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1.
Article in Chinese | WPRIM | ID: wpr-781327

ABSTRACT

OBJECTIVE@#To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA).@*METHODS@#For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed.@*RESULTS@#The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation.@*CONCLUSION@#The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.


Subject(s)
Alkyl and Aryl Transferases , Genetics , Amino Acid Metabolism, Inborn Errors , Genetics , China , Humans , Methylmalonyl-CoA Mutase , Genetics , Oxidoreductases , Genetics , Pedigree , Retrospective Studies
2.
Article in English | WPRIM | ID: wpr-179815

ABSTRACT

Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disorder characterized by an abnormal accumulation of methylmalonyl-CoA and methylmalonate in body fluids without hyperhomocysteinemia. Cardiac disease is a rarely known lethal complication of MMA, herein, we report a Korean neonate diagnosed with MMA on the basis of biochemical and genetic findings, who developed cardiomyopathy, resulting in sudden death. The patient presented vomiting and lethargy at 3 days of age. Initially, the patient had an increased plasma propionylcarnitine/acetylcarnitine concentration ratio of 0.49 in a tandem mass spectrometry analysis and an elevated ammonia level of 537 µmol/L. Urine organic acid analysis showed increased excretion of methylmalonate. Subsequent sequence analysis of the methylmalonyl-CoA mutase (MUT) gene revealed compound heterozygous mutations c.323G>A (p.Arg108His) in exon 1 and c.1033_1034del (p. Leu345Serfs*15) in exon 4, the latter being a novel mutation. In summary, this is the first case of MMA and cardiomyopathy in Korea that was confirmed by genetic analysis to involve a novel MUT mutation.


Subject(s)
Ammonia , Body Fluids , Cardiomyopathies , Death, Sudden , Exons , Frameshift Mutation , Heart Diseases , Humans , Hyperhomocysteinemia , Infant, Newborn , Korea , Lethargy , Methylmalonyl-CoA Mutase , Plasma , Sequence Analysis , Tandem Mass Spectrometry , Vomiting
3.
Article in Chinese | WPRIM | ID: wpr-247722

ABSTRACT

<p><b>OBJECTIVE</b>To explore the molecular etiology for a Chinese family affected with isolated methylmalonic acidemia (MMA).</p><p><b>METHODS</b>Potential mutations of MUT, MMAA and MMAB genes in the proband were screened by PCR and Sanger sequencing. The pathogenicity of identified mutations was analyzed using Polyphen2, SIFT, HSF, DNAMAN 6.0 and Swiss-PdbViewer4.1.0 software.</p><p><b>RESULTS</b>Two novel mutations of the MUT gene, including c.581C>T (p.P194L) and c.1219A>T (p.N407Y), were discovered in the proband, which were inherited respectively from his mother and father. Bioinformatics analysis suggested that both mutations were damaging. The affected codons P194 and N407, both located in the (beta, alpha) 8 barrel domain and to which the substrate methylmalonyl-CoA is bound, are highly conserved across various species. Both mutations can disrupt the space conformation of its protein product, affecting the function of the MCM protein.</p><p><b>CONCLUSION</b>The novel mutations of MUT gene probably underlie the isolated MMA in this family.</p>


Subject(s)
Adult , Amino Acid Metabolism, Inborn Errors , Genetics , Amino Acid Sequence , Animals , Asians , Genetics , Base Sequence , China , Female , Humans , Infant , Male , Methylmalonyl-CoA Mutase , Genetics , Molecular Sequence Data , Mutation , Mutation, Missense , Pedigree , Point Mutation , Sequence Alignment
4.
Article in Chinese | WPRIM | ID: wpr-247711

ABSTRACT

<p><b>OBJECTIVE</b>To identify pathogenic mutations in a Chinese pedigree affected with methylmalonic academia for genetic counseling and prenatal diagnosis.</p><p><b>METHODS</b>Molecular analysis of the MUT, MMACHC, MMAA and MMAB genes was performed for the proband with methylmalonic academia by Ion Torrent semiconductor sequencing. Candidate mutations were validated by Sanger sequencing. The couple was offered prenatal diagnosis via analyzing of the fetal DNA through amniocentesis.</p><p><b>RESULTS</b>The proband was found to be compound heterozygous for c.609G>A (p.Trp203X) and c.658-660del AAG (p.Lys220del) mutations, which were inherited respectively from each of his parents. Prenatal diagnosis showed that the fetus has inherited two wild-type parental alleles.</p><p><b>CONCLUSION</b>The targeted Ion Torrent PGM sequencing has detected pathogenic mutations in the Chinese pedigree affected with methylmalonic academia, which has provided molecular evidence for clinical diagnosis, genetic counseling and prenatal diagnosis for the family.</p>


Subject(s)
Adult , Alkyl and Aryl Transferases , Genetics , Amino Acid Metabolism, Inborn Errors , Embryology , Genetics , Asians , Genetics , Base Sequence , Carrier Proteins , Genetics , China , Female , High-Throughput Nucleotide Sequencing , Methods , Humans , Infant , Male , Methylmalonyl-CoA Mutase , Genetics , Mitochondrial Membrane Transport Proteins , Genetics , Molecular Sequence Data , Mutation , Pedigree , Pregnancy , Prenatal Diagnosis , Methods
5.
Article in Chinese | WPRIM | ID: wpr-239501

ABSTRACT

<p><b>OBJECTIVE</b>To analyze the clinical features and mutation of MUT gene in a Chinese patient with isolated methylmalonic acidemia.</p><p><b>METHODS</b>The clinical characteristics and laboratory tests data were collected. Genomic DNA was extracted from peripheral blood leukocytes. The 13 exons and their flanking sequences of the MUT gene were amplified with polymerase chain reaction and subjected to direct DNA sequencing.</p><p><b>RESULTS</b>The patient has featured failure to thrive, lethargy, seizure, hypotonia, severe ketoacidosis and hyperammonemia. Tandem mass results showed reduction of multiple acylcarnitine. Urine organic acid testing showed pronounced increase in methylmalonate excretion. Homocysteine was normal. The patient showed no response to vitamin B12 treatment. The above results suggested that the patient had isolated methylmalonic acidemia. DNA sequencing analysis confirmed that the patient has carried two MUT gene mutations, c.755dupA and a novel mutation c.944dupT.</p><p><b>CONCLUSION</b>Inherited metabolic disease screening plays an important role in the diagnosis of clinical diseases. However, to confirm the results will need gene mutation analysis.</p>


Subject(s)
Amino Acid Metabolism, Inborn Errors , Genetics , Base Sequence , Female , Humans , Infant, Newborn , Methylmalonyl-CoA Mutase , Genetics , Molecular Sequence Data , Mutation
6.
Article in Chinese | WPRIM | ID: wpr-279959

ABSTRACT

Methylmalonyl CoA mutase deficiency due to MUT gene defect has been known as the main cause of isolated methylmalonic acidemia in Mainland China. This study reported a patient with isolated methylmalonic aciduria (MUT type) characterized as acute brainstem encephalitis and myelitis. The previously healthy girl presented with fever, lethargy and progressive weakness in her extremities at the age of 3 years and 2 months. Three day later, she had respiratory distress and consciousness. Cranial MRI revealed bilateral symmetrical lesion of pallidum, brain stem and spinal cord, indicating acute brainstem encephalitis and myelitis. Her blood propionylcarnitine (6.83 μmol/L vs normal range 1.0 to 5.0 μmol/L) and urinary methylmalonic acid (133.22 mmol/mol creatinine vs normal range 0.2 to 3.6 mmol/mol creatinine) increased significantly. Plasma total homocysteine was normal. On her MUT gene, a reported mutation (c.1630_1631GG>TA) and a novel mutation (c.1663C>T, p.A555T) were identified, which confirmed the diagnosis of methylmalonic aciduria (MUT type). After cobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine, progressive improvement has been observed. The clinical manifestation of patients with methylmalonic aciduria is complex. Metabolic study and gene analysis are keys for the diagnosis and treatment of the disorder.


Subject(s)
Acute Disease , Amino Acid Metabolism, Inborn Errors , Brain Stem , Pathology , Child, Preschool , Encephalitis , Female , Humans , Methylmalonyl-CoA Mutase , Genetics , Mutation , Myelitis
7.
Article in Chinese | WPRIM | ID: wpr-237200

ABSTRACT

<p><b>OBJECTIVE</b>To explore the clinical feature, therapeutic effect and prognosis of isolated methylmalonic acidemia.</p><p><b>METHODS</b>The clinical characteristics, laboratory findings, treatment and outcome of 40 patients were retrospectively analyzed. The main treatment was a low-protein diet supplemented with L-carnitine and special milk free of leucine, valine, threonine and methionine. Vitamin B12 was also given to cobalamin responders. The patients were followed up every 1-3 months.</p><p><b>RESULTS</b>Mutations in the MUT gene were identified in 30 of 33 patients who had accepted DNA testing. Thirty cases were treated and followed up regularly for from 1 month to 8 years. Eight cases had died, 8 had developed normal intelligence, among whom 4 from newborn screening were asymptomatic. Psychomotor developmental delay and mental retardation were present in 14 cases. The propionylcarnitine level, ratio of propionylcarnitine/acetylcarnitine in blood, methylmalonic acid and methylcitric acid levels in urine have decreased significantly, with the median values reduced respectively from 24.15 (7.92-81.02) μmol/L, 1.08 (0.38-6.01), 705.34 (113.79-3078.60) and 7.71 (0.52-128.21) to 10.50 (3.00-30.92) μmol/L, 0.63 (0.25-2.89), 166.23 (22.40-3322.21) and 3.96 (0.94-119.13) (P < 0.05).</p><p><b>CONCLUSION</b>The prognosis of isolated methylmalonic acidemia may be predicted with the enzymatic subgroup, age at onset and cobalamin responsiveness. Outcome is unfavorable in neonatal patients and those who were non-responsive to cobalamin.</p>


Subject(s)
Amino Acid Metabolism, Inborn Errors , Diagnosis , Diet Therapy , Metabolism , Carnitine , Metabolism , Child , Child, Preschool , Diet, Protein-Restricted , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Methylmalonyl-CoA Mutase , Genetics , Retrospective Studies
8.
Article in Chinese | WPRIM | ID: wpr-287392

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the MUT gene mutations in patients with methylmalonic acidemia (MMA), and analyze the genotype-phenotype correlation in patients with methylmalonyl-CoA mutase deficiency.</p><p><b>METHODS</b>The diagnosis of the disease mainly depends on the measurement of C3 (acylcarnitine), C3/C0 (free carnitine) and C3/C2 (acetylcarnitine) in the blood by tandem mass spectrometry, the detection of methylmalonic acid in the urine by gas-chromatography mass spectrometry, the determination of total homocysteine in the serum, and the loading test of vitamin B(12). The entire coding region of the MUT gene was screened by PCR combined with direct DNA sequencing in 21 isolated MMA patients. Novel mutations were identified by restriction fragment length polymorphism (RFLP) and sequence analysis in 100 controls.</p><p><b>RESULTS</b>Seventeen MUT gene mutations were detected in 14 of the 21 patients, among them 8 mutations were novel, and R108H, D244LfsX39 and G544X were more frequent, with the frequencies of 9.5%, 7.1% and 9.5%, respectively. Most mutations were missense mutations (64.7%), and majority of them were in exons 2 and 3 (55.6%). Ten out of the 14 patients with MUT gene mutations had early-onset disease, while one case had late-onset disease, and the remaining 3 cases were detected by newborn screening. In addition, 11 of these 14 patients did not respond to vitamin B(12).</p><p><b>CONCLUSION</b>This study revealed partial MUT gene mutation spectrum in Chinese patients with isolated MMA. The patients carrying MUT mutations often had early-onset disease, and most of them were VitB(12)- non-responsive.</p>


Subject(s)
Amino Acid Metabolism, Inborn Errors , Genetics , Base Sequence , China , Female , Humans , Infant , Infant, Newborn , Male , Methylmalonic Acid , Metabolism , Methylmalonyl-CoA Mutase , Genetics , Molecular Sequence Data , Mutation
9.
Invest. clín ; 48(1): 99-105, mar. 2007. tab
Article in Spanish | LILACS | ID: lil-486695

ABSTRACT

La aciduria metilmalónica es una acidemia orgánica, autosómica recesiva, causada por la deficiencia de la metilmalonil CoA-mutasa, o por defectos en la biosíntesis del cofactor adenosilcobalamina. Del defecto enzimático, existen dos formas: mut (o) sin actividad enzimática y mut (-) con actividad reducida. Su presentación clínica puede variar desde una forma neonatal grave con acidosis y muerte, hasta una forma crónica progresiva. A continuación se describe el caso de un niño de 4 años de edad, con deficiencia de metilmalonil-CoA mutasa tipo mut (-), que se presentó en forma aguda. El estudio molecular del gen MUT mostró 2 mutaciones c.607G>A (G203R) y c.2080C > T(R694W), confirmadas posteriormente en los padres. El objetivo de este reporte es destacar la importancia de indicar el análisis de ácidos orgánicos en orina entre los estudios de primera línea, en todo niño con un cuadro clínico de presentación aguda y severamente enfermo, sin etiología definida. Por otra parte, se desea resaltar que el diagnóstico oportuno y definitivo es importante ya que permite iniciar un tratamiento específico, lograr una evolución favorable y prevenir las secuelas.


Subject(s)
Humans , Male , Female , Methylmalonic Acid , Methylmalonyl-CoA Mutase , Organic Acids , Biochemistry , Venezuela
10.
Arch. argent. dermatol ; 56(3): 103-105, mayo-jun. 2006. ilus
Article in Spanish | LILACS | ID: lil-454424

ABSTRACT

La Acidemia Metilmalónica es un trastorno metabólico, caracterizado por un adecuado metabolismo de los aminoácidos esenciales. Las manifestaciones cutáneas en esta entidad son poco frecuentes en relación a otras aminoacidopatías. Presentamos la ocurrencia de lesiones cutáneas semejantes al Síndrome Estafilicocóccico de la Piel Escaldada en un neonato de 13 días de vida con diagnóstico de acidemia metilmalónica que fueron tratadas con antibióticos sin respuesta clínica, observándose la resolución de las mismas al ser compensado su cuadro metabólico


Subject(s)
Humans , Female , Infant, Newborn , Methylmalonic Acid/blood , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/diet therapy , Methylmalonyl-CoA Mutase , Staphylococcal Scalded Skin Syndrome/diagnosis
11.
Rev. méd. Chile ; 130(3): 259-266, mar. 2002. tab
Article in Spanish | LILACS | ID: lil-314851

ABSTRACT

Background: Propionic aciduria (PA) and Methymalonic aciduria (MMA) result from an inherited abnormality of the enzymes propionyl CoA carboxylase and methylmalonyl CoA mutase respectively. This produces marked increases in the amino acids methionine, threonine, valine and isoleucine (MTVI). Their clinical presentation can be neonatal or late onset forms. Aim: To report 23 children with organic acidurias. Material and methods: Twenty three cases of organic acidurias diagnosed since 1980 (17 PA and 6 MMA) and followed at the Institute of Nutrition and Food Technology, are reported. Results: The average age of diagnosis was 3.9 days for the neonatal form and 8.3 months for the late onset form. The most frequent symptoms were hypotonia, lethargy and vomiting. Neonatal PA had mean ammonemias of 1089ñ678.3 µg/dl. The figure for MMA was 933ñ801.9 µg/dl. Seven children were dialyzed and 30 percent died. 16 children are followed and 81.2 percent have normal weight for age. Seven children required gastrostomy because of anorexia and failure to thrive. The nutritional treatment is based on natural and artificial proteins without MTVI, with periodical controls, amino acid and ammonia quantification. Some patients were submitted to enzyme assays and molecular studies. Conclusions: An early diagnosis and a very strict follow up allows a normal development of children with organic aciduras. There is a relationship between prognosis and the presentation form, the nutritional status and the emergency treatment during acute episodes. The importance of the enzymatic and molecular studies is emphasized because they facilitate treatment, accurate diagnosis and allow an adequate genetic counseling


Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Methylmalonic Acid/urine , Propionates/urine , Amino Acid Metabolism, Inborn Errors/diagnosis , Methylmalonic Acid/metabolism , Propionates/metabolism , Amino Acids/administration & dosage , Energy Intake , Amino Acid Metabolism, Inborn Errors/diet therapy , Amino Acid Metabolism, Inborn Errors/drug therapy , Methylmalonyl-CoA Mutase , Nutritional Status
12.
Article in Korean | WPRIM | ID: wpr-183912

ABSTRACT

We experienced a case of vitamin B12 unresponsive methlymalonic acidemia in a 4 day old female, who had poor feeding, dehydration with metabolic acidosis, and hyperammonernia and died at 7 days of age. Diagnosis was made by gas chromatography and mass spectrometry, and this case is probably a methylmalonyl CoA mutase apoenzyme deficiency type.


Subject(s)
Acidosis , Apoenzymes , Chromatography, Gas , Dehydration , Diagnosis , Female , Humans , Mass Spectrometry , Methylmalonyl-CoA Mutase , Vitamin B 12
13.
Article in Korean | WPRIM | ID: wpr-204951

ABSTRACT

BACKGROUND: Methylmalonic aciduria can be caused by inherited defects in the methylmalonyl-CoA mutase enzyme, Inherited defects in the metabolism of vitamin Bl2 and acquired or inherited vitamin Bl2 deficiency. Quantitation of urinary methylmalonic acid (MMA) is very useful In diagnosis of methylmalonic acidemia and cobalamin deficiency. We evaluated a quantitation method of urinary MMA and determined reference values. METHODS: The method involved stable isotope dilution gas chromatographymass spectrometry (GC-MS) with (methyl 2H3)-MMA as the internal standard. We determined the detection limit, linearity and periodic variations of the assay. Urinary MMA levels were measured in 70 individuals of ages newborn to 58 years with no metabolic disorders. RESULTS: The lower limit of detection calculated from blank runs (mean+/-3SD) was 2.62nmo1/m1. One control urine tramp)e analyzed 23 times within 3 weeks game results of 7.83+/-1.09 (mean+/-SD, CV=13.8%) nmol/mL. The linearity at four different concentrations of MMA was acceptable (R2=0.9992). The concentration of urinary MMA in 70 individuals was 2.33+/-2.19 mmol/mol creatinine (mean+/-SD). Age related reference values which decreased with age were also reported (p=1.23x10-9). CONCLUSIONS: The described method is sensitive, specific and noninvasive, which is considered the gold standard method for measuring MMA. The method could be used as a screening test for cobalamin deficiency and inherited methyl malonic acidemia. On the basis of the narrow range of normal concentration, it is expected that the method would readily detect mild cobalamin deficiency.


Subject(s)
Chromatography, Gas , Creatinine , Diagnosis , Gas Chromatography-Mass Spectrometry , Humans , Infant, Newborn , Limit of Detection , Mass Screening , Metabolism , Methylmalonic Acid , Methylmalonyl-CoA Mutase , Reference Values , Spectrum Analysis , Vitamin B 12 , Vitamins
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