index.php）. Among these mutations, c.609G〉A （p.W203X） was reported to be the most frequent cblC mutation in Chinese patients.
基金Commission for Families and Children of Orange County
文摘Background:Effects of circulatory arrest upon an inborn error of metabolism patient are unknown.Methods:A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein’s cardiac anomaly was performed.Results:The levels of ammonia,methylmalonic acid,free carnitine,and propionylcarnitine of the patient were improved.The patient survived surgery following institution of four metabolic treatment principles:1)restriction of toxic substrate;2)promotion of anabolism via administration of carbohydrate and lipid calories;3)administration of detoxifying levocarnitine and sodium benzoate;and 4)cobalamin enzymatic co-factor administration.The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe,cobalamin non-responsive disease:c.322C>T/c.1233del3(p.R108C/p.ΔI412).Conclusion:Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment.
基金the National Key Research and Development Program(2019YFA0110800 and 2020YFA0707900 to W.L.,and 2018YFA0108400 and 2019YFA0903800 to Q.Z.)Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030403 to W.L.)+1 种基金National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.).
文摘Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.
