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PubMed1968

Methylmalonic aciduria: metabolic block localization and vitamin B 12 dependency.

Methylmalonic aciduria is an inborn error of metabolism characterized by neonatal or infantile ketoacidosis. Leukocytes isolated from the peripheral blood of a 1-year-old child with this disorder converted negligible quantities of propionate-3-C(14) to carbon dioxide, but oxidized succinate-1,4-C(14) normally, an indication of a block in the conversion of propionate to succinate. Parenteral administration of vitamin B(18) resulted in a reduction in methylmalonic acid excretion and an increase in propionate oxidation by leukocytes in vitro. The results suggest a mutation of methylmalonyl-CoA isomerase, a vitamin B(12), dependent enzyme which converts methylmalonyl-CoA to succinyl-CoA, and provide the first demonstration of vitamin B(12) "dependency" in man.

Acidosis↗
PubMed1992

An unusual presentation of medium-chain acyl coenzyme A dehydrogenase deficiency.

OBJECTIVE: To report an atypical presentation of medium-chain acyl Coenzyme A dehydrogenase deficiency in a 13-year-old girl with hyperammonemic encephalopathy and orotic aciduria meeting the accepted criteria for diagnosis of a female heterozygous for ornithine transcarbamylase deficiency. DESIGN: Case report and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANT: One teenager. INTERVENTIONS: Diagnosis and treatment with carnitine. MEASUREMENTS/MAIN RESULTS: Assay ornithine transcarbamylase deficiency had normal results. The diagnosis was confirmed by DNA analysis, which revealed homozygosity for prevalent mutation (the adenine to guanine transition at position 985). CONCLUSIONS: Patients with a clinical diagnosis of Reye's syndrome have, in general, an inborn error of metabolism. Medium-chain acyl Coenzyme A dehydrogenase deficiency and other disorders of fatty acid oxidation may present long after infancy. They may mimic the presentation of defects in the urea cycle.

Adolescent↗
PubMed1991

Glutaric aciduria type I. Brain CT features and a diagnostic pitfall.

Serial CT findings in an infant with glutaric aciduria type I (GA-I) are reported. The major CT features were dilatation of the insular cisterns, regression of the temporal lobes, with "bat wings" dilatation of the Sylvian fissures and hypodensity of the lenticular nuclei. CT changes preceded the onset of symptoms by 3 months. An improvement in the temporal lobe atrophy was seen after a period of treatment, coinciding with marked clinical improvement. A peculiar feature was the presence of external hydrocephalus, which diverted the attention from manifestations of the primary disease and thus constituted a diagnostic pitfall. The delineation and recognition of the characteristic radiologic manifestations of GA-I are essential for allowing an adequate radiologist/clinician interaction in diagnosing this inborn error of metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed1982

Argininosuccinic aciduria in a Finnish woman presenting with psychosis and mental retardation.

Argininosuccinic aciduria (ASA-uria) is a rare inborn error of the urea cycle, in which there is massive excretion of argininosuccinic acid (ASA) in the urine together with elevated concentrations of ASA in the plasma and the CSF. The characteristic symptoms are either those of overwhelming metabolic disease in the newborn period, or variable psychomotor retardation. The present patient, the first Finnish one to be reported, was a 49-year-old woman. She was hospitalized at the age of 26 with a diagnosis schizophrenia and mental retardation. Her clinical symptoms consisted of ataxia, disturbance of coordination, clumsiness, intention treMor and a positive Romberg's sign. The laboratory findings were consistent with the mild, late-onset type of ASA-uria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Carnitine deficiency in inherited organic acid disorders and Reye syndrome.

A large quantity of propionylcarnitine in the urine of patients with propionic acidemia and methylmalonic aciduria was demonstrated. The amount excreted depended on the administered L-carnitine dose from 25 to 75 mg/kg/day. A high level of propionylcarnitine was also detected in the amniotic fluid of fetuses at risk of methylmalonic aciduria. Glutaric aciduria type 1 was characterized by excessive urinary excretion of glutarylcarnitine. In a neonate with glutaric aciduria type 2, several specific acylcarnitines were detected in the urine. These included isovaleryl-, acetyl-, isobutyryl-, and butyrylcarnitine as major carnitine esters and glutaryl-, and octanoylcarnitine as minor components. However, the pattern of acylcarnitines excreted changed from isovalerylcarnitine (via leucine) to isobutyrylcarnitine (via valine) during early life. In patients diagnosed as Reye syndrome, tissue carnitine deficiency was not always recognized and no decrease in the free/total carnitine ratio was found in the liver or muscle. The clinical and pathophysiological manifestations seen in these disorders are considered to relate to mitochondrial activity. Therefore, it is necessary to measure acylcarnitine fractions in the urine in order to obtain more precise information about mitochondrial function because carnitine and acylcarnitine compounds may express the metabolic state of mitochondria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1984

Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine.

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl-CoA Dehydrogenases↗
PubMed1990

[Ultrasound, computed tomography and magnetic resonance tomography in a child with macrocephaly and glutaric aciduria type I].

The rare case of glutaric aciduria type I (GA Type I) is described. Its characteristics are discussed and compared with cases in the literature. This disease is basically due to a lack of glutaryl-CoA-dehydrogenase with increased excretion of glutaric acid. Most authors describe frontotemporal cerebral atrophy. In the majority of cases macrocephaly is also present. This sign was also seen in our case and was the reason for performing an ultrasound examination, CT and MR. Ultrasound and CT showed a large insular cistern with incomplete formation of the opercula and frontal atrophy. In addition MR revealed hyperintensity of the basal ganglia and the periventricular white matter. To our knowledge this is the first publication of radiological findings in GA Type I in the German language.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Reliability of biochemical parameters used in prenatal diagnosis of combined methylmalonic aciduria and homocystinuria.

Prenatal diagnosis for combined methylmalonic aciduria and homocystinuria was performed in five at-risk pregnancies by determination of methylmalonic acid (MMA) and total homocysteine (Hcy) in amniotic fluid supernatant. The incorporation rate of [14C] propionate (+/- OHCbl) and the synthesis of cobalamin derivatives in cultured amniocytes were investigated as well as the [14C] MTHF incorporation rate in intact chorion biopsy. Our experience showed that total Hcy and MMA were clearly elevated in amniotic fluid of affected fetuses. Both the study of [14C] propionate incorporation and that of cobalamin synthesis in cultured amniocytes are useful to confirm the results of metabolite determination. The incorporation of [14C] MTHF in intact chorion biopsy seems not to be a reliable diagnostic method.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.

Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and alpha-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I-IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.

Acetyl Coenzyme A↗
PubMed1996

Subdural hemorrhage as an initial sign of glutaric aciduria type 1: a diagnostic pitfall.

The case of a 9-month-old girl with glutaric aciduria type 1 (GA 1) is reported. On initial presentation at 6 months of age, the patient demonstrated bilateral subdural hemorrhages and widening of the basal cisterns. After neurosurgical intervention the subdural effusions regressed; their etiology remained unclear. At the age of 9 months the patient presented again because of progressive loss of psychomotor abilities and a dystonic movement disorder. Cerebral MRI revealed regressive subdural hematoma, but marked frontotemporal atrophy as well. Because of a suspected metabolic disorder, urinary analysis of organic acids was performed. This repeatedly showed marked excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid, indicating a diagnosis of GA 1. Considering our patient's history, we recommend the inclusion of GA 1 in the differential diagnosis of patients with unexplained subdural hematoma and neurological deficits.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria.

We studied two patients with 3-methylglutaconic aciduria in order to determine the molecular defect. A new assay for 3-methylglutaconyl-coenzyme A (CoA) hydratase has been developed in which the substrate, [5-14C]3-methylglutaconyl-CoA, was synthesized using 3-methylcrotonyl-CoA carboxylase purified from bovine kidney. In this assay the products of the reaction are isolated by reverse-phase high performance liquid chromatography and the rates of conversion from substrate are measured. The Michaelis constant for 3-methylglutaconyl-CoA in normal fibroblasts was 6.9 mumol/liter. The mean activity of 3-methylglutaconyl-CoA hydratase in control fibroblasts was 495 pmol/min per mg protein. In the two patients the values were 11 and 17 pmol/min per mg protein, or 2-3% of normal.

Amino Acid Metabolism, Inborn Errors↗
PubMed1975

Metabolic studies of a family with massive formiminoglutamic aciduria.

We have described two siblings who excrete massive amounts (up to 3.89 mmol/24 hr) of N-formiminoglutamic acid (FIGLU) in their urine. This unusual compound was isolated from urine, purified, and firmly identified as FIGLU by combined gas chromatography-mass spectrometry. The patients presumably have a deficiency in activity of the hepatic enzyme, glutamate formiminotransferase, which carries out the fourth sequential step in the main pathway of histidine degradation. Unlike children reported previously with this disorder, our patients had normal serum folate levels, had no hematologic abnormalities, and were not mentally retarded. Very small amounts of FIGLU were present in the plasma of one of the patients, but FIGLU was not detectable in the cerebrospinal fluid of either patient. Administration of pharmacologic doses of folic or folinic acid produced a decrease in excretion of FIGLU in urine. Histidine loading caused a small and comparable urinary excretion of FIGLU in the children's parents and in control adult subjects.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Urine screening for aminoacidopathies: is it beneficial? Results of a long-term follow-up of cases detected bny screening one millon babies.

One million 6-week-old infants were screened for aminoacidurias and the long-term follow-up analyzed to assess the benefits of the screening program. Apart from phenylketonuria, now normally detected by blood screening at five days, the most frequent abnormalities identified were cystinuria, histidinemia, Hartnup disease, and iminoglycinuria. Other disorders occurred less frequently than 1:100,000. Early diagnosis provided unequivocal clinical benefit only for phenylketonuria. There was probable benefit to patients with cystinuria, homocystinuria, argininosuccinic aciduria, and to some patients with Hartnup disease. However, benefit of early diagnosis in these disorders, of which the combined incidence was 1:10,000, was not clear-cut; for example, in 68 cystinuric children, four had already developed renal stones despite close medical supervision and a regimen of increased fluid intake to the limits of tolerance. No patient detected with any other condition benefited, either because the condition appeared benign and was not treated, or because the disorder was serious or lethal and there was a bad outcome despite early diagnosis and treatment. Existing urine screening programs should explore the incidence and clinical significance of further biochemical abnormalities detectable in the newborn infant, but there is no indication at present for the initiation of new urine screening programs designed to detect only aminoacidurias.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria.

Distinct genotypic and phenotypic forms of methylmalonyl CoA mutase (MCM) apoenzyme deficiency can be delineated by biochemical analysis of mutant fibroblasts. One form, designated mut-, expresses a phenotype in which residual enzyme activity is evident in cultured cells exposed to high concentrations of hydroxycobalamin. We describe cloning of an MCM cDNA from cells exhibiting a mut- phenotype and characterization of the mutant gene product overexpressed in primary muto human fibroblasts and Saccharomyces cerevisiae. Three novel base changes were observed. Recombinant clones containing one of these base changes (G717V) express four characteristics of the mut- phenotype: failure to constitute [14C]propionate incorporation activity in fibroblasts assayed under basal cell culture conditions, constitution of [14C]propionate incorporation activity in fibroblasts stimulated with 0.1-1.0 micrograms/ml hydroxycobalamin, interallelic complementation with alleles bearing an R93H mutation, and an apparent Km (adenosylcobalamin) 1,000-fold higher than normal. These results demonstrate that the G717V mutation produces the mut- phenotype and localizes determinants for adenosylcobalamin binding near the carboxyl terminus of MCM.

Amino Acid Sequence↗
PubMed2003

Prenatal diagnosis for arginase deficiency: a case study.

Arginase deficiency is a rare, autosomal recessive, disorder of the urea cycle characterized by mild hyperammonaemia, hyperargininaemia, dibasic aminoaciduria and orotic aciduria, associated with progressive spastic tetraplegia, seizures, psychomotor retardation, and growth failure. We report a family who presented with their daughter at 4 years 11 months of age with an acute encephalopathy. Initial laboratory results revealed hyperammonaemia (160 micromol/L; normal 0-34), hyperargininaemia (512 micromol/L; normal 23-86) and orotic aciduria. A diagnosis of arginase deficiency was confirmed by enzyme assay, and treatment with a modified protein-restricted diet along with sodium benzoate therapy was initiated. Over time, intellectual development has been normal, but the child developed spasticity in her lower extremities. Subsequently, the mother presented at 6 weeks of pregnancy seeking prenatal diagnosis. Prenatal testing for arginase deficiency has only been reported in one other case. Arginase is not expressed in cultured amniotic fluid cells or chorionic villus samples. Testing for arginase activity assay in red blood cells, isolated by cordocentesis, was performed and predicted an unaffected fetus. The result was confirmed by postnatal enzyme analysis of red cells from the newborn. On the basis of our experience, prenatal diagnosis of arginase deficiency by cord red blood cell arginase activity assay appears possible.

Adult↗
PubMed2006

Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.

The metabolic disease 3-methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A (3-MG-CoA) hydratase activity within the leucine degradation pathway. The human AUH gene has been reported to encode for a bifunctional enzyme with both RNA-binding and enoyl-CoA-hydratase activity. In addition, it was shown that mutations in the AUH gene are linked to MGA1. Here we present kinetic data of the purified gene product of AUH using different CoA-substrates. The best substrates were (E)-3-MG-CoA (V(max) = 3.9 U.mg(-1), K(m) = 8.3 microM, k(cat) = 5.1 s(-1)) and (E)-glutaconyl-CoA (V(max) = 1.1 U.mg(-1), K(m) = 2.4 microM, k(cat) = 1.4 s(-1)) giving strong evidence that the AUH gene encodes for the major human 3-MG-CoA hydratase in leucine degradation. Based on these results, a new assay for AUH activity in fibroblast homogenates was developed. The only missense mutation found in MGA1 phenotypes, c.719C>T, leading to the amino acid exchange A240V, produces an enzyme with only 9% of the wild-type 3-MG-CoA hydratase activity.

Acyl Coenzyme A↗
PubMed2004

Neuroradiological findings in glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency).

This article summarizes the magnetic resonance imaging features of glutaric aciduria type I (GA I) based on the cases presented at the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency together with a review of previously reported neuroimaging characteristics of GA I. Previous reports have focused on characteristic findings, such as basal ganglia injury and frontotemporal atrophy or hypoplasia, subdural effusions and white-matter disease. Most of these findings have been demonstrated in symptomatic children, i.e. after manifestation of acute encephalopathic crises. In contrast, prospective investigations in presymptomatically diagnosed children are rare. Since more recent investigations have highlighted CNS changes in patients without encephalopathic crises, systematic prospective investigations of neuroradiological findings in this disease are indispensable for a better understanding of this disease. Based on these findings a suggestion for a MRI protocol is presented, supporting a standardized evaluation of patients with GA I.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

[Inborn errors of metabolism: lessons from a clinical case].

Dramatic advances in recent years in the diagnosis and treatment of inborn errors of metabolism (IEM) make it imperative for the physician to be both aware of their occurrence and acquainted with their clinical presentations. Many may present with symptoms and signs common to sick infants, such as refusal to feed, vomiting and convulsions. Failure to include IEM in the differential diagnosis may have grave consequences, because only prompt recognition and appropriate treatment of a metabolic crisis can help prevent irreversible brain damage or death. We describe a 3-week-old female infant, eventually diagnosed as having an IEM (3-hydroxy-3-methyl-glutaric aciduria), who was admitted to various hospitals and died during her last admission. We focused on the clinical and laboratory findings of each of the first 2 admissions which might have provided clues to the true nature of the illness had the clinicians been aware of the possibility of IEM. Patients with IEM are generally managed in specialized centers; however, the responsibility for initial recognition and immediate treatment of a metabolic emergency lies with the primary physician. The purpose of our case presentation and the discussion of the lessons derived from it, is to prompt the clinician to an awareness and understanding of a subject that used to be considered reserved for specialists. In fact, all that is needed is clinical alertness and the performance of certain well-focused, simple laboratory tests for IEM.

Amino Acid Metabolism, Inborn Errors↗