A case of combined methylmalonic aciduria and homocysteinemia presenting with hydrocephalus as an early manifestation was reported for its rarity to see and to discuss the relationship between metabolic diseases and hydrocephalus by literature review. The case was an infant with seizures and hydrocephalus as an early manifestation of the disease, combined with macrocyticanemia, development retardation and visual hearing function lesions. The EEG showed hypsarrhythmia and the MRI showed hydrocephalus. Plasma homocysteinemia level increased (143.06 umol/L) and urine methylmalonic aciduria was 1483 times beyond normal. Based on gene analysis results and increased methylmalonic aciduria and homocysteinemia levels, combined methylmalonic aciduria and homocysteinemia was confirmed, presenting CblC defect (gene mutations homozygous for c.609G>A). After treatment by venous injection of vitamin B12, oral folic acid and betaine, seizures were controlled and development was progressive with ventricle retraction. It was concluded that hydrocephalus can be the early presentation in children with combined methylmalonic aciduria and homocysteinemia. Doctors should carry out metabolic disease screening for patients with hydrocephalus, especially when the cause of hydrocephalus is uncertain.
Amino Acid Metabolism, Inborn Errors ; complications ; Humans ; Hydrocephalus ; etiology ; Hyperhomocysteinemia ; complications ; Infant ; Male

OBJECTIVETo screen out differentially expressed microRNAs (miRNAs) in the plasma of children with methylmalonic acidemia (MMA), to determine the expression of miR-9-1 in plasma and to preliminarily evaluate the significance of miR-9-1 as a biomarker in MMA.

METHODSPlasma was obtained from 17 MMA children, 10 hyperhomocysteinemia (HHcy) children without MMA (HHcy group), and 10 normal controls. Of 17 MMA children, 12 had HHcy (MMA+HHcy group), and 5 had no HHcy (MMA group). The differentially expressed miRNAs were screened out by miRNA microarray. Differentially expressed miR-9-1 was selected, and plasma miR-9-1 levels were determined by RT-PCR. Urine was collected from MMA patients who received vitamin B12 treatment, and plasma miR-9-1 levels were determined by RT-PCR after treatment.

RESULTSThe miRNA microarray analysis showed that 26 miRNAs were differentially expressed, among which 16 miRNAs (including miR-9-1) were down-regulated over 2 times, while 10 miRNAs were up-regulated over 2 times. The MMA+HHcy , MMA and HHcy groups had significantly down-regulated miR-9-1 compared with the normal control group (P<0.01). The patients who showed a good response to vitamin B12 treatment had significantly increased plasma miR-9-1 levels, without significant difference compared with the normal control group.

CONCLUSIONSPlasma miR-9-1 is significantly down-regulated in MMA patients, but it is significantly up-regulated after vitamin B12 treatment, suggesting that miR-9-1 may act as a biomarker in monitoring the progression of MMA.

Adolescent ; Amino Acid Metabolism, Inborn Errors ; genetics ; Child ; Female ; Humans ; Hyperhomocysteinemia ; genetics ; Male ; MicroRNAs ; blood

PURPOSE: Seizure associated with fever may indicate the presence of underlying inherited metabolic diseases. The present study was performed to investigate the presence of underlying metabolic diseases in patients with complex febrile seizures, using analyses of urine organic acids. METHODS: We retrospectively analyzed and compared the results of urine organic acid analysis with routine laboratory findings in 278 patients referred for complex febrile seizure. RESULTS: Of 278 patients, 132 had no abnormal laboratory findings, and 146 patients had at least one of the following abnormal laboratory findings: acidosis (n=58), hyperammonemia (n=55), hypoglycemia (n=21), ketosis (n=12). Twenty-six (19.7%) of the 132 patients with no abnormal findings and 104 (71.2%) of the 146 patients with statistically significant abnormalities showed abnormalities on the organic acid analysis (P<0.05). Mitochondrial respiratory chain disorders (n=23) were the most common diseases found in the normal routine laboratory group, followed by PDH deficiency (n=2 ) and ketolytic defect (n=1). In the abnormal routine laboratory group, mitochondrial respiratory chain disorder (n=29) was the most common disease, followed by ketolytic defects (n=27), PDH deficiency (n=9), glutaric aciduria type II (n=9), 3-methylglutaconic aciduria type III (n=6), biotinidase deficiency (n=5), propionic acidemia (n=4), methylmalonic acidemia (n=2), 3-hydroxyisobutyric aciduria (n=2), orotic aciduria (n=2), fatty acid oxidation disorders (n=2), 2-methylbranched chain acyl CoA dehydrogenase deficiency (n=2), 3-methylglutaconic aciduria type I (n=1), maple syrup urine disease (n=1), isovaleric acidemia (n=1), HMG-CoA lyase deficiency (n=1), L-2-hydroxyglutaric aciduria (n=1), and pyruvate carboxylase deficiency (n=1). CONCLUSION: These findings suggest that urine organic acid analysis should be performed in all patients with complex febrile seizure and other risk factors for early detection of inherited metabolic diseases.
Acetyl-CoA C-Acetyltransferase ; Acidosis ; Acyl-CoA Dehydrogenase ; Amino Acid Metabolism, Inborn Errors ; Biotinidase Deficiency ; Brain Diseases, Metabolic, Inborn ; Electron Transport ; Fever ; Humans ; Hydroxybutyrates ; Hyperammonemia ; Hypoglycemia ; Isovaleryl-CoA Dehydrogenase ; Ketosis ; Maple Syrup Urine Disease ; Metabolic Diseases ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; Propionic Acidemia ; Pyruvate Carboxylase Deficiency Disease ; Pyruvate Dehydrogenase Complex Deficiency Disease ; Retrospective Studies ; Risk Factors ; Seizures ; Seizures, Febrile

OBJECTIVEMethylmalonic acidemia complicated with homocysteinemia, cblC type, is the most common inborn error of cobalamin metabolism. The gene MMACHC (OMIM 277400) is located on chromosome 1p34.1 with four coding exons and a 5th non-coding exon. It encodes for a protein with 282 amino acid residues. So far, more than 40 mutations have been detected, in which 271dupA (R91KfsX14) is the hot spot of MMACHC gene. However, there have not been relevant reports in China. The present study aimed to identify the mutation types of MMACHC gene and analyze the genotype-phenotype correlations in Chinese patients.

METHODThe diagnosis of this disease mainly depends on the measurement of C3 propionylcarnitine, 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 B12. The entire coding region of MMACHC gene was screened by polymerase chain reaction (PCR) combined with DNA direct sequencing in 28 Chinese patients. Genomic DNA was extracted using phenol-chloroform method from the peripheral blood leukocytes of each patient. PCR amplification products were checked by 1.8% agarose gel electrophoresis and were subsequently sequenced with both the forward and reverse primers. Mutational analyses were performed using normal human genomic MMACHC sequence as a reference (GenBank ID: 25974).

RESULTIn this study, ten mutations were identified in 27 of 28 Chinese patients. Most of them were located in exons 3 and 4 (91.3%). We detected four mutations reported, which were 609G>A (W203X), 217C>T (R73X), 271dupA (R91KfsX14), and 394C>T (R132X), and six novel mutations, which were 1A>G, 365A>T, 658_660delAAG, 301-3_327del 30, 567_568insT, and 625_626insT. The 609G>A (W203X) is the most common mutation, which was detected in 30 of 56 alleles (53.6%), including 10 homozygote mutations and 10 heterozygote mutations. In addition, three gene polymorphisms were detected, namely, -302T>G (rs3748643), -234A>G (rs3728644), and 321G>A (rs2275276). These mutations include missense mutations, nonsense mutations, duplication, deletions, and insertions.

CONCLUSIONIn this study, we found a part of gene mutations spectrum in Chinese patients with methylmalonic acidemia and homocysteinemia, in which the 609G>A (W203X) may be the hotspot mutation of MMACHC gene. This would be helpful in the prenatal diagnosis and gene screening programs of methylmalonic acidemia and homocystinemia.

Amino Acid Metabolism, Inborn Errors ; complications ; genetics ; Cysteine ; blood ; DNA ; DNA Mutational Analysis ; Exons ; Humans ; Hyperhomocysteinemia ; complications ; genetics ; Methylmalonic Acid ; blood ; Mutation

OBJECTIVETo study the clinical features and treatment outcomes of cardiovascular system involvement in children with methylmalonic aciduria combined with hyperhomocysteinemia (MMACHC).

METHODSThe clinical data of 10 children with methylmalonic aciduria combined with hyperhomocysteinemia and who had cardiovascular system involvement were retrospectively analyzed and the treatment outcomes were followed up.

RESULTSIn the 10 patients, there were 4 cases with initial presentations of cardiovascular system symptoms such as shortness of breath and dyspnea, 3 cases with urinary tract symptoms such as edema, hematuria and proteinuria, and 3 cases with nervous system symptoms such as developmental retardation and convulsions. The 10 patients had different types and severity of cardiovascular injuries. After 3 months to 8 years of follow-up, the congenital heart defects resolved naturally in 2 cases, and the patient with arrhythmia had no obvious changes. In 5 cases of hypertension, blood pressures recovered to normal in 3 cases, and 1 case was lost to follow-up. In 5 patients with pulmonary hypertension, 2 died, 2 recovered, and 1 case had mildly elevated pulmonary artery pressure. Seven patients underwent MMACHC gene testing, and 5 showed c.80A>G mutations.

CONCLUSIONSMetabolic disease should be taken into account for the children with unexplained pulmonary hypertension and hypertension with the onset of the shortness of breath and dyspnea. The severity of cardiovascular system involvement might be one of the most important factors affecting the prognosis of children with MMACHC. Cardiavascular system involvement of the patients may be related to MMACHC c.80A>G mutations.

Amino Acid Metabolism, Inborn Errors ; complications ; genetics ; Cardiovascular Diseases ; etiology ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Hyperhomocysteinemia ; complications ; genetics ; Infant ; Infant, Newborn ; Male ; Retrospective Studies

Adult ; Amino Acid Metabolism, Inborn Errors ; blood ; diagnosis ; Bipolar Disorder ; blood ; diagnosis ; Gas Chromatography-Mass Spectrometry ; Humans ; Hyperhomocysteinemia ; blood ; diagnosis ; Male ; Tandem Mass Spectrometry ; Vitamin B 12 ; blood

Humans ; Amino Acid Metabolism, Inborn Errors/genetics* ; Haploinsufficiency

OBJECTIVE: To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis. METHODS: Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products. RESULTS: The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection. CONCLUSION Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
Humans ; Amino Acid Metabolism, Inborn Errors/genetics* ; Hydrocephalus ; Oxidoreductases

Amino Acid Metabolism, Inborn Errors ; Humans ; Infant, Newborn ; Isovaleryl-CoA Dehydrogenase ; deficiency ; Male ; Metabolism, Inborn Errors ; physiopathology

OBJECTIVETo study the clinical features of organic acidemia in neonates admitted to the intensive care unit.

METHODSThe clinical features of neonates from 15 neonatal intensive care units of Henan Province, who were diagnosed with congenital organic acidemia by gaschromatography-mass spectrometry (GC-MS) between June 2008 and August 2011 were retrospectively reviewed.

RESULTSFifty neonates of 287 high risk neonates were confirmed as having or highly suspected to have inborn errors of metabolism. Of the 50 cases, 32 cases were diagnosed with organic acidemia disease, including 28 cases of methylmalonic acidemia, 2 cases of propionic acidemia, 1 case of maple syrup urine disease and 1 case of isovaleric acldemla. In most cases, disease onset occurred in the first week after birth in most of cases (75%). Neonates whose symptoms occurred immediately after or within a few hours of birth presented with serious conditions. Clinical manifestations were various and mainly related to neurologic, respiratory and gastrointestinal symptoms such as poor response, coma, drowsiness, abnormal muscle tone, convulsions, polypnea, dyspnea, milk refusal, diarrhea and jaundice. Initial symptoms were non-specific and included dyspnea, poor response, milk refusal, lethargy and seizures.

CONCLUSIONSMethylmalonic acidemia is a common inherited metabolic disease in the neonatal period. Clinical manifestations of organic acid metabolism abnormalities in neonates are atypical and early onset is associated with more serious conditions.

Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; Diagnosis, Differential ; Female ; Gas Chromatography-Mass Spectrometry ; Humans ; Infant, Newborn ; Intensive Care Units, Neonatal ; Male ; Maple Syrup Urine Disease ; complications ; diagnosis ; Propionic Acidemia ; complications ; diagnosis