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At least 19 recordsLinked to original sources
PubMed1995

Analysis of aliphatic dicarboxylic acids in pharmaceuticals and cosmetics by liquid chromatography (HPLC) with fluorescence detection.

2-Bromoacetyl-6-methoxynaphthalene has been found to be a useful prechromatographic fluorescent labelling reagent for the analysis of dicarboxylic acids. The derivatization reaction of azelaic acid and meglutol with this reagent yieded stable and highly fluorescent diesters which could be analysed by reversed-phase HPLC with fluorescence detection. According to the nature of the sample, the derivatization reaction could be carried out in acetonitrile or in an aqueous micellar system. The proposed methods proved to be suitable for the quality control of various complex pharmaceutical and cosmetic formulations of the azelaic acid and meglutol.

Chromatography, High Pressure Liquid↗
PubMed1988

Sequence and analysis of promoter region of human insulin-receptor gene.

The promoter region of the human insulin-receptor (HINSR) gene was isolated from a human chromosome 19 bacteriophage library. With S1 nuclease mapping and primer-extension analysis, we identified multiple transcription-initiation sites. Dexamethasone, a known inducer of HINSR transcription, enhanced transcription of all major transcription-initiation sites. DNA sequence analysis indicated that the HINSR promoter has neither a TATA box nor a CAAT box. The HINSR promoter region contains six GGGCGG sequences that may be binding sites for the transcription factor Sp1. In addition, there were three TCCC sequences that were putative promoter regulatory regions. The HINSR gene promoter has structural similarity to the epidermal growth factor receptor gene promoter and has some features of the promoter of the meglutol (hydroxymethylglutaryl, HMG) CoA reductase gene and the early promoter of simian virus 40.

Base Sequence↗
PubMed1999

Deconvolution gas chromatography/mass spectrometry of urinary organic acids--potential for pattern recognition and automated identification of metabolic disorders.

The National Institute of Standards and Technology (NIST) Automated Mass Spectral Deconvolution and Identification System (AMDIS) is applied to a selection of data files obtained from the gas chromatography/mass spectrometry (GC/MS) analysis of urinary organic acids. Mass spectra obtained after deconvolution are compared with a special user library containing both the mass spectra and retention indices of ethoxime-trimethylsilyl (EO-TMS) derivatives of a set of organic acids. Efficient identification of components is achieved and the potential of the procedure for automated diagnosis of inborn errors of metabolism and for related research is demonstrated.

Acyl-CoA Dehydrogenase↗
PubMed1983

Identification of 3-hydroxy-3-ethylglutaric acid in urine of patients with propionic acidaemia.

By gas chromatographic mass spectrometric analysis, 3-hydroxy-3-ethylglutaric acid was identified in the urine of patients with propionyl CoA carboxylase deficiency. Simultaneously, large amounts of 3-hydroxyvaleric acid and 3-oxovaleric acid, as well as a number of metabolites previously well known in this disorder, were also found in the urine of the patients. It is suggested that formation of 3-oxovaleric acid and 3-hydroxyvaleric acid proceeds via 3-hydroxy-3-ethylglutaryl CoA as an intermediate by a mechanism similar to that of ketone body formation.

Carboxy-Lyases↗
PubMed2006

NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism.

A diagnosis of 3-methylglutaconic aciduria type I (OMIM: 250950) based on elevated urinary excretion of 3-methylglutaconic acid (3MGA), 3-methylglutaric acid (3MG) and 3-hydroxyisovaleric acid (3HIVA) was made in a 61-year-old female patient presenting with leukoencephalopathy slowly progressing over more than 30 years. The diagnosis was confirmed at the enzymatic and molecular level. In vivo brain MR spectroscopic imaging (MRSI) was performed at 3.0 T, and one-dimensional and two-dimensional in vitro NMR spectroscopy of body fluids of the patient was performed at 11.7 T. Additionally, we measured 1D (1)H-NMR spectra of urine of seven patients with a total of four different inborn errors of leucine metabolism. Increased concentrations of 3HIVA, 3MGA (cis and trans) and 3MG were observed in the NMR spectra of the patient's urine. In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher than in the plasma of the patient and only the cis isomer of 3MGA was observed. In vivo brain MRSI showed an abnormal resonance at 1.28 ppm that may be caused by 3HIVA. Comparison of (1)H-NMR spectra of urine samples from all eight patients studied, representing five different inborn errors of leucine metabolism, showed that each disease has typical NMR characteristics. Our leukoencephalopathy patient suffers from a late-onset form of 3-methylglutaconic aciduria type I. In the literature, only very few adult patients with this conditions have been described, and 3HIVA accumulation in white matter in the brain has not been presented before in these patients. Our data demonstrate that (1)H-NMR spectroscopy of urine can easily discriminate between the known inborn errors of leucine metabolism and provide the correct diagnosis.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

A nonsense mutation in the exon 2 of the 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL) gene producing three mature mRNAs is the main cause of 3-hydroxy-3-methylglutaric aciduria in European Mediterranean patients.

3-Hydroxy-3-methylglutaric aciduria is a rare recessive monogenic disorder that affects ketogenesis and the catabolism of L-leucine. We report the biochemical and molecular characterization of a mutation in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene in four new probands, three Spanish and one Turkish, affected by 3-hydroxy-3-methylglutaric aciduria, all homozygous for the nonsense mutation Glu37Ter, which was reported by our group in two probands of Portuguese and Moroccan origin (15). In addition to the aberrant mRNAs found in the two previous probands, a novel species of mature HL mRNA was observed in the patients studied here, since a new cDNA, skipped in exons 2 and 3, was obtained from the mRNAs by reverse-transcription PCR (RT-PCR). Thus, three mRNA species were produced in aberrant splicings as a result of this nonsense mutation: (i) one of the expected size that contains the premature stop codon UAA, (ii) another with a deletion of 84 bp corresponding to the whole of exon 2, and (iii) a new species found now, with a deletion of 192 bp corresponding to skipping of the whole of exons 2 and 3, whose translation product led to the loss of seven amino acids in the leader peptide and 57 amino acids in the terminal domain of the mature enzyme. The association of a nonsense mutation with the skipping of the exon that contains it, plus the following exon, is an unusual finding not seen previously in HL deficiencies. The mutation described here shows the highest incidence (> 37%) of total HL deficiencies reported.

Child, Preschool↗
PubMed1998

Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric aciduria in a French patient.

Two novel point mutations in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene were found in a French patient with double heterozygous 3-hydroxy-3-methylglutaric aciduria. Amplification by reverse transcriptase-polymerase chain reaction of the mRNA using five different pairs of oligonucleotides produced no differences in the fragments amplified with respect to the control. Single-strand conformation polymorphism analysis showed that only one amplified fragment was different in the patient vs. control. Sequencing of the amplified fragments showed two missense point mutations, A698G and T788C, each of them mixed with the wild-type sequence. These mutations produced the changes H233R and L263P, leading to changes in the enzyme activity, which was largely abolished. The father and one brother of the proband were heterozygous for the L263P mutation and the mother and one daughter were heterozygous for the H233R mutation, which confirms the double-heterozygous character of the patient. Another sibling was free of the mutations. An enzymatic restriction analysis has been proposed to screen the occurrence of these two mutations in future patients.

Alleles↗
PubMed2000

Evaluation of urinary acylglycines by electrospray tandem mass spectrometry in mitochondrial energy metabolism defects and organic acidurias.

We analyzed the urinary acylglycine excretion in 26 patients with mitochondrial energy metabolism disorders and in 55 patients with organic acidurias by electrospray tandem mass spectrometry (ESI-MS/MS), monitoring precursor ions of m/z 90. Urinary concentrations of the different acylglycines were quantified using deuterated internal standards. Normal values for the most important acylglycines were established. In MCAD and MAD (neonatal form) deficiencies, typical excretion patterns of urinary acylglycines were found in all the samples. In isovaleric aciduria, propionic aciduria, and 3-methylcrotonylglycinuria typical glycine conjugates were always found. Methylmalonic aciduria (mutase deficiency), multiple carboxylase deficiency, and 3-hydroxy-3-methylglutaric aciduria revealed pathological acylglycine profiles, even if not specific for the disease. In all these diseases acylglycine excretion seems to be less influenced by the clinical status than organic acid excretion. This method is a useful diagnostic tool for these metabolic disorders, complementary to organic acids and acylcarnitine profiles.

Acyl-CoA Dehydrogenase↗
PubMed2001

3-Hydroxy-3-methylglutaric aciduria in an Italian patient is caused by a new nonsense mutation in the HMGCL gene.

3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). Up to now only a few mutations have been reported in the HMGCL gene. We report the first Italian patient, a female who presented metabolic acidosis at 3 days of age and then 3 months later. Analysis of urinary organic acids showed the excretion of 3-hydroxy-3-methylglutaric acid, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. A defect of HMGCL activity was suspected and then confirmed on cultured skin fibroblasts. Brain RM showed a diffuse mild abnormality of cerebral white matter in the periventricular regions, and the single voxel proton MRI spectroscopy showed abnormal peaks. In the patient's full-length HMGCL-cDNA a new c286C > T transition that leads to the stop codon Q96X was detected at the homozygous level. This mutation, that gives rise to a truncated protein, was confirmed in the patient's and also her parents' genomic DNA. The severe genetic lesion identified in the patient, which is in contrast with the mild clinical phenotype, stresses the importance of early diagnosis and therapy in HMGCL deficiency.

Brain↗
PubMed1981

CT findings in a case of deficiency of 3-hydroxy-3-methylglutaryl-CoA-lyase.

Two CT scans have been performed on a child with a biochemically confirmed 3-HMG-CoA-lyase deficiency. Macrocephalus, widespread hypodensity of the white matter with cystic alterations and progressive dilatation of the ventricles were found. The clinical features and CT findings are surprisingly similar to findings in patients with spongy degeneration (Canavan).

Acyl Coenzyme A↗
PubMed1987

Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria.

Persistent excretion of 3-methylglutaconic acid was found in a 6-month-old infant with multiple minor physical malformations and delayed development. During two episodes of intercurrent viral illness, the patient developed severe metabolic acidosis and excreted large amounts of lactate, 3-hydroxybutyrate and acetoacetate. The excretion of 3-methylglutaconic acid did not change during these episodes, nor did it increase following leucine loading. In vitro studies suggest that in this patient, as in the majority of other patients with 3-methylglutaconic aciduria, a primary defect in leucine metabolism is not responsible for the biochemical abnormality.

Abnormalities, Multiple↗
PubMed1985

3-Methylglutaconic and 3-methylglutaric aciduria in a patient with suspected 3-methylglutaconyl-CoA hydratase deficiency.

A girl suffering from marked muscular hypotonia, severe statomotor and mental retardation, bilateral optic atrophy with chorioretinal degeneration, convulsions and a moderate compensated metabolic acidosis is described. Screening for metabolic disorders revealed massive 3-methylglutaconic with 3-methylglutaric aciduria leading to the tentative diagnosis of 3-methylglutaconyl-CoA hydratase deficiency. Metabolite excretion was correlated with variation of leucine intake. 3-methyl-3-hydroxyglutaryl-CoA lyase activity in cultured fibroblasts was normal. The suspected metabolic defect was not demonstrable in cultured skin fibroblasts, however.

Acidosis↗
PubMed1989

Monoamine metabolites and amino acids in serum from schizophrenic patients before and during sulpiride treatment.

Twenty-four acutely ill schizophrenic patients (DSM-III-R), 18-42 years old, were treated for 6 weeks with sulpiride. Sulpiride was administered in three different daily dosages (starting with 400, 800 or 1200 mg) according to a double blind randomized administration schedule. The monoamine metabolites (MAM) homovanillic acid (HVA), 5-hydroxy-indoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-phenylglycol (HMPG) and the amino acids tyrosine, tryptophan, glutamate and glutamine were measured in serum before treatment and once a week during treatment. There were no significant differences between healthy controls and schizophrenic patients in serum levels of monoamine metabolites and amino acids before treatment. There was no dose-response effect of sulpiride on serum levels of the monoamine metabolites or the amino acids. The results are therefore based on the whole group of patients. During treatment the HMPG levels were reduced at all points in time. The serum level of HVA was significantly reduced after 6 weeks. The 5-HIAA and the amino acid levels were not changed during treatment. There were no significant correlations among the monoamine metabolites before treatment. During treatment, however, significant correlations were found among MAM and amino acids. Since the biochemical findings during the treatment were not related to the dose or the concentration of sulpiride the results may be related to secondary biochemical effects of sulpiride and/or to changes in the clinical state following treatment.

Adolescent↗
PubMed1985

Dizygotic twins with 3-hydroxy-3-methylglutaric aciduria; unusual presentation, family studies and dietary management.

A 4-month-old infant with hypotonia and macrocephaly was diagnosed as having 3-hydroxy-3-methylglutaric aciduria, using gas chromatography and mass spectrometry and confirmatory enzyme studies. The same diagnosis was made on his asymptomatic non-identical twin. Examination of the pedigree is consistent with an autosomal recessive mode of inheritance. Dietary treatment improved the symptoms of the propositus, but did not prevent episodes similar to Reye's syndrome in both twins. One such episode closely followed immunisation and our experience suggests that children with this disorder should be observed carefully following immunisation. These episodes were accompanied by an overflow of a wide range of abnormal metabolites. Examination of the urine for organic acids should be considered in infants with unexplained hypotonia and macrocephaly, especially if accompanied by abnormal biochemical indices.

Acidosis↗
PubMed1989

Prenatal diagnosis of 3-hydroxy-3-methylglutaric aciduria by GC-MS and enzymology on cultured amniocytes and chorionic villi.

This paper reports the prenatal diagnosis of HMG CoA lyase deficiency at 16 weeks' gestation by direct chemical analysis of cell-free amniotic fluid and by measurement of HMG CoA lyase activity in cultured amniocytes. Termination of an affected fetus allowed study of chorionic villus tissue, the results providing the basis for future first trimester prenatal diagnoses of this condition. An abstract report of this work has appeared elsewhere.

Amino Acid Metabolism, Inborn Errors↗