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At least 721 records · Page 40Linked to original sources
PubMed2006

Riboflavin-responsive glutaryl CoA dehydrogenase deficiency.

We report here riboflavin responsiveness in a patient with glutaryl CoA dehydrogenase (GCDH) deficiency, compound heterozygous for the S139L and P248L mutations and with 20% residual GCDH enzyme activity in vitro. Our results suggest the mitochondrial GCDH homotetramer remains intact with one of these mutations associated with the binding site of the single FAD cofactor and that pharmacological doses of the cofactor precursor may be sufficient to induce an increase in activity in the mutant GCDH enzyme, although not sufficient to normalise urinary organic acid excretion. Serine139 is one of nine conserved amino acid residues that line the binding site of the protein and is in close proximity to both substrate and FAD cofactor. It is possible that steric alterations caused by substitution of serine with leucine at this position may be overcome with high cofactor concentrations. P248L is also associated with some residual GCDH activity in other patients and the unique combination of S139L with P248L may also explain the results in our patient. Responsiveness to riboflavin in our patient has been compared with two other patients with glutaric aciduria type 1 and minimal residual GCDH activity, one with homozygosity for the R257Q mutation and one with heterozygosity for the G354S mutation and a novel G156V mutation. A low lysine diet reduced glutaric acid excretion in our riboflavin-responsive GCDH-deficient patient almost to control values. She is now 21 years of age and clinically and neurologically normal.

Adult↗
PubMed1989

Glutaric aciduria type I: enzymatic and neuroradiologic investigations of two kindreds.

Two kindreds with glutaric aciduria type I were investigated. Of 20 family members who underwent neurologic examination and organic acid analysis of urine, 18 had glutaryl-coenzyme A dehydrogenase (GDH) activity determined in cultured skin fibroblasts and 12 had computed tomographic brain scans. Six homozygotes were identified who had undetectable GDH activity and identical biochemical profiles (consisting of glutaric and 3-hydroxyglutaric aciduria, reduced serum carnitine concentrations, and frontotemporal atrophy). Serial computed tomographic brain scans of one homozygous infant demonstrated the sequential postnatal development of this atrophy during 3 years before the development of clinical manifestations. In three of the six homozygotes, including the father in one kindred, there were no clinical manifestations of glutaric aciduria type I. These findings raise questions about the value of prenatal diagnosis in predicting clinical manifestations in homozygous newborn infants.

Adult↗
PubMed1997

D-2-hydroxyglutaric aciduria: hypotonia, cortical blindness, seizures, cardiomyopathy, and cylindrical spirals in skeletal muscle.

An infant girl was demonstrated to have D-2-hydroxyglutaric aciduria, the fifth case described and the first with muscle biopsy of this rare organic aciduria that differs clinically and genetically from the more common L-2-hydroxyglutaric aciduria. Her clinical features included mildly dysmorphic facies, developmental delay, generalized hypotonia, myoclonic seizures, cortical blindness, and dilated cardiomyopathy requiring treatment. Muscle biopsy demonstrated only excessive glycogen histochemically, but ultrastructural examination revealed subsarcolemmal cylindrical spirals and normal mitochondria. Because of the metabolism of D-2-hydroxyglutaric aciduria, we regard valproic acid as contraindicated in the treatment of epilepsy in this disease.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

The synthesis of oxylate from hydroxypyruvate by isolated perfused rat liver. The mechanism of hyperoxaluria in L-glyceric aciduria.

Hydroxypyruvate and glycolate inhibited the oxidation of [U-14C]glyoxylate to [14C]oxalate in isolated perfused rat liver, but stimulated total oxalate and glycolate synthesis. [14C]Oxalate synthesis from [14C]glycine was similarly inhibited by hydroxypyruvate, but conversion of [14C1]glycolate to [14C]oxalate was increased three-fold. Pyruvate had no effect on the synthesis of [14C]-oxalate or total oxalate. The inhibition studies suggest that hydroxypyruvate is a precursor of glycolate and oxalate and that the conversion of glycolate to oxalate does not involve free glyoxylate as an intermediate. [14C35Hydroxypyruvate, but not [14C1]hydroxypyruvate, was oxidized to [14C]oxalate in isolated perfused rat liver. Isotope dilution studies indicate the major pathway involves the decarboxylation of hydroxypyruvate forming glycolaldehyde which is subsequently oxidized to oxalate via glycolate. The oxidation of serine which is subsequently oxidized to oxalate via glycolate. The oxidation of serine to oxalate appears to proceed predominantly via hydroxypyruvate rather than glycine or ethanolamine. The hyperoxaluria of L-glyceric aciduria, primary hyperoxaluria type II, is induced by the oxidation of the hydroxypyruvate, which accumulates because of the deficiency of D-glyceric dehydrogenase, to oxalate.

Acetaldehyde↗
PubMed2006

Magnetic resonance spectroscopic characteristics of glutaric aciduria type II.

Magnetic resonance spectroscopy (MRS) of a 12-year-old female patient with glutaric aciduria type II was compared with data obtained from four healthy age- and sex-matched volunteers. In the clinically active phase, conventional magnetic resonance imaging showed mild ventricular dilatation. Frontal lobe choline/creatine (Cho/Cr) ratio (1.98) was higher than the ratios reported for the comparison participants (1.64 [SD 0.21]). The N-acetylaspartate/creatine (NAA/Cr) ratio (1.95) was lower than normal limits (2.66 [SD 0.23]). After successful riboflavin treatment and dietary restriction for proteins, the NAA/Cr ratio was within the normal range (2.44) and Cho/Cr ratio was below the normal range (1.15), suggesting riboflavin-responsive multiple acyl-coA dehydrogenase deficiency. An elevated Cho/Cr ratio and decreased NAA/Cr ratio is consistent with a demyelinating process in the active phase of glutaric aciduria type II. MRS helps to monitor the progress of the disease and the efficacy of treatment by revealing changes in NAA/Cr and Cho/Cr ratios.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Acute pancreatitis in a patient with glutaric acidemia type II.

We describe a two-year-old girl who presented with coma following an upper respiratory tract infection. Nonketotic hypoglycemia, metabolic acidosis and mild hyperammonemia were detected. The urinary organic acid profile was consistent with glutaric aciduria type II. Pancreatitis was diagnosed at autopsy. Although pancreatitis has been described in a number of inborn errors of metabolism including organic acidemias, to the best of our knowledge this is the first report of acute pancreatitis occurring in glutaric acidemia type II. It was stressed, therefore, that this complication should be searched for in organic aciduria patients, and the measurement of plasma amylase and lipase levels should be added to the battery of laboratory investigations in such cases.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

ETHE1 mutations are specific to ethylmalonic encephalopathy.

Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G-->A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

Alleles↗
PubMed1987

Molecular basis of enzyme abnormalities in urea cycle disorders. With special reference to citrullinemia and argininosuccinic aciduria.

This paper deals with enzymological, immunochemical and molecular genetic analyses of citrullinemia and argininosuccinic aciduria. Citrullinemia has been classified by Saheki et al. [J. inher. Metab. Dis. 8: 155-156, 1985] into three types from the properties of the deficient argininosuccinate synthetase (ASS) of the patients. Analysis of hepatic mRNA coding for ASS revealed certain characteristics in type II and III citrullinemic patients whose hepatic ASS protein was low. A newly developed enzyme-linked immunosorbent assay (ELISA) of argininosuccinate lyase (ASL) protein showed that 8 out of ten cases of argininosuccinic aciduria had no detectable ASL protein in the liver, erythrocytes, cultured skin fibroblasts or cultured amniocytes.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian.

We studied a six-month-old infant with severe megaloblastic anemia, coma and hyperpigmentation of the extremities. He was found to have methylmalonic aciduria (79 mumol per milligram of creatinine) and homocystinuria (0.85 mumol per milligram of creatinine). Additional biochemical abnormalities included cystathioninuria, glycinuria, methylcitric aciduria, 3-hydroxypropionic aciduria and formic aciduria. The concentration of vitamin B12 in the serum was 20 pg per milliliter. This severe nutritional deficiency was a consequence of inadequate intake, for the infant was exclusively breast-fed by a strictly vegetarian mother who manifested methylmalonic aciduria. Our observations emphasize the importance of educating strict vegetarians about the deficiency of vitamin B12 in their diets and the importance of vitamin B12 supplementation.

Adult↗
PubMed1998

Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria).

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare metabolic disorder of 4-aminobutyric acid degradation, has been identified in approximately 150 patients. Affected individuals accumulate large quantities of 4-hydroxybutyric acid, a compound with a wide range of neuropharmacological activities, in physiological fluids. As a first step in beginning an investigation of the molecular genetics of SSADH deficiency, we have utilized SSADH cDNA and genomic sequences to identify two point mutations in the SSADH genes derived from four patients. These mutations, identified by standard methods of reverse transcription, PCR, dideoxy-chain termination, and cycle sequencing, alter highly conserved sequences at intron/exon boundaries and prevent the RNA-splicing apparatus from properly recognizing the normal splice junction. Each family segregated a mutation in a different splice site, resulting in exon skipping and, in one case, a frameshift and premature termination and, in the other case, an in-frame deletion in the resulting protein. Family members, including parents and siblings of these patients, were shown to be heterozygotes for the splicing abnormality, providing additional evidence for autosomal recessive inheritance. Our results provide the first evidence that 4-hydroxybutyric aciduria, resulting from SSADH deficiency, is the result of genetic defects in the human SSADH gene.

Aldehyde Oxidoreductases↗
PubMed1987

Identification of glutarylcarnitine in glutaric aciduria type 1 by carboxylic acid analyzer with an ODS reverse-phase column.

A technique for the identification of glutarylcarnitine in urine from a patient with glutaric aciduria type 1 is described. The patient's urine sample was partially purified using an anion exchange column and analyzed by a carboxylic acid analyzer fitted with an ODS reverse-phase column. The chromatogram of the patient's urine sample revealed 3 different peaks, which corresponded respectively to those of carnitine with amino acids, acetylcarnitine and glutarylcarnitine. Following hydrolysis of the sample, the chromatogram had no peaks of acetylcarnitine and glutarylcarnitine but had remarkably amplified peaks of carnitine, acetic acid and glutaric acid. The eluent fraction of glutarylcarnitine from the non-hydrolyzed sample was hydrolyzed and analyzed again. It no longer had the glutarylcarnitine peak on the chromatogram, but had only two separate peaks of carnitine and glutaric acid. This technique simplifies the identification of glutarylcarnitine, in that it requires only removal of organic acids for preparation of samples, and does not require radioisotope or mass spectrometry.

Acetylcarnitine↗
PubMed1999

Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia.

Since 1998, the NSW Newborn Screening Program has used electrospray tandem mass spectrometry (MS/MS) to analyse samples from all babies born in NSW and the ACT (approximately 95000 per year) for selected amino acids and acylcarnitines. The software rules editor initially interprets all results where ratio of analyte to internal standard is modified by input from the external standard curves per analyte. The numerical results are then downloaded to the NSW Newborn Screening database, which provides automatic, analyte specific follow-up test cascade. We have analysed samples from 137 120 consecutive newborns received by the program, requested repeat samples from 122 babies, and found abnormal levels in 17 babies with phenylketonuria, 1 tetrahydrobiopterin deficiency, 3 hyperphenylalaninaemia, 1 maple syrup urine disease, 1 tyrosinaemia type II, 1 congenital lactic acidosis, 2 medium-chain acyl CoA dehydrogenase deficiency, 1 short-chain acyl CoA dehydrogenase deficiency, 1 beta-ketothiolase deficiency, 2 vitamin B12 deficient babies of vegan mothers and 1 glutaric aciduria type I. Using population data plus that obtained from retrospective samples with proven disorders we have established cut-off levels for each analyte tested. This coupled with the ability of the database to provide ratios of various analytes gives excellent screening specificity and sensitivity for the detection of at least 40 rare inborn errors of metabolism.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria.

3-Methylglutaconic aciduria is the biochemical marker of several inherited metabolic diseases. Four types of 3-methylglutaconic aciduria can be distinguished. In the type I form, accumulation of 3-methylglutaconate is due to deficient activity of 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine degradation pathway. In the other forms, 3-methylglutaconic acid is not derived from leucine but is of unidentified origin, possibly derived from other metabolic pathways, such as mevalonate metabolism. We report five patients, all presenting a severe early-onset phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, cataract, hypotonia/developmental delay, lactic acidosis, and normal 3-methylglutaconyl-CoA hydratase activity. This peculiar phenotype, for which a primary mitochondrial disorder is hypothesized, identifies a novel subtype of 3-methylglutaconic aciduria.

Acidosis, Lactic↗
PubMedDate not supplied

[Variants of inborn errors of metabolism with late onset but nevertheless life threatening course].

BACKGROUND: There is a growing number of inborn errors of metabolism (IEM) with late onset but nevertheless life threatening course. PATIENTS: Patients with late onset variants of urea cycle defects, fatty acid oxidation defects and organic acidurias are demonstrated. METHODS: Biochemical, enzymatic, molecular methods and especially tandem mass spectrometry (TMS) are used for diagnostic purposes. RESULTS: IEM variants with late onset are difficult to be detected. TMS has some advantages as the simple sampling of dried blood on filter paper cards and the simultaneous detection of a broad spectrum of disturbances in amino acids and acylcarnitines. This may facilitate a prompt diagnosis. Asymptomatic persons not only carry an unrecognized risk for severe metabolic decompensation but also pass on their mutation of IEM and the associated disease risk to the next generation (Non-disease). CONCLUSION: TMS, which is used in newborn screening centers is very convenient to establish a prompt diagnosis in some unexpected late onset metabolic crisis following surgeries, infections or other catabolic stress. Furthermore TMS may be a suitable and rapid adjunct method to improve transplantation management.

Adult↗
PubMed1984

Prenatal diagnosis of glutaric aciduria type II by direct chemical analysis of dicarboxylic acids in amniotic fluid.

A method for the measurement of dicarboxylic acids in amniotic fluid was developed that utilizes isolation of the acids by liquid partition chromatography and quantification by ammonia chemical ionization selected ion monitoring, gas chromatography-mass spectrometry. The concentrations of dicarboxylic acids in ten normal samples of amniotic fluid (mumol/l +/- 1 S.D.) were glutaric acid 0.91 +/- 0.15, adipic acid 0.33 +/- 0.08, suberic acid 0.27 +/- 0.08, and sebacic acid 0.21 +/- 0.10. A highly elevated concentration of 14.48 mumol/l glutaric acid was found in the amniotic fluid of a pregnancy in which the fetus was affected with glutaric aciduria type II. Adipic, suberic and sebacic acids were also significantly elevated. The dicarboxylic acids were normal in the amniotic fluid of a pregnancy at risk for glutaric aciduria type II in which the fetus was unaffected. This method is suitable for the rapid prenatal diagnosis of glutaric aciduria types I and II and of potential value for the prenatal diagnosis of other inherited disorders in which dicarboxylic acids accumulate.

Adipates↗
PubMed1979

Treatment of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria). Experience with diet, riboflavin, and GABA analogue.

The autosomal recessive inherited disorder glutaryl-CoA dehydrogenase deficiency (glutaric aciduria) runs a progressive course with severe choreoathetosis and dystonia, eventually leading to total helplessness and early death. Theree patients were observed during therapeutic trials with a protein-low diet, riboflavin and GABA analogue. Diet and riboflavin had a slight-to-moderate effect on the clinical symptoms; the excretion of glutaric acid and 2-amino-adipic acid decreased considerably during treatment. Regression of neurologic symptoms was observed during treatment with GABA analogue. It is concluded that the patients should be treated as early as possible with protein-low diet, riboflavin, and GABA analogue.

2-Aminoadipic Acid↗
PubMed1999

3-Methylglutaconic aciduria and hypermethioninaemia in a child with clinical and neuroradiological findings of Leigh disease.

We report on a child with a clinical and neuroradiological picture consistent with Leigh disease and an unusual association of isolated hypermethioninaemia and 3-methylglutaconic aciduria. A low-methionine diet normalized both plasma methionine and urine 3-methylglutaconic acid; a methionine-loading test led to significant increase of both metabolites. In the skin fibroblasts the activity of 3-methylglutaconyl-CoA hydratase was essentially normal. No explanation of this uncommon association of hypermethioninaemia and glutaconic aciduria is available. The possibility of a common transporter for 3-methylglutaconic acid and methionine is an attractive hypothesis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1999

Facial anomalies in D-2-hydroxyglutaric aciduria.

D-2-hydroxyglutaric aciduria is a rare autosomal recessive organic aciduria with variable clinical expression. The biochemical defect is still unknown, and genetic heterogeneity has been suggested. Here, we report on facial anomalies in two unrelated cases of D-2-hydroxyglutaric aciduria presenting with epileptic encephalopathy. In a review, we found that minor facial anomalies have been mentioned in three patients. A flat face with a broad nasal bridge and external ear anomalies were present in our patients and in reported cases. We suggest giving consideration to D-2-hydroxyglutaric aciduria as a cause of minor facial anomalies in epileptic encephalopathy of unknown origin.

Amino Acid Metabolism, Inborn Errors↗