Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typi...Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.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
BACKGROUND Pulmonary hypertension (PH) causes significant morbidity and mortality in diverse childhood diseases.However,limited information has been reported to obtain a good understanding of pediatric PH.Gaps exist b...BACKGROUND Pulmonary hypertension (PH) causes significant morbidity and mortality in diverse childhood diseases.However,limited information has been reported to obtain a good understanding of pediatric PH.Gaps exist between genome sequencing and metabolic assessments and lead to misinterpretations of the complicated symptoms of PH.Here,we report a rare case of a patient who presented with severe PH as the first manifestation without significant cardiovascular malformation and was finally diagnosed with methylmalonic aciduria (MMA) after metabolic and genomic assessments.CASE SUMMARY An 11-year-old female presented with an aggressive reduction in activity capability and shortness of breath for only 4 mo and suffered from unexplained PH.A series of examinations was performed to evaluate any possible malformations or abnormalities of the cardiovascular system and lungs,but negative results were obtained.The blood tests were normal except for manifestations of microcytic anemia and elevated total homocysteine.Computed tomography and magnetic resonance imaging failed to identify any pulmonary diseases.Cardiac catheterization examination identified a small right coronary artery to pulmonary artery shunt and severe PH.During the follow-up,PH progressed rapidly.Then,genome sequencing and metabolic disorder screening were performed,which confirmed a diagnosis of MMA with MMACHC c.80A>G/c and 609G> A mutations.Vitamin B12,betaine and bosentan were then administered as the main treatments.During the 6-mo follow-up,the pulmonary artery pressure dropped to 45 mmHg,while the right ventricle structure recovered.The patient’s heart function recovered to NYHA class Ⅱ.Metabolic disorder analysis failed to identify significant abnormalities.CONCLUSION As emerging types of metabolic dysfunction have been shown to present as the first manifestation of PH,and taking advantage of next generation sequencing technology,genome sequencing and metabolic disorder screening are recommended to have a more superior role when attempting to understand unclear or aggressive PH.展开更多
Context: Metformin is frequently prescribed for the treatment of type 2 diabetes mellitus. It is recommended as a first line agent by the American Diabetes Association. Vitamin B12 deficiency has been suggested as a s...Context: Metformin is frequently prescribed for the treatment of type 2 diabetes mellitus. It is recommended as a first line agent by the American Diabetes Association. Vitamin B12 deficiency has been suggested as a side effect of metformin therapy;however, previous studies have not assessed the utility of methylmalonic acid levels as an indicator of vitamin B12 status. Objective: To investigate the prevalence of vitamin B12 deficiency in patients on metformin therapy for diabetes by utilizing both vitamin B12 and methylmalonic acid levels. Design, Setting, and Patients: Eighty-eight patients with diabetes, who were either on or off metformin therapy for at least thirty days, were enrolled in a case-controlled study. Blood work and questionnaires were used for analysis. Main Outcome Measures Study: Aims were to detect a clinically significant difference in the prevalence of vitamin B12 deficiency between metformin users and non-users, where such deficiency is defined by both low vitamin B12 and elevated methylmalonic acid levels. Results: Two Sample Equal Variance T-Tests were used to compare averages of measured values and the Chisquare test was used to determine the significance of calculated vitamin B12 deficiency rates between the two groups of patients. Two separate methods for defining vitamin B12 deficiency were utilized. There was no difference in the prevalence of vitamin B12 deficiency in metformin users compared with non-users by either method. Average homocysteine levels were higher in those not on metformin therapy. Conclusion: Vitamin B12 deficiency as defined by an elevated methylmalonic acid level was no greater in patients with diabetes on metformin therapy versus those patients not on metformin treatment.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:There are few detailed consensus and guidelines on perioperative clinical characteristicsof liver transplantation(LT)in patients with methylmalonic acidemia(MMA).This retrospective studyinvestigated details...Background:There are few detailed consensus and guidelines on perioperative clinical characteristicsof liver transplantation(LT)in patients with methylmalonic acidemia(MMA).This retrospective studyinvestigated details of the clinical course and individualized treatment plan of the center with largestexperience in China.Methods:A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 toDecember 2017 were enrolled in the study,whose clinical data(clinical characteristics,laboratory findings,chronological changes in urine MMA levels,treatment,etc.)during perioperative period were analyzedretrospectively.All the patients received strict postoperative management.Results:All the 7 cases were confirmed to have isolated MMA,among which,3 cases received livingdonor liver transplantation(LDLT),4 cases received deceased donor liver transplantation(DDLT).A wildfluctuate of metabolic condition was observed within the first few days after surgery and two weeks afterLT,the mean base excess of blood value(BE-B)restored to normal whereas plasma bicarbonate(HCO3-)was still below normal value even with intermittent sodium bicarbonate correction.It also showed markedreduction in propionylcarnitine(C3)and C3/C2 level and the mean urine MMA by gas chromatographymassspectrometry(GC-MS)was reduced by 81.7%(P<0.01)but remained>72×higher than upper limitof normal.The metabolism-correcting medications were administered as before.The renal function ofone case with renal insufficiency before LT(serum creatinine rising)maintained stable by adjusting theimmunosuppressive regimen during the observation period.All patients survive to date.Conclusions:LT is an effective treatment to prevent metabolic crisis,but patients with MMA tend to bemetabolically fragile even after surgery.During perioperative period,close monitoring should be given foracidosis episodes so as to implement sodium bicarbonate correction.Metabolism-correcting medications arestill needed.Special immunosuppressive regimen is an effective way of maintaining renal function for thosewith kidney dysfunction.展开更多
Background Methylmalonic aciduria （MMA） is the most frequent disease of organic aciduria in China. Various biochemical strategies are followed for the prenatal diagnosis of MMA. However, since fetuses affected by MM...Background Methylmalonic aciduria （MMA） is the most frequent disease of organic aciduria in China. Various biochemical strategies are followed for the prenatal diagnosis of MMA. However, since fetuses affected by MMA have decreased excretion of methylmalonic acid, the difficulties of prenatal biochemical diagnosis are obvious. Gas chromatography mass spectrometry （GC/MS） and tandem mass spectrometry （ESl/MS/MS） have allowed us to identify the disease in affected fetuses. The aim of this study was to determine the value of analysis of organic acids and total homocysteine in amniotic fluid in prenatal diagnosis of MMA. Methods The clinical diagnoses and outcomes of nine probands with MMA and the prenatal diagnoses based on biochemical analysis of nine fetuses at risk for MMA were investigated. Amniotic fluid samples from pregnancies at risk for MMA and metabolically normal pregnancies were obtained at 16-24 weeks of gestation. Methylmalonic acid and methylcitric acid were measured by GC/MS, propionylcarnitine was analyzed by ESl/MS/MS, and total homocysteine was determined by fluorescence polarization immunoassay. Results In two pregnancies, high levels of methylmalonic acid, methylcitric acid, propionylcarnitine, and total homocysteine indicated combined MMA and homocysteinemia in the fetuses. One of the mothers continued pregnancy and received cobalamin supplement as prenatal treatment, and the other terminated her pregnancy. In one pregnancy, significantly elevated levels of methylmalonic acid, methylcitric acid, and propionylcarnitine, and normal level of total homocysteine was found indicating isolated MMA in the fetus; abortion was performed on this case. In the other six pregnancies, all the levels of the above mentioned metabolites were normal suggesting that the fetuses were not affected by MMA. The diagnoses were confirmed after delivery by testing urinary organic acids and plasma total homocysteine. Conclusions The metabolic abnormalities of MMA occur early in gestation. The level of total homocysteine in amniotic fluid may be an additional indicator of fetal combined MMA and homocysteinemia. Determination of total homocysteine level in amniotic fluid may become a convenient and reliable method for prenatal diagnosis of the disease.展开更多
Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: For...Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identified MUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.展开更多
Background Methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to wh...Background Methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging （DTI） is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. Methods We retrospectively analyzed DTI images of 12 patients with MMA （7 males, 5 females, age range： 7-12 months, mean age： 9.25±1.70 months） with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy （FA） of different white matter tracts of the brain was measured in both groups. Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed （P〈0.01）. Conclusions In addition to conventional TlW and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.展开更多
Background:Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT).This study aimed to verify whether missens...Background:Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT).This study aimed to verify whether missense mutations in MUT in Chinese patients affect the stability and enzymatic activity of MCM.Methods:Eight Chinese patients were identified with novel mutations.Plasmids carrying the wild-type and mutated MUT cDNA were constructed and transfected into HEK293T cells for functional analyses.The expression and activity of MCM were determined by western blot and ultra-performance liquid chromatography,respectively.Results:All patients had high levels of blood propionylcarnitine and urinary methylmalonyl acid.By the end of the study,two patients were lost to follow-up,three died,and three survived with mental retardation.Compared to the wild-type protein,the expression levels of all missense mutations of in vitro MCM protein were decreased (P<0.05) except those for I597R,and the MCM activity of the mutations was reduced in a permissive assay.Conclusion:The missense mutations L140P,A141T,G161V,W309G,I505T,Q514K,I597R and G723D affected the stability and enzymatic activity of MCM,indicating that they had a disease-causing capacity.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
Background Liver transplantation(LT)has been proposed as a viable treatment option for selected methylmalonic acidemia(MMA)patients.However,there are still controversies regarding the therapeutic value of LT for MMA.T...Background Liver transplantation(LT)has been proposed as a viable treatment option for selected methylmalonic acidemia(MMA)patients.However,there are still controversies regarding the therapeutic value of LT for MMA.The systematic assessment of health-related quality of life(HRQoL)-targeted MMA children before and after LT is also undetermined.This study aimed to comprehensively assess the long-term impact of LT on MMA,including multiorgan sequelae and HRQoL in children and families.Methods We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022.Pre-and post-transplant data were compared,including metabolic profiles,neurologic consequences,growth parameters,and HRQoL.To further assess the characteristics of the HRQoL outcomes in MMA,we compared the results with those of children with biliary atresia(BA).Results All patients had early onset MMA,and underwent LT at a mean age of 4.3 years.During 1.3–8.2 years of follow-up,the patient and graft survival rates were 100%.Metabolic stability was achieved in all patients with liberalized dietary protein intake.There was a significant overall improvement in height Z scores(P=0.0047),and some preexisting neurological complications remained stable or even improved after LT.On the Pediatric Quality of Life Inventory(PedsQL™)generic core scales,the mean total,physical health,and psychosocial health scores improved significantly posttransplant(P<0.05).In the family impact module,higher mean scores were noted for all subscales post-LT,especially family function and daily activities(P<0.01).However,the total scores on the generic core scales and transplant module were significantly lower(Cohen’s d=0.57–1.17)when compared with BA recipients.In particular,social and school functioning(Cohen’s d=0.86–1.76),treatment anxiety,and communication(Cohen’s d=0.99–1.81)were far behind,with a large effect size.Conclusions This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival,metabolic control,and HRQoL in children and families.The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care.展开更多
AIM: To analyze a large population of patients with diabetes and peripheral neuropathy(PN) to determine other meaningful comorbid etiologies for PN.METHODS: Peripheral Neuropathy is a common complication of type 1 and...AIM: To analyze a large population of patients with diabetes and peripheral neuropathy(PN) to determine other meaningful comorbid etiologies for PN.METHODS: Peripheral Neuropathy is a common complication of type 1 and 2 diabetes mellitus;however,other potential causes for PN may be co-existing in patients with diabetes.A prospective cohort study was performed to assess patients with diabetes and PN.We compared patients having PN due solely to diabetes with patients possessing co-existing comorbidities,performing clinical(Toronto Clinical Scoring System and the Utah Early Neuropathy Scale),laboratory and electrophysiological assessments in all patients.RESULTS: Patients with either type 1 or 2 diabetes mellitus and co-existing comorbidities did not have more severe clinical or electrophysiological PN phenotypes overall.However,in patients with type 1 diabetes,presence of a lipid disorder was associated with greater PN severity.In type 2 diabetes patients,both a lipid disorder and cobalamin deficiency were associated with greater PN severity.There was no additive effect upon PN severity with presence of three or more comorbid etiologies.CONCLUSION: The presence of specific,and not general,comorbidities in patients with type 1 or 2 diabetes corresponds with greater PN severity.展开更多
Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the ...Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.展开更多
Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.El...Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.展开更多
Vitamin B 12 is an organometallic compound with important metabolic derivatives that act as cofactors of certain enzymes,which have been grouped into three subfamilies depending on their cofactors.Among them,methylmal...Vitamin B 12 is an organometallic compound with important metabolic derivatives that act as cofactors of certain enzymes,which have been grouped into three subfamilies depending on their cofactors.Among them,methylmalonyl-CoA mutase (MCM) has been extensively studied.This enzyme catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin (AdoCbl) as a cofactor participating in the generation of radicals that allow isomerization of the substrate.The crystal structure of MCM determined in Propionibacterium freudenreichii var.shermanii has helped to elucidate the role of this cofactor AdoCbl in the reaction to specify the mechanism by which radicals are generated from the coenzyme and to clarify the interactions between the enzyme,coenzyme,and substrate.The existence of human methylmalonic acidemia (MMA) due to the presence of mutations in MCM shows the importance of its role in metabolism.The recent crystallization of the human MCM has shown that despite being similar to the bacterial protein,there are significant differences in the structural organization of the two proteins.Recent studies have identified the involvement of an accessory protein called MMAA,which interacts with MCM to prevent MCM's inactivation or acts as a chaperone to promote regeneration of inactivated enzyme.The interdisciplinary studies using this protein as a model in different organisms have helped to elucidate the mechanism of action of this isomerase,the impact of mutations at a functional level and their repercussion in the development and progression of MMA in humans.It is still necessary to study the mechanisms involved in more detail using new methods.展开更多
文摘Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.
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BACKGROUND Pulmonary hypertension (PH) causes significant morbidity and mortality in diverse childhood diseases.However,limited information has been reported to obtain a good understanding of pediatric PH.Gaps exist between genome sequencing and metabolic assessments and lead to misinterpretations of the complicated symptoms of PH.Here,we report a rare case of a patient who presented with severe PH as the first manifestation without significant cardiovascular malformation and was finally diagnosed with methylmalonic aciduria (MMA) after metabolic and genomic assessments.CASE SUMMARY An 11-year-old female presented with an aggressive reduction in activity capability and shortness of breath for only 4 mo and suffered from unexplained PH.A series of examinations was performed to evaluate any possible malformations or abnormalities of the cardiovascular system and lungs,but negative results were obtained.The blood tests were normal except for manifestations of microcytic anemia and elevated total homocysteine.Computed tomography and magnetic resonance imaging failed to identify any pulmonary diseases.Cardiac catheterization examination identified a small right coronary artery to pulmonary artery shunt and severe PH.During the follow-up,PH progressed rapidly.Then,genome sequencing and metabolic disorder screening were performed,which confirmed a diagnosis of MMA with MMACHC c.80A>G/c and 609G> A mutations.Vitamin B12,betaine and bosentan were then administered as the main treatments.During the 6-mo follow-up,the pulmonary artery pressure dropped to 45 mmHg,while the right ventricle structure recovered.The patient’s heart function recovered to NYHA class Ⅱ.Metabolic disorder analysis failed to identify significant abnormalities.CONCLUSION As emerging types of metabolic dysfunction have been shown to present as the first manifestation of PH,and taking advantage of next generation sequencing technology,genome sequencing and metabolic disorder screening are recommended to have a more superior role when attempting to understand unclear or aggressive PH.
文摘Context: Metformin is frequently prescribed for the treatment of type 2 diabetes mellitus. It is recommended as a first line agent by the American Diabetes Association. Vitamin B12 deficiency has been suggested as a side effect of metformin therapy;however, previous studies have not assessed the utility of methylmalonic acid levels as an indicator of vitamin B12 status. Objective: To investigate the prevalence of vitamin B12 deficiency in patients on metformin therapy for diabetes by utilizing both vitamin B12 and methylmalonic acid levels. Design, Setting, and Patients: Eighty-eight patients with diabetes, who were either on or off metformin therapy for at least thirty days, were enrolled in a case-controlled study. Blood work and questionnaires were used for analysis. Main Outcome Measures Study: Aims were to detect a clinically significant difference in the prevalence of vitamin B12 deficiency between metformin users and non-users, where such deficiency is defined by both low vitamin B12 and elevated methylmalonic acid levels. Results: Two Sample Equal Variance T-Tests were used to compare averages of measured values and the Chisquare test was used to determine the significance of calculated vitamin B12 deficiency rates between the two groups of patients. Two separate methods for defining vitamin B12 deficiency were utilized. There was no difference in the prevalence of vitamin B12 deficiency in metformin users compared with non-users by either method. Average homocysteine levels were higher in those not on metformin therapy. Conclusion: Vitamin B12 deficiency as defined by an elevated methylmalonic acid level was no greater in patients with diabetes on metformin therapy versus those patients not on metformin treatment.
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This work was supported by The Capital Health Research and Development of Special(No.2016-1-2021)and Beijing Municipal Administration of Hospitals Ascent Plan(Code:DFL20150101).
文摘Background:There are few detailed consensus and guidelines on perioperative clinical characteristicsof liver transplantation(LT)in patients with methylmalonic acidemia(MMA).This retrospective studyinvestigated details of the clinical course and individualized treatment plan of the center with largestexperience in China.Methods:A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 toDecember 2017 were enrolled in the study,whose clinical data(clinical characteristics,laboratory findings,chronological changes in urine MMA levels,treatment,etc.)during perioperative period were analyzedretrospectively.All the patients received strict postoperative management.Results:All the 7 cases were confirmed to have isolated MMA,among which,3 cases received livingdonor liver transplantation(LDLT),4 cases received deceased donor liver transplantation(DDLT).A wildfluctuate of metabolic condition was observed within the first few days after surgery and two weeks afterLT,the mean base excess of blood value(BE-B)restored to normal whereas plasma bicarbonate(HCO3-)was still below normal value even with intermittent sodium bicarbonate correction.It also showed markedreduction in propionylcarnitine(C3)and C3/C2 level and the mean urine MMA by gas chromatographymassspectrometry(GC-MS)was reduced by 81.7%(P<0.01)but remained>72×higher than upper limitof normal.The metabolism-correcting medications were administered as before.The renal function ofone case with renal insufficiency before LT(serum creatinine rising)maintained stable by adjusting theimmunosuppressive regimen during the observation period.All patients survive to date.Conclusions:LT is an effective treatment to prevent metabolic crisis,but patients with MMA tend to bemetabolically fragile even after surgery.During perioperative period,close monitoring should be given foracidosis episodes so as to implement sodium bicarbonate correction.Metabolism-correcting medications arestill needed.Special immunosuppressive regimen is an effective way of maintaining renal function for thosewith kidney dysfunction.
基金This study was supported by grants from the Foundation lor Human Disease Genomics of Peking University （2001-02）, the National Natural Science Foundation of China （No. 30471832）, and the Clinical Key Program of China Ministry of Health （No. 2001-0912）.Acknowledgements： We thank Prof. Yosuke Shigematsu at the Department of Health Science and Pediatrics, Faculty of Medical Sciences, University of Fukui for technical assistance and collaboration Prof. GU Xue-fan at Shanghai Institute for Pediatrics Research, Shanghai Jiaotong University and Prof. LUO Xiao-ping at the Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology and other colleagues for their support and helpful discussion.
文摘Background Methylmalonic aciduria （MMA） is the most frequent disease of organic aciduria in China. Various biochemical strategies are followed for the prenatal diagnosis of MMA. However, since fetuses affected by MMA have decreased excretion of methylmalonic acid, the difficulties of prenatal biochemical diagnosis are obvious. Gas chromatography mass spectrometry （GC/MS） and tandem mass spectrometry （ESl/MS/MS） have allowed us to identify the disease in affected fetuses. The aim of this study was to determine the value of analysis of organic acids and total homocysteine in amniotic fluid in prenatal diagnosis of MMA. Methods The clinical diagnoses and outcomes of nine probands with MMA and the prenatal diagnoses based on biochemical analysis of nine fetuses at risk for MMA were investigated. Amniotic fluid samples from pregnancies at risk for MMA and metabolically normal pregnancies were obtained at 16-24 weeks of gestation. Methylmalonic acid and methylcitric acid were measured by GC/MS, propionylcarnitine was analyzed by ESl/MS/MS, and total homocysteine was determined by fluorescence polarization immunoassay. Results In two pregnancies, high levels of methylmalonic acid, methylcitric acid, propionylcarnitine, and total homocysteine indicated combined MMA and homocysteinemia in the fetuses. One of the mothers continued pregnancy and received cobalamin supplement as prenatal treatment, and the other terminated her pregnancy. In one pregnancy, significantly elevated levels of methylmalonic acid, methylcitric acid, and propionylcarnitine, and normal level of total homocysteine was found indicating isolated MMA in the fetus; abortion was performed on this case. In the other six pregnancies, all the levels of the above mentioned metabolites were normal suggesting that the fetuses were not affected by MMA. The diagnoses were confirmed after delivery by testing urinary organic acids and plasma total homocysteine. Conclusions The metabolic abnormalities of MMA occur early in gestation. The level of total homocysteine in amniotic fluid may be an additional indicator of fetal combined MMA and homocysteinemia. Determination of total homocysteine level in amniotic fluid may become a convenient and reliable method for prenatal diagnosis of the disease.
基金supported by grants from the National Key Technology R&D Program(2012BAI09B04)the Special Basic Work of Science and Technology(2014FY110700).
文摘Background: This study aims to study MUT gene mutation spectrum in Chinese patients with isolated methylmalonic academia (MMA) and their clinical features for the potential genotype-phenotype correlation. Methods: Forty-three patients were diagnosed with isolated MMA by elevated blood propionylcarnitine, propionylcarnitine to acetylcarnitine ratio, and urine methylmalonate without hyperhomocysteinemia. The MUT gene was amplifi ed by polymerase chain reaction and directly sequenced. Those patients with at least one variant allele were included. The novel missense mutations were assessed by bioinformatic analysis and screened against alleles sequenced from 50 control participants. Results: Among the 43 patients, 38 had typical clinical presentations, and the majority (30/38) experienced early-onset MMA. Eight patients died and seven were lost to follow-up. Twenty patients had poor outcomes and eight showed normal development. The 43 identified MUT gene mutations had at least one variant allele, whereas 35 had two mutant alleles. Of the 33 mutations reported before, eight recurrent mutations were identified in 32 patients, and c.729_730insTT (p.D244Lfs*39) was the most common (12/78) in the mutant alleles. Of the 10 novel mutations, six were missense mutations and four were premature termination codon mutations. The six novel missense mutations seemed to be pathogenic. Conclusions: A total of 10 novelMUT mutations were detected in the Chinese population. c.729_730insTT (p.D244Lfs*39) was the most frequent mutation. A genotype-phenotype correlation could not be found, but the genotypic characterization indicated the need of genetic counseling for MMA patients and early prenatal diagnoses for high-risk families.
基金This work was supported by National Science Foundation of China （No. 50537030）.
文摘Background Methylmalonic acidemia （MMA） is a multifactorial autosomal recessive inborn error of organic acid metabolism, often presenting with neurological symptoms. As neurological disorders are often related to white matter injury, diffusion tensor imaging （DTI） is an excellent tool for assessment of white matter injury and possibly for diagnosing this disorder. Methods We retrospectively analyzed DTI images of 12 patients with MMA （7 males, 5 females, age range： 7-12 months, mean age： 9.25±1.70 months） with negative MRI findings. And another 12 age-matched and gender-matched infants were enrolled as control subjects. Fractional anisotropy （FA） of different white matter tracts of the brain was measured in both groups. Results For patients with negative MRI findings, compared with healthy infants, a statistically significant reduction in DTI FA value of the frontal white matter, temporal white matter, and occipital white matter was observed （P〈0.01）. Conclusions In addition to conventional TlW and T2W MR Image, Brain DTI presents a useful, sensitive and complementary tool for the assessment of brain damage in patients with MMA.
文摘Background:Isolated methylmalonic acidemia is a rare autosomal recessive metabolic disorder mostly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MUT).This study aimed to verify whether missense mutations in MUT in Chinese patients affect the stability and enzymatic activity of MCM.Methods:Eight Chinese patients were identified with novel mutations.Plasmids carrying the wild-type and mutated MUT cDNA were constructed and transfected into HEK293T cells for functional analyses.The expression and activity of MCM were determined by western blot and ultra-performance liquid chromatography,respectively.Results:All patients had high levels of blood propionylcarnitine and urinary methylmalonyl acid.By the end of the study,two patients were lost to follow-up,three died,and three survived with mental retardation.Compared to the wild-type protein,the expression levels of all missense mutations of in vitro MCM protein were decreased (P<0.05) except those for I597R,and the MCM activity of the mutations was reduced in a permissive assay.Conclusion:The missense mutations L140P,A141T,G161V,W309G,I505T,Q514K,I597R and G723D affected the stability and enzymatic activity of MCM,indicating that they had a disease-causing capacity.
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supported by the National Natural Science Foundation of China(82270685)Capital's Funds for Health Improvement and Research(No.2024-4-1111)Research Foundation of Beijing Friendship Hospital,Capital Medical University(No.yybsh2021006)。
文摘Background Liver transplantation(LT)has been proposed as a viable treatment option for selected methylmalonic acidemia(MMA)patients.However,there are still controversies regarding the therapeutic value of LT for MMA.The systematic assessment of health-related quality of life(HRQoL)-targeted MMA children before and after LT is also undetermined.This study aimed to comprehensively assess the long-term impact of LT on MMA,including multiorgan sequelae and HRQoL in children and families.Methods We retrospectively evaluated 15 isolated MMA patients undergoing LT at our institution between June 2013 and March 2022.Pre-and post-transplant data were compared,including metabolic profiles,neurologic consequences,growth parameters,and HRQoL.To further assess the characteristics of the HRQoL outcomes in MMA,we compared the results with those of children with biliary atresia(BA).Results All patients had early onset MMA,and underwent LT at a mean age of 4.3 years.During 1.3–8.2 years of follow-up,the patient and graft survival rates were 100%.Metabolic stability was achieved in all patients with liberalized dietary protein intake.There was a significant overall improvement in height Z scores(P=0.0047),and some preexisting neurological complications remained stable or even improved after LT.On the Pediatric Quality of Life Inventory(PedsQL™)generic core scales,the mean total,physical health,and psychosocial health scores improved significantly posttransplant(P<0.05).In the family impact module,higher mean scores were noted for all subscales post-LT,especially family function and daily activities(P<0.01).However,the total scores on the generic core scales and transplant module were significantly lower(Cohen’s d=0.57–1.17)when compared with BA recipients.In particular,social and school functioning(Cohen’s d=0.86–1.76),treatment anxiety,and communication(Cohen’s d=0.99–1.81)were far behind,with a large effect size.Conclusions This large single-center study of the mainland of China showed an overall favorable impact of LT on isolated MMA in terms of long-term survival,metabolic control,and HRQoL in children and families.The potential for persistent neurocognitive impairment and inherent metabolic fragility requires long-term special care.
文摘AIM: To analyze a large population of patients with diabetes and peripheral neuropathy(PN) to determine other meaningful comorbid etiologies for PN.METHODS: Peripheral Neuropathy is a common complication of type 1 and 2 diabetes mellitus;however,other potential causes for PN may be co-existing in patients with diabetes.A prospective cohort study was performed to assess patients with diabetes and PN.We compared patients having PN due solely to diabetes with patients possessing co-existing comorbidities,performing clinical(Toronto Clinical Scoring System and the Utah Early Neuropathy Scale),laboratory and electrophysiological assessments in all patients.RESULTS: Patients with either type 1 or 2 diabetes mellitus and co-existing comorbidities did not have more severe clinical or electrophysiological PN phenotypes overall.However,in patients with type 1 diabetes,presence of a lipid disorder was associated with greater PN severity.In type 2 diabetes patients,both a lipid disorder and cobalamin deficiency were associated with greater PN severity.There was no additive effect upon PN severity with presence of three or more comorbid etiologies.CONCLUSION: The presence of specific,and not general,comorbidities in patients with type 1 or 2 diabetes corresponds with greater PN severity.
文摘Combined liver and kidney transplantation(CLKT)is indicated in patients with failure of both organs,or for the treatment of end-stage chronic kidney disease(ESKD)caused by a genetic defect in the liver.The aim of the present review is to provide the most up-to-date overview of the rare conditions as indications for CLKT.They are major indications for CLKT in children.However,in some of them(e.g.,atypical hemolytic uremic syndrome or primary hyperoxaluria),CLKT may be required in adults as well.Primary hyperoxaluria is divided into three types,of which type 1 and 2 lead to ESKD.CLKT has been proven effective in renal function replacement,at the same time preventing recurrence of the disease.Nephronophthisis is associated with liver fibrosis in 5%of cases and these patients are candidates for CLKT.In alpha 1-antitrypsin deficiency,hereditary C3 deficiency,lecithin cholesterol acyltransferase deficiency and glycogen storage diseases,glomerular or tubulointerstitial disease can lead to chronic kidney disease.Liver transplantation as a part of CLKT corrects underlying genetic and consequent metabolic abnormality.In atypical hemolytic uremic syndrome caused by mutations in the genes for factor H,successful CLKT has been reported in a small number of patients.However,for this indication,CLKT has been largely replaced by eculizumab,an anti-C5 antibody.CLKT has been well established to provide immune protection of the transplanted kidney against donor-specific antibodies against class I HLA,facilitating transplantation in a highly sensitized recipient.
基金supported by grants from the National Natural Science Foundation of China(No.82072979).
文摘Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.
基金Project (No.IN208411) partially supported by the PAPIIT-UNAM of Mexico
文摘Vitamin B 12 is an organometallic compound with important metabolic derivatives that act as cofactors of certain enzymes,which have been grouped into three subfamilies depending on their cofactors.Among them,methylmalonyl-CoA mutase (MCM) has been extensively studied.This enzyme catalyzes the reversible isomerization of L-methylmalonyl-CoA to succinyl-CoA using adenosylcobalamin (AdoCbl) as a cofactor participating in the generation of radicals that allow isomerization of the substrate.The crystal structure of MCM determined in Propionibacterium freudenreichii var.shermanii has helped to elucidate the role of this cofactor AdoCbl in the reaction to specify the mechanism by which radicals are generated from the coenzyme and to clarify the interactions between the enzyme,coenzyme,and substrate.The existence of human methylmalonic acidemia (MMA) due to the presence of mutations in MCM shows the importance of its role in metabolism.The recent crystallization of the human MCM has shown that despite being similar to the bacterial protein,there are significant differences in the structural organization of the two proteins.Recent studies have identified the involvement of an accessory protein called MMAA,which interacts with MCM to prevent MCM's inactivation or acts as a chaperone to promote regeneration of inactivated enzyme.The interdisciplinary studies using this protein as a model in different organisms have helped to elucidate the mechanism of action of this isomerase,the impact of mutations at a functional level and their repercussion in the development and progression of MMA in humans.It is still necessary to study the mechanisms involved in more detail using new methods.
