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At least 757 records · Page 42Linked to original sources
PubMed1998

An unusual late-onset case of propionic acidaemia: biochemical investigations, neuroradiological findings and mutation analysis.

UNLABELLED: We report a 5-year-old boy with propionic acidaemia who developed a rapidly fatal necrosis of the basal ganglia after an episode of clinical deterioration. Neither metabolic acidosis nor hyperammonaemia were present. Organic acid analysis in both urine and CSF showed increased levels of methylcitric and 3-hydroxypropionic acids. Propionic acidaemia was confirmed by demonstrating a propionyl-CoA carboxylase deficiency (11% of control value) in skin fibroblasts. DNA analysis revealed that the patient was a compound heterozygote for two mutations in the PCCB gene. CONCLUSION: Propionic acidaemia can present as a sudden and fatal neurological disease and not only as an organic aciduria with severe biochemical dis-turbances and progressive neurological deterioration.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

[Carnitine in the treatment of methylmalonic aciduria (MMA)].

Carnitine metabolism was studied and a therapeutic trial with L-carnitine was undertaken in 3 patients with methylmalonic aciduria. Prior to carnitine therapy, the concentration of free carnitine was diminished and the contribution of acylated carnitine to total carnitine was increased in both plasma and urine. During a metabolic crisis, in a patient the intravenous administration of L-carnitine greatly increased, the urinary excretion of acylcarnitine and the plasma concentration of methylmalonic acid fell. In all 3 patients, the chronic oral administration of L-carnitine resulted in the normalisation of the plasma free carnitine concentrations and an increased urinary excretion of carnitine esters. One patient clearly showed clinical improvement under carnitine therapy. The administration of L-carnitine to patients with methylmalonic aciduria results in an increased elimination of toxic propionyl groups and thus to a regeneration of intramitochondrial CoA. In conjunction with appropriate dietary measures, this may improve the metabolic situation of these patients.

Amino Acid Metabolism, Inborn Errors↗
PubMed1976

Organic aciduria. Treatable cause of floppy infant syndrome.

A floppy infant is described who has an inborn error of organic acid metabolism due to defective activity of the enzyme beta-methylcrotonyl CoA carboxylase. She presented with hyperventilation, hypotonia, and regression of motor and intellectual development. She responded to treatment with biotin.

Amino Acid Metabolism, Inborn Errors↗
PubMed1994

Decreased hyperammonaemia and orotic aciduria due to inactivation of ornithine aminotransferase in mice with a hereditary abnormal ornithine carbamoyltransferase.

Mice with the X-chromosomal sparse-fur (spf) mutation are an animal model of some hereditary deficiencies of ornithine carbamoyltransferase (OCT) in man. Orotic aciduria and hyperammonaemia are the most conspicuous metabolic changes in these diseases. Selective inactivation of ornithine aminotransferase (OAT) by 5-fluoromethylornithine raises endogenous ornithine concentrations so that citrulline formation is effectively catalysed by the aberrant OCT, in spite of its low affinity for ornithine. As a consequence, blood and tissue ammonia concentrations and orotic acid excretion are reduced near to normal values, and the abnormal amino acid patterns in blood, brain and liver are normalized. Selective inactivation of OAT seems a promising therapeutic approach in some hereditary OCT deficiencies, and a total that may allow us to clarify the role of ammonia and orotic acid in the development of nanism and abnormal behaviour in spf mutant mice.

Amino Acids↗
PubMed1986

Carnitine as an essential nutrient.

Carnitine performs a critically important role in energy metabolism and is synthesized in the healthy adult predominantly in the liver and kidney. The typical well balanced American diet contains significant amounts of carnitine as well as the essential amino acids and micronutrients needed for carnitine biosynthesis. Thus carnitine is an infrequent problem in the healthy, well nourished adult population in the United States. However, carnitine can be a conditionally essential nutrient for several different types of individuals. Preterm infants require carnitine for life-sustaining metabolic processes but have a carnitine biosynthetic capability that is not fully developed. There is an increasing number of documented problems with carnitine metabolism in preterm infants not receiving an exogenous source of carnitine indicating that endogenous biosynthesis of carnitine is not adequate to meet the infant's need. Children with different forms of organic aciduria appear to have a greatly increased need for carnitine to function in the excretion of the accumulating organic acids. This need exceeds their dietary carnitine intake and carnitine biosynthetic capability. Renal patients treated with chronic hemodialysis appear to lose carnitine via the hemodialysis treatment, and this loss cannot be repleted simply by endogenous biosynthesis and dietary intake. Treatment with drugs such as valproic acid and metabolic stresses such as trauma, sepsis, organ failure, etc, can also result in a requirement for exogenous carnitine. Accurate assessment of the carnitine status of patients at risk for carnitine deficiency is fundamental to the identification of those patients who require carnitine as the result of altered metabolism.

Adult↗
PubMed1975

Alpha-ketoadipic aciduria: degradation studies with fibroblasts,.

Observation of one patient with alpha-ketoadipic aciduria initiated degradation studies with radiolabelled lysine metabolites in fibroblasts in order to localise the metabolic defect. Liberation of 14-CO-2 from alpha-D,L-(1-14-C) aminoadipate and alpha-(1-14-C) ketoadipate was considerably less in the patient's fibroblasts than in the patient's fibroblasts than in normal controls, whereas 14-CO-2 production from (1,5-14-C) glutarate was in the normal range. These results indicate a defect in the oxidative decarboxylation of alpha-ketoadipate as the probable cause of alpha-ketoadipic aciduria; Cultured amniotic fluid cells from pregnancies of the 15th and 16th week of gestation degrade alpha-(1-14-C) ketoadipate with a similar activity to fibroblast cultures from normal humans after birth.

Adipates↗
PubMed1994

Neurological manifestations of organic acid disorders.

Neurological manifestations are very common and can be the leading and/or presenting feature in organic acid disorders, sometimes in the absence of metabolic derangement. Review of the time course and presentation of neurological disease in organic acid disorders reveals characteristic clinical findings of ataxia, myoclonus, extrapyramidal symptoms, metabolic stroke and megalencephaly. A group of organic acid disorders presents exclusively with neurological symptoms. These include glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I), succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria), mevalonic aciduria, N-acetylaspartic aciduria (Canavan disease) and L-2-hydroxyglutaric aciduria. As a group these "cerebral" organic acid disorders appear to remain often undiagnosed and their true incidence is much less well-known than that of the "classical" organic acid disorders. Unfortunately, stringent guidelines for a clinical preselection of neuropaediatric patients to be investigated for organic acid disorders cannot be provided. Today, screening for neurometabolic disorders should be as comprehensive as possible and include determinations of amino acids, purines and pyrimidines and markers of peroxisomal function in addition to organic acid analysis.

Brain Diseases, Metabolic↗
PubMedDate not supplied

Clinical and MRI findings in a case of D-2-hydroxyglutaric aciduria.

We report the 3rd case in the literature of a 3-year-old boy with D-2-hydroxyglutaric (D-2-HG) aciduria, who presented primarily generalized hypotonia and feeding difficulty during the neonatal period, with eventual development of generalized myoclonic seizures. Gas chromatographic analysis of urinary organic acids showed persistent excretion of D-2-HG. The clinical manifestations are quite similar to those of the 2nd reported case with D-2-HG aciduria. Serial MRI performed 1 year and 2 1/2 years after birth demonstrated bilateral symmetrical periventricular lesions in the parieto-occipital white matter, which might reflect the cortical blindness in our patient.

Amino Acid Metabolism, Inborn Errors↗
PubMed1985

Use of a diode array detector in investigation of neonatal organic aciduria.

We investigated the use of a diode array detector in conjunction with isocratic cation-exchange liquid chromatography for detection of organic acids in urine. The spectra and retention times of abnormal peaks found on chromatography of urine from patients with methylmalonic aciduria, maple syrup urine disease, and lactic aciduria were recorded and compared with those obtained for group of pure organic acids. Our results show that diode array detection helps considerably in tentatively identifying peaks appearing on an abnormal chromatogram while awaiting confirmation by mass spectrometry.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

[Hyperglycinemia in clinical-laboratory practice].

Hyperglycinemia is a non rarely observed biochemical finding which can be caused by a primary defect of the glycine cleavage system (nonketotic hyperglycinemia) or by an enzymatic block due to toxic metabolites (ketotic hyperglycinemia in organic acidurias) or to specific drugs (such as sodium valproate). The Authors report their clinical and laboratory experience in the diagnosis of different forms of hyperglycinemia. Three patients with nonketotic hyperglycinemia (1 patient with transient neonatal form, 1 with the classic neonatal form, and 1 with late onset form), 6 patients with ketotic hyperglycinemia (1 propionic acidemia, 5 methylmalonic acidurias), and 8 patients with hyperglycinemia during sodium valproate treatment are described. In this study the diagnostic iter and the importance of a precise diagnosis of the hyperglycinemia for the appropriate treatment are discussed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1981

alpha-Aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child.

The case of a mentally retarded girl with a number of dysmorphic features, Raynaud's phenomenon, hypotonia and petit mal seizures is presented. Laboratory investigations showed alpha-aminoadipic aciduria and a high level of fetal haemoglobin. Oral L-lysine loading resulted in a marked increase of alpha-aminoadipic acid in blood and urine. After 3 months of pyridoxine medication the increase of alpha-aminoadipic acid in blood and urine during the oral L-lysine loading test was less than in the test before treatment. A normal degradation rate of DL-alpha-amino [1-14C] adipic acid in fibroblasts of the patient, as measured by 14CO2 production, did not indicate a primary enzyme defect in the alpha-aminoadipic acid transamination or decarboxylation steps. The persistent HbF could be the result of stress on the erythropoiesis by a secondary induced defect in an early stage of haemoglobin synthesis in which alpha-amino-beta-ketoadipic acid, a structural analogue of alpha-amino-adipic acid, is an intermediate.

2-Aminoadipic Acid↗
PubMed1999

Blood levels of ammonia and nitrogen scavenging amino acids in patients with inherited hyperammonemia.

Plasma levels of glutamine (456 determinations), alanine (434 determinations), and asparagine (431 determinations) and corresponding ammonia levels (260 determinations) were retrospectively analyzed in 30 patients with hyperammonemia secondary to urea cycle disorders (including 3 patients with amino acid transport defects) and 5 patients with propionic acidemia (PA). All patients had elevated glutamine levels on one or more testing except for 2 patients with severe PA and 1 patient with a mild urea cycle disorder. All but 4 patients with urea cycle disorders showed a maximal glutamine level higher than 100 micromol/dl, and 3 patients had a maximal glutamine level of higher than 200 micromol/dl. The only exceptions were 2 asymptomatic ornithine transcarbamylase (OTC)-deficient females, 1 male with mild OTC deficiency, and 1 patient with citrullinemia (CIT) whose plasma glutamine levels were never above 100 micromol/L. Patients with CIT and argininosuccinic aciduria (ASA) showed statistically significant lower levels of glutamine than patients with other urea cycle disorders. However, the maximal glutamine level did not directly correlate with severity of the disorder and within disorders correlated inversely with severity of outcome. Patients with PA showed statistically significant lower glutamine, alanine, and asparagine levels than patients with urea cycle disorders and the severity of this disorder correlated inversely with plasma glutamine levels. Plasma ammonia levels showed a positive correlation with glutamine in patients with carbamyl phosphate synthetase I and OTC deficiency and a negative correlation in patients with PA. Although, most patients also showed elevated levels of alanine and asparagine, their levels generally did not show a good correlation with glutamine (R2 = 0.25 and 0.34, respectively).

Adolescent↗
PubMed2000

Cloning and characterization of a putative human d-2-hydroxyacid dehydrogenase in chromosome 9q.

There is little information on d-isomer-specific dehydrogenases in humans. Identification of d-2-hydroxyglutaric aciduria, an inherited metabolic disorder associated with severe neurological dysfunction, highlights the role of d-isomers in human metabolism. The possibility of a defect in d-2-hydroxyglutarate dehydrogenation prompted us to employ E. coli d-2-hydroxyacid dehydrogenase cDNA to search the human expressed sequence tags database. Two human EST homologues were retrieved and sequenced. Analysis showed the two clones were identical with 1258 nucleotides encoding 248 amino acids of the putative human d-2-hydroxyacid dehydrogenase. It was highly homologous to bacterial d-2-hydroxyacid dehydrogenases (46%), d-phosphoglycerate dehydrogenase (38%), and formate dehydrogenase (36%) at the amino acid level. The gene is expressed ubiquitously in tissue, most abundantly in liver, and was mapped to chromosome 9q between markers WI-3028 and WI-93330. To our knowledge this is the first cloning and characterization of the cDNA for a human d-isomer specific NAD(+)-dependent 2-hydroxyacid dehydrogenase.

Alcohol Oxidoreductases↗
PubMed2003

Disease-related metabolites in culture medium of fibroblasts from patients with D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, and combined D/L-2-hydroxyglutaric aciduria.

BACKGROUND: D-2-Hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and the combined D/L-2-hydroxyglutaric aciduria (D/L-2-HGA) are poorly understood organic acidurias. To investigate the usefulness of cultured human skin fibroblasts for both diagnostic and research purposes, we measured disease-related metabolites in the cell culture medium. METHODS: We measured D-2-hydroxyglutarate (D-2-HG), L-2-hydroxyglutarate (L-2-HG), succinate, 2-ketoglutarate, and citrate in fibroblast cell medium by stable-isotope-dilution gas chromatography-mass spectrometry and glutamine, glutamic acid, and lysine with an amino acid analyzer. We used six cell lines from patients with D-2-HGA, two from patients with L-2-HGA, three from patients with D/L-2-HGA, and seven control cell lines. Culture medium was analyzed after a 96-h incubation period. RESULTS: Culture media from cell lines from D-2-HGA patients contained D-2-HG at concentrations 5- to 30-fold higher than media from controls, whereas the concentration of L-2-HG in media was not increased. Media from L-2-HGA cell lines showed a fivefold increase in L-2-HG compared with controls. Media containing fibroblasts from D/L-2-HGA patients contained moderately increased amounts of both D-2-HG and L-2-HG. For all cell lines, succinate concentrations in the blank medium were higher than after 96 h of incubation with the exception of two of three D/L-2-HGA cell lines. Media of D-2-HGA cell lines had 2-ketoglutarate concentrations that were 40% of that for controls. Glutamic acid concentrations in media of these cell lines were 60% lower than in controls. CONCLUSIONS: Cell culture media from fibroblasts from patients with D-2-HGA, L-2-HGA, or D/L-2-HGA contain increased amounts the corresponding 2-HGs, demonstrating the suitability of fibroblasts for both diagnosis of and research concerning 2-HGAs.

Biomarkers↗
PubMed1990

Ornithine transcarbamylase deficiency in male adolescence and adulthood.

A discrete deficiency of hepatic ornithine transcarbamylase (OTC) was found in male patients who were 58, 46 and 17 years old. Each had developed hyperammonemic coma. The mother and a sister of the 17-year-old patient exhibited orotic aciduria either spontaneously or after protein loading, thus demonstrating heterozygosity. A sister of one other patient and a daughter of the third patient showed a smaller orotic aciduria after protein loading. These observations indicate that inherited deficiency of OTC should be included in the differential diagnosis of hyperammonemic states in adult male patients.

Adolescent↗
PubMed1983

Propionic acidaemia. First case in the Finnish population.

Propionic acidaemia is a defect of propionyl-CoA-carboxylase activity characterized by urinary excretion of propionic acid, its metabolites and hyperglycinaemia. The clinical picture of this autosomally, recessively inherited disorder, which has been reported in the literature in 63 patients varies from overwhelming metabolic crisis in the neonate to an almost asymptomatic disease responding to protein restriction and biotin supplementation. The first Finnish patient with propionic acidaemia had a severe type of disease with neonatal onset simulating nonketotic hyperglycinaemia. In spite of protein restriction and biotin supplementation this infant developed progressive psychomotor retardation and died of intercurrent infection at the age of 8.5 months. The definite, correct diagnosis was not reached until a severe infection occurred, during which the pathognomonic organic aciduria manifested. This delay in the diagnosis illustrates the importance of performing the analysis of urinary excretion of organic acids during stress situations, such as infections, since the metabolic block may be undetectable under normal conditions.

Amino Acid Metabolism, Inborn Errors↗