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PubMed1991

Organic acidurias: a review. Part 1.

Organic acidemias are disorders of intermediary metabolism that lead to accumulation of organic acids in biologic fluids, disturb acid-base balance, and derange intracellular biochemical pathways. Their clinical presentation reflects the resultant systemic disease and progressive encephalopathy. While in some organic acidemias, disturbed acid-base metabolism is the predominant presenting feature, in others it is less prominent or even absent. The etiologies of the more than 50 different phenotypes include impaired metabolism of branched-chain amino acids, vitamins, glucose, lipids, glutathione, and gamma-aminobutyric acid and defects of oxidative phosphorylation. Most organic acidemias present with neurologic manifestations, which include acutely or subacutely progressive encephalopathy that involves different parts of the nervous system. The age of presentation and the associated systemic, hematologic, and immune findings provide additional guidelines for differential diagnosis. We summarize major organic acidemias, while emphasizing their usual and unusual neurologic presentations.

Acid-Base Imbalance↗
PubMed2004

Assessment of an electron-impact GC-MS method for organic acids and glycine conjugates in amniotic fluid.

We assessed the reliability of a method designed for common electron-impact GC-MS systems to determine in a single run most organic acids and glycine conjugates of clinical interest in amniotic fluid. Suitable sensitivity was achieved by dividing the selected-ion chromatogram into 12 time segments during which the monitoring dwelt on specific ions. Twelve metabolites were simultaneously quantified in amniotic fluid, with performances ranging from very good to clinically acceptable. The total coefficient of variation was 2.5-14.1% and the detection limit was well below the lower value of the physiological range. For five other metabolites, the precision was lower and/or the detection limit was near the physiological range. The method was clinically assessed by the prenatal detection of three cases of tyrosinaemia type I and one case of propionic acidaemia. Analytical and clinical evaluation of the method showed that GC-MS with electron-impact fragmentation can be an informative analytical approach for low-level organic acids in physiological fluids. Apart from the case of glycine conjugates, the method shows a fair reliability for amniotic fluid analysis, which might warrant its use for prenatal diagnosis of organic acidurias. However, this method cannot replace procedures using isotopic internal standards, nor GC-MS based on chemical ionization fragmentation, which remain confirmatory analytical methods of choice.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Identification of the human and bovine ATP:Cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant.

In humans, deficiencies in coenzyme B12-dependent methylmalonyl-CoA mutase (MCM) lead to methylmalonyl aciduria, a rare disease that is often fatal in newborns. Such deficiencies can result from inborn errors in the MCM structural gene or from mutations that impair the assimilation of dietary cobalamins into coenzyme B12 (Ado-B12), the required cofactor for MCM. ATP:cob(I)alamin adenosyltransferase (ATR) catalyzes the terminal step in the conversion of cobalamins into Ado-B12. Substantial evidence indicates that inherited defects in this enzyme lead to methylmalonyl aciduria, but the corresponding ATR gene has not been identified. Here we report the identification of the bovine and human ATR cDNAs as well as the corresponding human gene. A bovine liver cDNA expression library was screened for clones that complemented an ATR-deficient bacterial strain for color formation on aldehyde indicator medium, and four positive clones were isolated. The DNA sequences of two clones were determined and found to be identical. Sequence similarity searching was then used to identify a homologous human cDNA (89% identity) and its corresponding gene that is located on chromosome XII. The bovine and human cDNAs were independently cloned and expressed in Escherichia coli. Enzyme assays showed that expression strains produced 87 and 98 nmol/min/mg ATR activity, respectively. These specific activities are in line with values reported previously for bacterial ATR enzymes. Subsequent studies showed that the human cDNA clone complemented an ATR-deficient bacterial mutant for Ado-B12-dependent growth on 1,2-propanediol. This demonstrated that the human ATR is active under physiological conditions albeit in a heterologous host. In addition, Western blots were used to show that ATR expression is altered in cell lines derived from cblB methylmalonyl aciduria patients compared with cell lines from normal individuals. We propose that inborn errors in the human ATR gene identified here result in methylmalonyl aciduria. The identification of genes involved in this disorder will allow improvements in the diagnosis and treatment of this serious disease.

Adenosine Triphosphate↗
PubMed1989

Argininosuccinic aciduria--an underdiagnosed cause of neonatal death?

We describe a case of neonatal argininosuccinic aciduria, a condition we suggest is underdiagnosed. Although the clinical presentation can be of overwhelming septicaemia, certain routine biochemical investigations are indicative of this inborn error of urea cycle metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Clinical and biochemical studies on Chinese patients with methylmalonic aciduria.

Methylmalonic aciduria is a common organic aciduria disease. Recently, gas chromatography-mass spectrometry has been used to diagnose methylmalonic aciduria in China. Often, however, the diagnosis of methylmalonic aciduria is delayed because of a lack of technical expertise and the limited experience of general clinicians in China. In this study, the natural history, clinical features, and outcome of 77 Chinese patients with methylmalonic aciduria were investigated. Of the 77 patients, 31 (40.3%) had isolated methylmalonic aciduria and 46 (59.7%) had methylmalonic aciduria combined with homocystinemia. Thus, we observed a higher rate of the combined disease than studies conducted in other countries, suggesting that it might be more common in China. Total plasma homocysteine measurement might enable differential diagnoses of methylmalonic aciduria to be distinguished. The clinical spectrum of these 77 patients with methylmalonic aciduria ranged from neonatal death and severe symptoms to benign asymptomatic organic aciduria. Neonatal and infantile onset, which was a characteristic of the majority of cases, was associated with a greater severity relative to later-onset cases. Among the 17 cases who had onset after 3 years of age, only 1 patient had isolated methylmalonic aciduria and 16 had combined methylmalonic aciduria and homocystinemia. Nine of the patients with combined methylmalonic aciduria and homocystinemia completely recovered and exhibited normal intelligence, whereas seven improved, with a mild handicap.

Adolescent↗
PubMed1997

Diagnostic applications of chromatography and capillary electrophoresis.

Capillary electrophoresis (CE) equipped with a diode-array detector, and GC-MS have been used to determine diagnostic metabolites occurring in urine of patients with various metabolic disorders. The urine samples were injected directly onto the CE instrument without any pretreatment. GC-MS required extraction and derivatisation before separation. Identification of abnormal metabolites was based on migration times and characteristic diode-array spectra, or mass spectral library search when GC-MS was used. The CE method has previously been shown capable of diagnosing several metabolic diseases, and was now used on more difficult cases. CE readily diagnosed glyceric aciduria and the secondary metabolite in lysinuric protein intolerance, orotic acid. Methylmalonic aciduria required pressure elution in addition to high voltage to accomplish diagnosis. In mevalonic aciduria the characteristic metabolite had weak light absorption and the mevalonate peak also co-eluted with endogenous aromatic acids making diagnosis difficult. Both in the latter case and with the disorders glutaric aciduria I and glyceroluria, GC-MS was the method of choice. A possible role of CE in the routine system for diagnosing metabolic disorders, might be to use this method for pre-testing all urine samples. Samples with abnormal CE-profiles would subsequently be given high priority for more elaborate analysis with GC-MS and amino acid analyzer. In a different project a CE instrument designed for serum protein analysis was used to study sera from patients with myelomatosis. The method also allowed identification of the various immunoglobulins using immunosubtraction. Samples collected after diagnosis as well as many years prior to disease were available through the Janus-bank. This large serum bank comprises samples collected since 1973 at intervals from nearly 300000 blood donors. It was found that the monoclonal immunoglobulins characteristic of the disease started to appear in serum up to 15 years before clinical diagnosis.

Acidosis↗
PubMed1989

Orotic acid overproduction in experimental cirrhosis of rats.

Ammonia clearance, portal blood ammonia, and amino acid concentrations were studied during induction of cirrhosis by carbon tetrachloride in rats. Exposure to CCl4 vapors twice weekly for 7-16 weeks doubled orotic acid excretion. If exposure was discontinued for 7 days, the orotic acid excretion decreased despite the presence of cirrhosis proven histologically. Replacement of dietary casein with soybean protein eliminated the CCl4-induced orotic aciduria in growing rats but not in adults. Supplementation of casein with 1.5% arginine did not prevent CCl4-induced orotic aciduria. [14C]Orotate uptake into RNA and DNA of liver was not impaired. Perfusion of livers of cirrhotic animals with ammonia concentrations between 0.2 and 3.0 mM revealed no significant decreases in urea synthesis rates due to cirrhosis and no increase in the tendency to make orotic acid at a given ammonia concentration. However, ammonia uptake by cirrhotic livers was significantly reduced, resulting in higher ammonia concentrations in the effluent when there was moderate-to-severe cirrhosis. Portal blood samples taken from rats exposed to CCl4 had higher ammonia concentrations as cirrhosis worsened. The results lend support to the "intact hepatocyte" hypothesis of cirrhosis which attributes metabolic abnormalities to intrahepatic shunts.

Ammonia↗
PubMed1989

Advances in the use of computerized gas chromatography-mass spectrometry and high-performance liquid chromatography with rapid scanning detection for clinical diagnosis.

A multi-component analytical system designed for the diagnosis of metabolic disorders is described. The urinary components are separated by a variety of chromatographic techniques, including automated amino acid analysis, high-performance liquid chromatography with diode-array detection and gas chromatography-mass spectrometry with a computerized mass spectral library search for identification of organic acids. The complete system can be used to diagnose over 100 different metabolic diseases. The usefulness of the chromatographic system is exemplified by the pre- and postnatal diagnosis of glutaric aciduria type I, the diagnosis of lysinuric protein intolerance and of alkaptonuria. Drugs and diet may cause interfering metabolites, as exemplified by glycofurol, used as a solvent for intravenous drugs, and saccharin. It is predicted that chromatography and mass spectrometry will continue to be important diagnostic tools for many years ahead.

Acids↗
PubMed1979

Recurrent hypoglycemia associated with glutaric aciduria type II in an adult.

Repeated episodes of hypoglycemia accompanied by elevated serum concentrations of free fatty acid without ketosis, fatty infiltration of the liver, hepatic dysfunction, and proximal myopathy in a 19-year-old woman, prompted us to analyze her urine for organic acids. Greatly increased quantities of glutaric acid, ethylmalonic acid, dicarboxylic acids with six to 10 carbons, and isovalerylglycine were consistently found in her urine. The ability of cultured skin fibroblasts from the patient to oxidize [1(-14)C]butyrate and [2(-14)C]lysine was reduced. These urinary and in vitro findings indicated defective activity of several acyl coenzyme A dehydrogenases, including glutaryl, isovaleryl, and butyryl coenzyme A dehydrogenases -- establishing a diagnosis of glutaric aciduria Type II. Carnitine concentrations in the skeletal muscle and liver were moderately reduced, but carnitine deficiency was considered a secondary biochemical abnormality. Although glutaric aciduria Type II has previously been described only in a neonate, the disease must be considered in the differential diagnosis of hypoglycemia in adults.

Adult↗
PubMed1995

Glutaric aciduria: improved MR appearance after aggressive therapy.

Advances in understanding the metabolic abnormalities which cause glutaric aciduria allow biochemical diagnosis on the basis of deficient enzyme and the potential for therapy. Brain abnormalities associated with this inborn error of metabolism have been demonstrated with CT and MR. The findings typically described are atrophy of the fronto-temporal regions with large insular cisterns and diffuse white matter hypodensities. We present a patient with glutaric aciduria, confirmed by enzymatic assay, who had these findings on CT and MR examination. Repeat imaging demonstrated significant improvement after dietary therapy and aggressive prevention of catabolism during febrile illness.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to D-2-hydroxyglutaric and gamma-hydroxybutyric acidurias.

We investigated the presence of hydroxyacid-oxoacid transhydrogenase (HOT), which catalyses the cofactor-independent conversion of gamma-hydroxybutyrate (GHB) to succinic semialdehyde coupled to reduction of 2-ketoglutarate (2-KG) to D-2-hydroxyglutarate (D-2-HG), in human liver extracts employing [2H6]GHB and 2-KG as substrates. We measured incorporation of 2H in D-[2H]2-HG using GC-MS analyses, providing evidence for HOT activity in humans. Kinetic characterization of HOT was undertaken in forward and reverse directions. We employed [2H6]GHB and [2H4]2-KG as cosubstrates in order to develop a HOT activity assay in cultured human fibroblasts derived from patients with D-2-hydroxyglutaric aciduria. HOT activity was quantified in this system by the measurement of D-[2H5]2-HG production. Fibroblasts derived from patients with D-2-hydroxyglutaric aciduria showed normal HOT activities. Our results provide the first demonstration and preliminary kinetic characterization of HOT activity in human tissues.

Alcohol Oxidoreductases↗
PubMed2005

Biotin deficiency in an infant fed with amino acid formula.

Biotin deficiency is rarely encountered in an infant on weaning from breast and formula feeding. It is characterized by alopecia and scaly, erythematous dermatitis distributed around the body orifices. We report a 5-month-old Japanese infant with typical skin lesions who had been diagnosed as a neonate with dyspepsia and fed only an amino acid formula. Serum and urine levels of biotin were below the normal range, but zinc and biotinidase were within normal range. Urinary excretion of 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, and methylcitric acid was significantly elevated. Daily oral supplementation with 1 mg of biotin resulted in dramatic improvement of the periorificial dermatitis and hair growth together with a complete disappearance of the organic aciduria. Our case shows that the characteristic skin manifestations are the most important clue to the diagnosis of biotin deficiency and demonstrated that urinary excretion of biotin and organic aciduria, rather than the serum concentration of biotin, are the sensitive indicators for evaluating the patient's status of biotin deficiency.

Biotin↗
PubMed1983

Arginine requirement of the young pig.

Four experiments were conducted with an arginine (Arg)-deficient, semipurified diet to determine the Arg requirement of the weanling pig. The semipurified diet contained .18% bioavailable Arg as determined by a chick bioassay procedure and, when properly supplemented with Arg, allowed rat growth equal to that obtained with a 19.2% protein corn-soybean meal diet. A preliminary experiment with pigs indicated that the semi-purified diet was markedly deficient in Arg. The Arg requirement of the pig was estimated by adding L-Arg to the semipurified diet such that final dietary Arg levels were .18, .23, .28, .38 and .48% (Exp. 2 and 3) or .48, .58 and .68% (Exp. 4). Weight gain and efficiency of feed utilization were maximized at .48% dietary Arg. Plasma urea-N was increased and plasma NH3-N decreased by .48% Arg compared with lower levels. A slight orotic aciduria was observed in pigs fed Arg levels below .48%. From these results, it is concluded that the Arg requirement of the weanling pig is .48% of the diet, a level twice the current NRC estimate.

Amino Acids↗
PubMedDate not supplied

[Carnitine: physiologic role, primary and secondary deficiency].

L-carnitine is essential in fatty acids metabolism, it is synthetized endogenically and supplied by nurishment as well. Ninety eight percent of it is stored in skeletal muscles. Its importance in primary deficiency, either systemic encephalomyopathies or isolated myopathies, is out of discussion. In deficiency states, life itself may be threatened. Numerous investigations point to secondary carnitine deficiencies. Favorable substitution effects are published, first of all, in organic acidurias in children, in ischemic heart diseases of adults, in hyperlipoproteinemias, in peripheral vascular disease, in patients on hemodialysis, and in muscle dystrophy. Favorable results are published also in total parenteral nourishment of newborns and adults. L-carnitine may prevent toxic effects of valoproates and antracyclins. The substance is not toxic and is well tolerated. LD50 values are almost like those of amino acids. Meanwhile, inspite of many reports on favorable results in secondary carnitne deficiencies the additional controlled clinical trials should be done, especially in children.

Carnitine↗
PubMed1980

Alpha-aminoadipic aciduria: chemical and enzymatic studies.

A new case of alpha-aminoadipic aciduria had an apparent immunodeficiency and died at the age of 4 months. The urine contained large amounts of alpha-aminoadipate and smaller quantities of alpha-keto- and alpha-hydroxyadipate. Post mortem, the highest concentrations of alpha-aminoadipate were found in liver and kidney. Enzymatic studies on liver and cultured fibroblasts failed to demonstrate the expected deficiency of alpha-amino-adipate aminotransferase, a result perhaps explicable by the presence of cytoplasmic aminotransferase activity.

2-Aminoadipic Acid↗
PubMed1994

Stroke, hemiparesis and deficient mitochondrial beta-oxidation.

We describe on a 3-year-old child referred for evaluation and therapy of a cerebral vascular accident with residual hemiplegia and partial epilepsy. Metabolic investigations initially showed normal urinary organic acids as well as normal blood and urinary amino acids. Blood carnitine fractions had been pathological and a secondary carnitine deficiency was diagnosed and treated by oral L-carnitine supplementation. During carnitine treatment, abnormal urinary acylcarnitine profiles were noticed with excessive amounts of several carnitine esters including propionylcarnitine, butyryl- and/or isobutyryl-carnitine, isovaleryl- and/or 2-methylbutyryl-carnitine, hexanoylcarnitine and octanoylcarnitine. Subsequently, an urinary organic acid profile suggestive of glutaric aciduria type II was recorded during a clinical decompensation crisis. Morphological and biochemical studies on skeletal muscle and skin fibroblasts were performed and confirmed the existence of a defect of the mitochondrial beta-oxidation pathways with lipidic myopathy, reduced palmitate and octanoate oxidation rates in cultured fibroblasts. Glutaric aciduria type II increases the list of metabolic disorders characterized by hemiplegia and other sequelae of brain ischaemia such as stroke-like episode, seizures, aphasia, ataxia and myoclonia, similar to those seen in MELAS.

Carnitine↗
PubMed1998

Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.

Alkaptonuria↗