OBJECTIVETo highlight recent researches which may show promise for histomolecular classification and new treatments for gliomas.

DATA SOURCESAll articles cited in this review were mainly searched from PubMed, which were published in English from 1996 to 2010.

STUDY SELECTIONOriginal articles and critical reviews selected were relevant to the isocitrate dehydrogenase-1/2 mutation in gliomas and other tumors.

RESULTSExtraordinary high rates of somatic mutations in isocitrate dehydrogenase-1/2 occur in the majority of World Health Organization grade II and grade III gliomas as well as grade IV secondary glioblastomas. Isocitrate dehydrogenase-1/2 mutations are associated with younger age at diagnosis and a better prognosis in patients with mutated tumors. The functional role of isocitrate dehydrogenase-1/2 mutations in the pathogenesis of gliomas is still unclear.

CONCLUSIONIsocitrate dehydrogenase-1/2 mutations define a specific subtype of gliomas and may have great significance in the diagnosis, prognosis, and treatment of patients with these tumors.

Adult ; Age Factors ; Brain Neoplasms ; genetics ; pathology ; Genes, p53 ; Glioma ; genetics ; pathology ; Glutarates ; metabolism ; Humans ; Isocitrate Dehydrogenase ; genetics ; physiology ; Ketoglutaric Acids ; metabolism ; Middle Aged ; Mutation ; NADP ; metabolism ; Neoplasm Grading ; Prognosis

Amino Acid Metabolism, Inborn Errors ; urine ; Female ; Glutarates ; urine ; Humans ; Infant ; Male

Amino Acid Metabolism, Inborn Errors ; etiology ; therapy ; Glutarates ; blood ; Humans ; Infant, Newborn ; Male

Amino Acid Metabolism, Inborn Errors ; diagnosis ; metabolism ; therapy ; Diagnosis, Differential ; Diet ; Glutarates ; metabolism ; urine ; Humans ; Infant ; Male ; Riboflavin ; therapeutic use ; Treatment Outcome

OBJECTIVEGlutaric aciduria type II, or multiple acyl-CoA dehydrogenase deficiency is an autosomal recessively inherited defect of mitochondrial energy metabolism. The authors report two cases of late-onset glutaric aciduria type II, and evaluate the procedures for the diagnosis and treatment of this rare disease.

METHODSThe clinical and biochemical characteristics of 2 patients with late-onset glutaric aciduria type II were documented. Case 1 presented with lipid storage myopathy for 3 years. Case 2 presented with intermittent episodes of non-ketotic hypoglycemia and muscle weakness for 9 years. The diagnosis of the 2 cases was confirmed with gas chromatography/mass spectrometry analysis of urine samples. Riboflavin supplementation and a low-fat, low-protein, high-carbohydrate diet were initiated as soon as the diagnosis was made.

RESULTSOrganic acid analysis on both untreated cases revealed massive glutaric acid with elevated concentrations of isovalerylglycine, isobutyrylglycine, ethylmalonic acid, adipic acid, suberic acid and other dicarboxylic acids. The clinical manifestations were improved remarkably after the administration of riboflavin and diet control. Consistent improvements of sera enzymes and urine organic acids were observed during the course of treatment.

CONCLUSIONPatients with unexplained myopathy, metabolic acidosis or hypoglycemia should be carefully screened for inherited metabolic disorders. Riboflavin in conjunction with appropriate diet control is an effective therapeutic regime for patients with late-onset glutaric aciduria type II.

Acyl-CoA Dehydrogenase ; deficiency ; Adolescent ; Age of Onset ; Child ; Female ; Gas Chromatography-Mass Spectrometry ; Glutarates ; urine ; Humans ; Metabolism, Inborn Errors ; diagnosis ; drug therapy ; urine ; Photosensitizing Agents ; therapeutic use ; Riboflavin ; therapeutic use ; Treatment Outcome

OBJECTIVEThe diagnosis of organic acidemia is very difficult and needs special test methods. Recently the tandem mass spectrometry has been used in screening for and diagnosis of this inborn error of metabolism. The aim of the present study was to utilize a dry blood filter paper method for acylcarnitines profiles test using tandem mass spectrometry in diagnosis of organic acidemias in high risk children.

METHODOne thousand patients (642 were males and 358 females) with high risk of inborn error of metabolism were studied, the median of their age was 2 years. The blood specimens were collected on filter paper, punched and extracted into methanol solution with stable isotope labeled internal standards of acylcarnitine, then derivatized with butanolic-HCI. After preparation, the samples were analyzed by tandem mass spectrometry. The volume of the acylcarnitines was calculated with special software.

RESULTSForty patients (4.0%) were diagnosed as organic acidemias among the 1000 patients, including 20 methylmalonic acidemia, 6 propionic acidemia, 3 isovaleric acidemia, 3 glutaric acidemia type I, 3 glutaric acidemia type II, 2 biotinidas deficiency, 1 3-methylcrotonyl-CoA carboxylase deficiency, 1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, and 1 beta-keto thiolase deficiency. The common clinical symptoms and signs of these patients were motor and mental developmental retardation, spasm, lethargy, coma, hypotonia, vomiting, and feeding difficulty. Routine laboratory tests suggested metabolic acidosis, hyperammonemia, hyperlactacidemia, hypoglycemia, anemia, and abnormal liver function.

CONCLUSIONA part of organic acidemias can be rapidly diagnosed by tandem mass spectrometry through acylcarnitine profiles analysis in dry blood filter paper. Combination of tandem mass spectrometry with urine gas chromatography mass spectrometry would improve more accurate diagnosis of organic acidemias.

Adolescent ; Child ; Child, Preschool ; Female ; Filtration ; Gas Chromatography-Mass Spectrometry ; Glutarates ; blood ; Humans ; Infant ; Male ; Metabolism, Inborn Errors ; diagnosis ; Methylmalonic Acid ; blood ; Pentanoic Acids ; blood ; Propionic Acidemia ; diagnosis ; Tandem Mass Spectrometry ; methods

Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; therapy ; Brain ; diagnostic imaging ; metabolism ; pathology ; Brain Diseases, Metabolic ; diagnosis ; genetics ; therapy ; Child, Preschool ; Diagnosis, Differential ; Glutarates ; metabolism ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; Humans ; Infant ; Infant, Newborn ; Lysine ; metabolism ; Magnetic Resonance Imaging ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; diagnosis ; genetics ; therapy ; Mutation ; Neonatal Screening ; methods ; Radiography

OBJECTIVETo investigate the clinical, biochemical and genetic profiles of 28 Chinese patients with glutaric aciduria type 1.

METHODTwenty-eight patients with glutaric aciduria type 1 seen in the Department of Pediatrics, Peking University First Hospital from July 2003 to October 2013 were studied. The data of clinical course, laboratory examinations, cranial MRI and GCDH gene mutations of the patients were analyzed.

RESULT(1) Three cases were detected by newborn screening, and the other patients were diagnosed at the age of 2 months to 17 years. (2) 22 patients (79%) were infant onset cases with psychomotor retardation, dystonia, seizures, athetosis, recurrent vomiting, drowsiness or feeding difficulty. Only two of the 22 patients with infant onset got normal intelligence and movement after treatment. Twenty of them were improved slowly with delayed development, dystonia and other neurological problems. Three patients (11%) had late onset. They had motor regression, headache and seizure at the age of 8, 9 and 17 years, respectively. Rapid improvement was observed after treatment. (3) Cranial MRI has been checked in 23 patients; 22 of them showed characteristic widening of the Sylvian fissure, abnormalities of the basal ganglia, leukoencephalopathy and brain atrophy. Thirty-five mutations in GCDH gene of the patients were identified; c.148T>C (p.W50R) was the most common mutation with the frequency of 7.7%; 6 mutations (c.628A>G, c.700C>T, c.731G>T, c.963G>C, c.1031C>T and c.1109T>C) were novel.

CONCLUSIONGlutaric aciduria type 1 usually induced neurological deterioration resulting in severe psychomotor retardation and dystonia. Most of our patients were clinically diagnosed. Patients with early onset usually remained having neurological damage. Phenotype and genotype correlation has not been found in the patients. Neonatal screening for organic acidurias should be expanded in China.

Age of Onset ; Amino Acid Metabolism, Inborn Errors ; diagnosis ; genetics ; metabolism ; Brain Diseases, Metabolic ; diagnosis ; genetics ; metabolism ; DNA Mutational Analysis ; Follow-Up Studies ; Gas Chromatography-Mass Spectrometry ; Glutarates ; urine ; Glutaryl-CoA Dehydrogenase ; deficiency ; genetics ; metabolism ; Humans ; Infant, Newborn ; Intellectual Disability ; etiology ; pathology ; Magnetic Resonance Imaging ; Movement Disorders ; etiology ; pathology ; Mutation ; Neonatal Screening ; methods ; Retrospective Studies

L-glutamic acid is the world's largest bulk amino acid product that is widely used in the food, pharmaceutical and chemical industries. Using Corynebacterium glutamicum G01 as the starting strain, the fermentation by-product alanine content was firstly reduced by knocking out the gene encoding alanine aminotransferase (alaT), a major by-product related to alanine synthesis. Secondly, since the α-ketoglutarate node carbon flow plays an important role in glutamate synthesis, the ribosome-binding site (RBS) sequence optimization was used to reduce the activity of α-ketoglutarate dehydrogenase and enhance the glutamate anabolic flow. The endogenous conversion of α-ketoglutarate to glutamate was also enhanced by screening different glutamate dehydrogenase. Subsequently, the glutamate transporter was rationally desgined to improve the glutamate efflux capacity. Finally, the fermentation conditions of the strain constructed using the above strategy were optimized in 5 L fermenters by a gradient temperature increase combined with a batch replenishment strategy. The glutamic acid production reached (135.33±4.68) g/L, which was 41.2% higher than that of the original strain (96.53±2.32) g/L. The yield was 55.8%, which was 11.6% higher than that of the original strain (44.2%). The combined strategy improved the titer and the yield of glutamic acid, which provides a reference for the metabolic modification of glutamic acid producing strains.
Glutamic Acid ; Corynebacterium glutamicum/genetics* ; Ketoglutaric Acids ; Metabolic Engineering ; Alanine

We produced α-ketoglutaric acid (α-KG) from L-glutamic acid, using enzymatic transformation approach with L-glutamate oxidase (LGOX). First, wild strain Streptomyces sp. FMME066 was mutated with NTG, a genetically stable mutant Streptomyces sp. FMME067 was obtained. Under the optimal nutrition conditions with fructose 10 g/L, peptone 7.5 g/L, KH2PO4 1 g/L and CaCl2 0.05 g/L, the maximum LGOX activity reached 0.14 U/mL. The LGOX was stable to pH and temperature, and Mn2+ had a stimulating effect. Finally, after 24 h enzymatic conversion under the optimal conditions, the maximum titer of α-KG reached 38.1 g/L from 47 g/L L-glutamic acid. Enzymatic transformation by LGOX is a potential approach for α-KG production.
Amino Acid Oxidoreductases ; metabolism ; Fermentation ; Glutamic Acid ; metabolism ; Ketoglutaric Acids ; metabolism ; Streptomyces ; genetics ; metabolism