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
BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no ef...BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no effective cure for this disease.Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality.Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.CASE SUMMARY A 12-day-old male neonate with“poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h”was hospitalized.The patient was the first child of nonconsanguineous ethnic Chinese parents.He was delivered by cesarean section due to breech position at 39+1 wk of gestation with a birth weight of 3.27 kg.Initially,he suffered from dyspnea and rhinobyon,and at 10 d after birth the patient suddenly developed poor feeding,low response,lethargy and seizures.Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine.The patient had an acute episode of IVA causing severe metabolic stress and eventually died.CONCLUSION A new case of an IVA patient carrying c.1193G>A(p.Arg398Gln)and c.1208A>G(p.Try403Cys)mutations is reported in China.展开更多
One of the most common recessively inherited organic acidemias is the Propionic Acidosis (PA) which results from Propionyle-CoA Carboxylase (PCC) enzyme deficiency that is necessary for the catabolism of the branched ...One of the most common recessively inherited organic acidemias is the Propionic Acidosis (PA) which results from Propionyle-CoA Carboxylase (PCC) enzyme deficiency that is necessary for the catabolism of the branched chain Amino Acids and other metabolites. Classically this disease presented with high anion gap metabolic acidosis with its clinical consequences. We report 4 patients who presented to our facility with sepsis like picture and no metabolic acidosis. All of them were found to have high ammonia level. Diagnosis was confirmed by tandem MS/MS and urine Gas Chromatography/ Mass Spectrometry (GC/MS). All of them were treated supportively and by supplementation of adequate calories and PA formula. The different presentations may be very well attributed to the PCC molecular defects heterogeneity. Mutations in both genes PCCA and PCCB can cause PA with more frequent heterogeneity of PCCA gene. In spite of the fact that PCCB gene is responsible for the most of the oriental cases, our first patient condition was attributed to PCCA gene with a rare mutation which was not described in the literatures.展开更多
Propionic acidemia is an autosomal recessive disorder that is due to deficiency in the enzyme propionyl-CoA carboxylase. Cardiomyopathy is a well-known phenomenon in propionic acidemia that it may rapidly progress to ...Propionic acidemia is an autosomal recessive disorder that is due to deficiency in the enzyme propionyl-CoA carboxylase. Cardiomyopathy is a well-known phenomenon in propionic acidemia that it may rapidly progress to death. Here we describe a case of propionic acidemia in a 27-year-old man who developed adult-onset secondary dilated cardiomyopathy. In early infancy he was diagnosed with propionic acidemia and was later noted to have mild mental retardation, mild renal failure, and optic nerve atrophy. Although he was in good energy status with a low-protein diet and carnitine supplementation, he was admitted to our university hospital with decompensate heart failure, which resulted in low-output cardiac syndrome with massive mitral regurgitation and left ventricular dyssynchrony. Cardiac resynchronization therapy (CRT) and continuous hemodiafiltration followed by hemodialysis (HD) dramatically improved his clinical status.展开更多
Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electro...Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.展开更多
BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple gen...BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.展开更多
Aim&objective The diagnosis of foetal distress in a clinical setting is based on foetal cardiotocography findings during labour.This study aims to analyse the total deceleration area(TDA)on intrapartum cardiotocog...Aim&objective The diagnosis of foetal distress in a clinical setting is based on foetal cardiotocography findings during labour.This study aims to analyse the total deceleration area(TDA)on intrapartum cardiotocogram which will predict neonatal acidemia at bith.Materials&methods The study participants included women in labour having intrapartum foetal distress(National Institute of Child Halth and Human Development criteria category II and persistent category II on cardiotocogram),who had the 30-min traces(prior to delivery/decision to delivery)and foetal umbilical cord blood gas analysis at delivery.The TDA was calculated and analysed against the cord blood pH obtained at delivery.The deceleration area is calculated as the width of the widest aspect of deceleration(below baseline)measured in minutes which is multiplied by the maximum depth below the baseline and divided by two.TDA is the summation of all the deceleration areas in the last 30 min before delivery.Results A total of 168 participants were analysed.There were 42 cases and 146 controls in the study.The mean TDA in the case and control group was 254.62 missed beats and 165 missed beats,respectively.It was observed that an intrapartum TDA of 2195 missed beats was associated with neonatal acidemia at birth and with an area under curve of 0.6576(95%CI 0.5305 to 0.7847)with a positive predictive value of 83.78%.Conclusion In this study,an intrapartum TDA of≥195 missed beats was significantly associated with neonatal acidemia at birth.The calculation of TDA has simplified intrapartum foetal monitoring.展开更多
Objective To explore brain MRI features of methylmalonic acidemia(MMA).Methods This observational study retrospectively analyzed the clinical and imaging data of 123 patients with MMA diagnosed at Shandong Provincial ...Objective To explore brain MRI features of methylmalonic acidemia(MMA).Methods This observational study retrospectively analyzed the clinical and imaging data of 123 patients with MMA diagnosed at Shandong Provincial Hospital Affiliated to Shandong First Medical University and Qilu Hospital of Shandong University from January 2010 to November 2022.The 123 patients were divided into 7 stages according to age of onset,neonatal period(0 to<1 month),infancy(1 month to<1 year),early childhood(1 to<4 years),preschool(4 to<7 years),school age(7 to<13 years),adolescent(13 to 17 years)and adult(>17 years).All patients underwent brain MRI scanning.The imaging performances were evaluated,including the number,location,morphology of the lesions.Results Of the 123 patients,40 were in the neonatal period,29 in infancy,13 in early childhood,9 in preschool,6 in school age,13 in adolescence,and 13 in adulthood.The first symptoms of patients in the neonatal period were mainly digestive system abnormalities,such as difficulty in breastfeeding(37.5%,15/40)and vomiting(25.0%,10/40),with neurological symptoms gradually becoming the main manifestations from infancy.Seventy-three cases(59.3%)showed significant abnormalities on cranial MRI,including 17 cases with 33 foci in the neonatal period,23 cases with 53 foci in infancy,11 cases with 16 foci in early childhood,2 cases with 2 foci in preschool,3 cases with 7 foci in school age,7 cases with 9 foci in adolescence,and 10 cases with 16 foci in adulthood.In neonatal period,the main manifestations were myelin dysplasia(18%,6/33),dilatation of the lateral ventricular system(18%,6/33),and pallidal bulb infarct foci(18%,6/33);in infancy,the main manifestations were hypoplasia or thinning of the corpus callosum(30%,16/53);in early childhood,the main manifestations were pallidal bulb infarct foci(38%,6/16);and the two MRI abnormalities in preschool were pallidum and thalamic infarct foci;in school age,the main manifestations were infarct foci in the chiasmatic nucleus(29%,2/7)and in the caudate nucleus(29%,2/7);in adolescence,the main manifestation was dilatation of the lateral ventricular system(33%,3/9);and in adulthood,the main manifestation was dilatation of the lateral ventricular system(19%,3/16).Conclusion By staging the age of onset,it is found that the imaging manifestations of MMApatients show significant differences with age,suggesting that there is a dynamic nature of MMA damage to brain structures at different developmental stages.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
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
报告以脑积水起病的晚发型戊二酸血症1型(glutaric acidemia type 1,GA1)1例。患者女性,21岁,以急性脑积水为主要临床表现,头颅MRI示脑内大范围脑白质、双侧基底节区及小脑半球蚓部异常信号,双侧脑室扩张,双侧颞极蛛网膜囊肿。血尿有机...报告以脑积水起病的晚发型戊二酸血症1型(glutaric acidemia type 1,GA1)1例。患者女性,21岁,以急性脑积水为主要临床表现,头颅MRI示脑内大范围脑白质、双侧基底节区及小脑半球蚓部异常信号,双侧脑室扩张,双侧颞极蛛网膜囊肿。血尿有机酸分析检出大量戊二酸和3-羟基戊二酸,GCDH基因检测发现为复合杂合性突变(S119L和R355H),确诊为戊二酸血症1型,给予相关治疗后,症状缓解。可见临床上如遇上难以解释的脑积水,头部MRI示典型对称性病灶,包括小脑损害,应进行血尿有机酸筛查以除外代谢性疾病。展开更多
目的探讨电子转移黄素蛋白脱氢酶(electron transfer flavoprotein dehydrogenase,ETFDH)基因变异致晚发型戊二酸血症Ⅱ型(glutaric acidemia typeⅡ,GAⅡ)的临床表现及遗传学特点。方法回顾性分析2020年1月首都医科大学附属首都儿童医...目的探讨电子转移黄素蛋白脱氢酶(electron transfer flavoprotein dehydrogenase,ETFDH)基因变异致晚发型戊二酸血症Ⅱ型(glutaric acidemia typeⅡ,GAⅡ)的临床表现及遗传学特点。方法回顾性分析2020年1月首都医科大学附属首都儿童医学中心收治的1例晚发型GAⅡ患者的临床表现及遗传学检测结果,在PubMed、中国知网和万方数据库检索2019—2024年间发表的相关文献,关键词包括“glutaric acidemia typeⅡ”“ETFDH gene”及“戊二酸血症Ⅱ型”“ETFDH基因”,检索策略结合MeSH词汇及自由词进行筛选。总结临床表现。结果患儿男,4月龄,表现为竖头不稳,嗜睡8 d。生后母乳喂养,发育落后,家长体健,否认家族性遗传病及传染病史。患儿对治疗反应差,出现脏器功能障碍、呼吸衰竭。遗传学检测结果提示该患儿ETFDH基因(NM_004453.2)存在Ex.1-Ex.6del以及c.1531G>C(p.D511H)复合杂合变异。根据美国医学遗传学与基因组学学会(American college of medical genetics and genomics,ACMG)指南判断该患者变异位点为疑似致病性变异。文献回顾共检索到11篇文献,共25例18岁以内起病的患者,其中早发型患者6例,4例(66.7%)表现为低血糖或代谢性酸中毒;晚发型患者19例,加上本文报道病例共20例,其中13例(65.0%)表现为肌痛、运动耐力下降或恶心呕吐等症状,5例(25.0%)仅表现为代谢筛查异常,无明显临床表现。包括本例在内的14例中国患者中,共检测到16个ETFDH基因变异位点,c.250G>A为最常见的变异位点,本例患者c.1531G>C突变为首次报道。结论GAⅡ缺乏典型的临床表现,患儿出现不明原因发育迟滞、肌痛、运动障碍、恶心呕吐、代谢异常时,需考虑GAⅡ,遗传学检测可明确诊断。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
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.
文摘BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no effective cure for this disease.Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality.Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.CASE SUMMARY A 12-day-old male neonate with“poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h”was hospitalized.The patient was the first child of nonconsanguineous ethnic Chinese parents.He was delivered by cesarean section due to breech position at 39+1 wk of gestation with a birth weight of 3.27 kg.Initially,he suffered from dyspnea and rhinobyon,and at 10 d after birth the patient suddenly developed poor feeding,low response,lethargy and seizures.Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine.The patient had an acute episode of IVA causing severe metabolic stress and eventually died.CONCLUSION A new case of an IVA patient carrying c.1193G>A(p.Arg398Gln)and c.1208A>G(p.Try403Cys)mutations is reported in China.
文摘One of the most common recessively inherited organic acidemias is the Propionic Acidosis (PA) which results from Propionyle-CoA Carboxylase (PCC) enzyme deficiency that is necessary for the catabolism of the branched chain Amino Acids and other metabolites. Classically this disease presented with high anion gap metabolic acidosis with its clinical consequences. We report 4 patients who presented to our facility with sepsis like picture and no metabolic acidosis. All of them were found to have high ammonia level. Diagnosis was confirmed by tandem MS/MS and urine Gas Chromatography/ Mass Spectrometry (GC/MS). All of them were treated supportively and by supplementation of adequate calories and PA formula. The different presentations may be very well attributed to the PCC molecular defects heterogeneity. Mutations in both genes PCCA and PCCB can cause PA with more frequent heterogeneity of PCCA gene. In spite of the fact that PCCB gene is responsible for the most of the oriental cases, our first patient condition was attributed to PCCA gene with a rare mutation which was not described in the literatures.
文摘Propionic acidemia is an autosomal recessive disorder that is due to deficiency in the enzyme propionyl-CoA carboxylase. Cardiomyopathy is a well-known phenomenon in propionic acidemia that it may rapidly progress to death. Here we describe a case of propionic acidemia in a 27-year-old man who developed adult-onset secondary dilated cardiomyopathy. In early infancy he was diagnosed with propionic acidemia and was later noted to have mild mental retardation, mild renal failure, and optic nerve atrophy. Although he was in good energy status with a low-protein diet and carnitine supplementation, he was admitted to our university hospital with decompensate heart failure, which resulted in low-output cardiac syndrome with massive mitral regurgitation and left ventricular dyssynchrony. Cardiac resynchronization therapy (CRT) and continuous hemodiafiltration followed by hemodialysis (HD) dramatically improved his clinical status.
文摘Glutaric acidemia type Ⅱ （GAⅡ）, also known as multiple acyl-CoA dehydrogenase defciency, is an auto-somal recessive inborn error of amino acid and fatty acid metabolism. We report a case of GAⅡ with novel electron transfer flavoprotein （ETF）-A mutations in a 2-year-old female with thalassemia minor. The patient developed an episode of hypoglycemia and hypotonicityon the postnatal first day. Laboratory investigations revealed elevations of multiple acyl carnitines indicat-ing glutaric acidemia type Ⅱ in newborn screening analysis. Urinary organic acids were evaluated for the confrmation and revealed a high glutaric acid excretion. Genetic analysis revealed two novel mutations in the ETF-A gene, which are considered to be compound heterozygote. At the 8 mo of life ketone therapy was added, which significantly increased the neuromotor development. The patient had been closely followed for two years with carnitine, ribofavin, coenzyme Q10, and ketone supplementation in addition to a high carbohydrate diet. Although the patient had comorbidity like thalassemia minor, her neuromotor developmentwas normal for her age and had no major health problems. This specific case expands the previously reported spectrum of this disease.
文摘BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.
文摘Aim&objective The diagnosis of foetal distress in a clinical setting is based on foetal cardiotocography findings during labour.This study aims to analyse the total deceleration area(TDA)on intrapartum cardiotocogram which will predict neonatal acidemia at bith.Materials&methods The study participants included women in labour having intrapartum foetal distress(National Institute of Child Halth and Human Development criteria category II and persistent category II on cardiotocogram),who had the 30-min traces(prior to delivery/decision to delivery)and foetal umbilical cord blood gas analysis at delivery.The TDA was calculated and analysed against the cord blood pH obtained at delivery.The deceleration area is calculated as the width of the widest aspect of deceleration(below baseline)measured in minutes which is multiplied by the maximum depth below the baseline and divided by two.TDA is the summation of all the deceleration areas in the last 30 min before delivery.Results A total of 168 participants were analysed.There were 42 cases and 146 controls in the study.The mean TDA in the case and control group was 254.62 missed beats and 165 missed beats,respectively.It was observed that an intrapartum TDA of 2195 missed beats was associated with neonatal acidemia at birth and with an area under curve of 0.6576(95%CI 0.5305 to 0.7847)with a positive predictive value of 83.78%.Conclusion In this study,an intrapartum TDA of≥195 missed beats was significantly associated with neonatal acidemia at birth.The calculation of TDA has simplified intrapartum foetal monitoring.
文摘Objective To explore brain MRI features of methylmalonic acidemia(MMA).Methods This observational study retrospectively analyzed the clinical and imaging data of 123 patients with MMA diagnosed at Shandong Provincial Hospital Affiliated to Shandong First Medical University and Qilu Hospital of Shandong University from January 2010 to November 2022.The 123 patients were divided into 7 stages according to age of onset,neonatal period(0 to<1 month),infancy(1 month to<1 year),early childhood(1 to<4 years),preschool(4 to<7 years),school age(7 to<13 years),adolescent(13 to 17 years)and adult(>17 years).All patients underwent brain MRI scanning.The imaging performances were evaluated,including the number,location,morphology of the lesions.Results Of the 123 patients,40 were in the neonatal period,29 in infancy,13 in early childhood,9 in preschool,6 in school age,13 in adolescence,and 13 in adulthood.The first symptoms of patients in the neonatal period were mainly digestive system abnormalities,such as difficulty in breastfeeding(37.5%,15/40)and vomiting(25.0%,10/40),with neurological symptoms gradually becoming the main manifestations from infancy.Seventy-three cases(59.3%)showed significant abnormalities on cranial MRI,including 17 cases with 33 foci in the neonatal period,23 cases with 53 foci in infancy,11 cases with 16 foci in early childhood,2 cases with 2 foci in preschool,3 cases with 7 foci in school age,7 cases with 9 foci in adolescence,and 10 cases with 16 foci in adulthood.In neonatal period,the main manifestations were myelin dysplasia(18%,6/33),dilatation of the lateral ventricular system(18%,6/33),and pallidal bulb infarct foci(18%,6/33);in infancy,the main manifestations were hypoplasia or thinning of the corpus callosum(30%,16/53);in early childhood,the main manifestations were pallidal bulb infarct foci(38%,6/16);and the two MRI abnormalities in preschool were pallidum and thalamic infarct foci;in school age,the main manifestations were infarct foci in the chiasmatic nucleus(29%,2/7)and in the caudate nucleus(29%,2/7);in adolescence,the main manifestation was dilatation of the lateral ventricular system(33%,3/9);and in adulthood,the main manifestation was dilatation of the lateral ventricular system(19%,3/16).Conclusion By staging the age of onset,it is found that the imaging manifestations of MMApatients show significant differences with age,suggesting that there is a dynamic nature of MMA damage to brain structures at different developmental stages.
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.
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.
文摘报告以脑积水起病的晚发型戊二酸血症1型(glutaric acidemia type 1,GA1)1例。患者女性,21岁,以急性脑积水为主要临床表现,头颅MRI示脑内大范围脑白质、双侧基底节区及小脑半球蚓部异常信号,双侧脑室扩张,双侧颞极蛛网膜囊肿。血尿有机酸分析检出大量戊二酸和3-羟基戊二酸,GCDH基因检测发现为复合杂合性突变(S119L和R355H),确诊为戊二酸血症1型,给予相关治疗后,症状缓解。可见临床上如遇上难以解释的脑积水,头部MRI示典型对称性病灶,包括小脑损害,应进行血尿有机酸筛查以除外代谢性疾病。
文摘目的探讨电子转移黄素蛋白脱氢酶(electron transfer flavoprotein dehydrogenase,ETFDH)基因变异致晚发型戊二酸血症Ⅱ型(glutaric acidemia typeⅡ,GAⅡ)的临床表现及遗传学特点。方法回顾性分析2020年1月首都医科大学附属首都儿童医学中心收治的1例晚发型GAⅡ患者的临床表现及遗传学检测结果,在PubMed、中国知网和万方数据库检索2019—2024年间发表的相关文献,关键词包括“glutaric acidemia typeⅡ”“ETFDH gene”及“戊二酸血症Ⅱ型”“ETFDH基因”,检索策略结合MeSH词汇及自由词进行筛选。总结临床表现。结果患儿男,4月龄,表现为竖头不稳,嗜睡8 d。生后母乳喂养,发育落后,家长体健,否认家族性遗传病及传染病史。患儿对治疗反应差,出现脏器功能障碍、呼吸衰竭。遗传学检测结果提示该患儿ETFDH基因(NM_004453.2)存在Ex.1-Ex.6del以及c.1531G>C(p.D511H)复合杂合变异。根据美国医学遗传学与基因组学学会(American college of medical genetics and genomics,ACMG)指南判断该患者变异位点为疑似致病性变异。文献回顾共检索到11篇文献,共25例18岁以内起病的患者,其中早发型患者6例,4例(66.7%)表现为低血糖或代谢性酸中毒;晚发型患者19例,加上本文报道病例共20例,其中13例(65.0%)表现为肌痛、运动耐力下降或恶心呕吐等症状,5例(25.0%)仅表现为代谢筛查异常,无明显临床表现。包括本例在内的14例中国患者中,共检测到16个ETFDH基因变异位点,c.250G>A为最常见的变异位点,本例患者c.1531G>C突变为首次报道。结论GAⅡ缺乏典型的临床表现,患儿出现不明原因发育迟滞、肌痛、运动障碍、恶心呕吐、代谢异常时,需考虑GAⅡ,遗传学检测可明确诊断。
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.
