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
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
Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positi...Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positive(FP):one true positive(TP)].In this work,our goal was to refne a classifcation model that can minimize the number of false positives,currently an unmet need in the upstream diagnostics of MMA.Methods We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction.We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients,followed by additional ratio feature construction.Feature selection strategies(selection by flter,recursive feature elimination,and learned vector quantization)were used to determine the input set for evaluating the performance of 14 classifcation models to identify a candidate model set for an ensemble model development.Results Our work identifed computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity.The best results[area under the receiver operating characteristic curve(AUROC)of 97%,sensitivity of 92%,and specifcity of 95%]were obtained utilizing an ensemble of the algorithms random forest,C5.0,sparse linear discriminant analysis,and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor.The model achieved a good performance trade-of for a screening application with 6%false-positive rate(FPR)at 95%sensitivity,35%FPR at 99%sensitivity,and 39%FPR at 100%sensitivity.Conclusions The classifcation results and approach of this research can be utilized by clinicians globally,to improve the overall discovery of MMA in pediatric patients.The improved method,when adjusted to 100%precision,can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families.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
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.
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.
基金supported by the National Key R&D Program of China grand No.2022YFC2703103the Clinical Research Plan of SHDC(SHDC2020CR6028,SHDC2020CR1047B)+1 种基金the Science and Technology Commission of Shanghai Municipality grant 22Y11906900the Second Century Fund(C2F),Chulalongkorn University,Bangkok,Thailand.
文摘Introduction Methylmalonic acidemia(MMA)is a disorder of autosomal recessive inheritance,with an estimated prevalence of 1:50,000.First-tier clinical diagnostic tests often return many false positives[fve false positive(FP):one true positive(TP)].In this work,our goal was to refne a classifcation model that can minimize the number of false positives,currently an unmet need in the upstream diagnostics of MMA.Methods We developed machine learning multivariable screening models for MMA with utility as a secondary-tier tool for false positives reduction.We utilized mass spectrometry-based features consisting of 11 amino acids and 31 carnitines derived from dried blood samples of neonatal patients,followed by additional ratio feature construction.Feature selection strategies(selection by flter,recursive feature elimination,and learned vector quantization)were used to determine the input set for evaluating the performance of 14 classifcation models to identify a candidate model set for an ensemble model development.Results Our work identifed computational models that explore metabolic analytes to reduce the number of false positives without compromising sensitivity.The best results[area under the receiver operating characteristic curve(AUROC)of 97%,sensitivity of 92%,and specifcity of 95%]were obtained utilizing an ensemble of the algorithms random forest,C5.0,sparse linear discriminant analysis,and autoencoder deep neural network stacked with the algorithm stochastic gradient boosting as the supervisor.The model achieved a good performance trade-of for a screening application with 6%false-positive rate(FPR)at 95%sensitivity,35%FPR at 99%sensitivity,and 39%FPR at 100%sensitivity.Conclusions The classifcation results and approach of this research can be utilized by clinicians globally,to improve the overall discovery of MMA in pediatric patients.The improved method,when adjusted to 100%precision,can be used to further inform the diagnostic process journey of MMA and help reduce the burden for patients and their families.
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.
