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PubMed1996

Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation.

A large family with ornithine transcarbamylase deficiency due to mutation R141Q was ascertained through a propositus who presented with acute neonatal hyperammonemic coma. Of 13 females at risk, 11 were evaluated clinically and had laboratory studies performed. Seven were found to be heterozygous for the mutation. Of these seven, five had chronic clinical symptoms and two were asymptomatic. None of the heterozygotes had elevated plasma ammonia on random testing. Of the five symptomatic females, three had markedly elevated plasma glutamine levels on random testing, while two had levels in the upper range of normal. Plasma citrulline and arginine levels were somewhat lower in the symptomatic individuals but still within the normal range. Five heterozygotes who were tested had either spontaneous orotic aciduria or elevated orotic acid following ingestion of allopurinol, whereas one unaffected female and one unaffected male had normal allopurinol tests. A higher than expected proportion of female heterozygous for the R141Q mutation were clinically and biochemically symptomatic but remained undiagnosed for many years. Plasma glutamine determination and allopurinol testing should be performed in females who present with a combination of relatively non-specific symptoms detailed in this report.

Allopurinol↗

PubMed1983

Arginine utilization of young rats fed diets with simple versus complex carbohydrates.

We proposed that increasing dietary complex carbohydrates would, by increasing fecal nitrogen loss and thus decreasing urinary nitrogen and the need for urea synthesis, ameliorate the effects of arginine deficiency. Two experiments using male, weanling, Sprague-Dawley rats with ad libitum access to water and isocaloric, isonitrogenous, 19% L-amino acid diets were carried out to test this hypothesis. The first was performed in two identical blocks of a 4 X 4 factorial experiment each with six rats per group. Four levels of arginine were fed: 0.0, 0.4, 0.8 and 1.2% of diet with four variations in dietary carbohydrates: sucrose alone, replacement of 2/3 of sucrose with dextrin, and 5 g of wheat bran or guar gum added to 100 g of the sucrose-based diets. Varying dietary carbohydrate quality did not influence growth of rats fed the 1.2% arginine diets, however, when added to the diet with 0.0 arginine, guar gum but not dextrin or wheat bran increased growth. This guar gum-induced weight increase was associated with partial reversal of arginine-deficiency-induced liver lipidosis and orotic aciduria and with higher fecal nitrogen and lower urinary nitrogen. The specificity of this guar gum effect was tested in a second experiment in which guar gum was added to diets containing 33% of the control level of arginine, histidine, leucine, methionine or phenylalanine. Only rats fed the diet deficient in arginine showed significant improvement in growth with added guar gum. We conclude that dietary guar gum but not dextrin or wheat bran, by increasing fecal nitrogen loss and decreasing the need for urea synthesis, partially ameliorates the effects of a low arginine intake. The practical application of feeding guar gum to alleviate certain ammonia-toxicity-related medical conditions is discussed.

Animals↗

PubMed1975

Alpha-ketoadipic aciduria, a new inborn error of lysine metabolism; biochemical studies.

Investigation of a psychomotorically retarded girl showed excretion of abnormal amounts of alpha-ketoadipic acid, alpha-hydroxyadipic acid, alpha-aminoadipic acid, 1,2-butenedicarboxylic acid and elevation of plasma alpha-aminoadipic acid levels. The identity of these metabolities was established by various methods. The excretion of alpha-aminoadipic acid correlated to the lysine intake. Degradation studies with cultured fibroblasts indicate a defect in the oxidative decarboxylation of alpha-ketoadipic acid (see Clin. Chim. Acta, 58 (1975) 271.

Adipates↗

PubMed1986

Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria.

We describe two patients with methylmalonic aciduria and homocystinuria (Cbl C). The disorder was not diagnosed in patient 1 until 4 1/2 years of age; he had a history of fatigue, anorexia, delirium, and spasticity. Moderate megaloblastic bone marrow changes were observed, and there was hyperreflexia of the lower limbs. His condition improved clinically with hydroxycobalamin therapy. Patient 2 was hospitalized at 6 weeks of age because of lethargy and poor feeding. She was found to have macrocytosis. Despite an initial good clinical response to hydroxycobalamin, she developed a striking pigmentary retinopathy. Methylmalonic aciduria persisted in both patients, and homocystinuria persisted in patient 1 despite therapy. The diagnosis of Cbl C disease has been confirmed in both patients by biochemical studies of cultured fibroblasts, including complementation studies. The differences in age of onset and clinical findings together with the similar biochemical findings in these two patients demonstrate the heterogeneity of phenotypic expression in patients with apparently identical abnormalities of vitamin B12 metabolism.

Amino Acid Metabolism, Inborn Errors↗

PubMed2002

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.

Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.

Adult↗

PubMed1998

Post- and prenatal diagnostic methods for the homocystinurias.

Diagnosis of the homozygous homocystinurias can be performed by investigations at the metabolite, enzyme and DNA level. The existence of variant forms due to the wide range of genetic variation may result in only small differences in various parameters between controls and affected subjects. 1. Sulphur amino acid concentrations in plasma, especially total homocysteine, are useful in first line diagnostic investigations. 2. Cystathionine-beta-synthase (CBS), methylenetetrahydrofolate reductase (MTHFR) and methylfolate homocysteine methyltransferase (MFMT) can be directly assayed in many tissues including fibroblasts (each) and blood cells (except CBS). Indirect whole cell assays which measure pathway activity dependent on a particular enzyme can provide useful diagnostic information. 3. Direct analysis of mutations is available for CBS, MTHFR and recently also for MFMT deficiencies. However the existence of a larger number of very rare, often private, mutations limits the usefulness of this approach in routine diagnosis. The above diagnostic approaches can generally be applied to prenatal diagnosis. Measurement of methylmalonic acid and other metabolites in amniotic fluid by stable isotope dilution / gas chromatography-mass spectrometry is well established for the methylmalonic acidurias. This method has also been applied to combined homocystinuria/methylmalonic aciduria supported by enzyme assays in cultured cells. Total homocysteine measurement in cell free amniotic fluid is also possible, performed so far in 14 cases with two affected fetuses. The indirect assay of methionine formation from [14C] labelled formate in intact cultured amniotic fluid cells has been for prenatal diagnosis of the remethylation defects.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1996

Propionylcarnitine excretion is not affected by metronidazole administration to patients with disorders of propionate metabolism.

UNLABELLED: Propionylcarnitine (PC) excretion has been measured during a clinical trial of metronidazole therapy in two patients with propionic acidaemia and two patients with methylmalonic aciduria. All patients were in good metabolic control and were receiving L-carnitine. While total propionate excretion was reduced by up to 40% in all four patients during metronidazole therapy, the excretion of propionylcarnitine remained largely unchanged. PC comprised up to 80% of total propionate excretion in patients with propionic acidaemia. CONCLUSION: These results suggest an extra-hepatic source and/or differing compartmentation for PC formation from those for the production of other metabolites of propionyl-CoA.

Amino Acid Metabolism, Inborn Errors↗

PubMed2005

Stable-isotope dilution gas chromatography-mass spectrometric measurement of 3-hydroxyglutaric acid, glutaric acid and related metabolites in body fluids of patients with glutaric aciduria type 1 found in newborn screening.

We developed a simple and sensitive stable-isotope dilution method for the quantification of 3-hydroxyglutaric acid (3HGA) and glutaric acid (GA) in body fluids. In our method, tert-butyldimethylsilyl (tBDMS) derivatives of 3HGA and GA were measured with a conventional electron-impact ionization (EI) mode in gas chromatography-mass spectrometry (GC-MS). The control values for 3HGA in nmol/ml were 0.15+/-0.08 (serum; n=10) and 0.07+/-0.03 (CSF; n=10). In addition, glutarylcarnitine and free carnitine were quantified by electrospray tandem mass spectrometry. Using these methods, we monitored 3HGA, GA, and glutarylcarnitine in the body fluids of three patients with glutaric aciduria type 1 found during newborn screening. None of the patients had experienced neurological strokes, which are possibly caused by the accumulation of 3HGA, at 15-24 months of age under a disease-specific treatment, including carnitine supplementation. Our data showed that 3HGA levels were relatively high in some serum samples with lower glutarylcarnitine and carnitine levels, suggesting that carnitine supplementation may play a role in preventing the accumulation of 3HGA in patients with this disease.

Amino Acid Metabolism, Inborn Errors↗

PubMed2006

Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin-responsive, multiple acyl-CoA dehydrogenase deficiency patient.

In this case report we studied alterations in mitochondrial proteins in a patient suffering from recurrent profound muscle weakness, associated with ethylmalonic-adipic aciduria, who had benefited from high dose of riboflavin treatment. Morphological and biochemical alterations included muscle lipid accumulation, low muscle carnitine content, reduction in fatty acid beta-oxidation and reduced activity of complexes I and II of the respiratory chain. Riboflavin therapy partially or totally reversed these symptoms and increased the level of muscle flavin adenine dinucleotide, suggesting that aberrant flavin cofactor metabolism accounted for the disease. Proteomic investigation of muscle mitochondria revealed decrease or absence of several flavoenzymes, enzymes related to flavin cofactor-dependent mitochondrial pathways and mitochondrial or mitochondria-associated calcium-binding proteins. All these deficiencies were completely rescued after riboflavin treatment. This study indicates for the first time a profound involvement of riboflavin/flavin cofactors in modulating the level of a number of functionally coordinated polypeptides involved in fatty acyl-CoA and amino acid metabolism, extending the number of enzymatic pathways altered in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.

Acyl-CoA Dehydrogenases↗

PubMed1997

750 MHz 1H NMR spectroscopy characterisation of the complex metabolic pattern of urine from patients with inborn errors of metabolism: 2-hydroxyglutaric aciduria and maple syrup urine disease.

750 MHz 1H NMR spectroscopy has been used to characterise in detail the abnormal low molecular weight metabolites of urine from two patients with inborn errors of metabolism. One case of the rare condition 2-hydroxyglutaric aciduria has been examined. There is at present no rapid routine method to detect this genetic defect, although NMR spectroscopy of urine is shown to provide a distinctive pattern of resonances. Assignment of a number of prominent urinary metabolites not normally seen in control urine could be made on the basis of their known NMR spectral parameters including the diagnostic marker 2-hydroxyglutaric acid, which served to confirm the condition. In addition, 750 MHz 1H NMR spectroscopy has been used to characterise further the abnormal metabolic profile of urine from a patient with maple syrup urine disease. This abnormality arises from a defect in branched chain keto-acid decarboxylase activity and results in a build up in the urine of high levels of branched chain oxo- and hydroxy-acids resulting from altered metabolism of the branched chain amino acids, valine, leucine and isoleucine. A number of previously undetected abnormal metabolites have been identified through the use of one-dimensional and two-dimensional J-resolved and COSY 750 MHz 1H NMR spectroscopy, including ethanol, 2-hydroxy-isovalerate, 2,3-dihydroxy-valerate, 2-oxo-3-methyl-n-valerate and 2-oxo-isocaproate. NMR spectroscopy of urine, particularly when combined with automatic data reduction and computer pattern recognition using a combination of biochemical markers, promises to provide an efficient alternative to other techniques for the diagnosis of inborn errors of metabolism.

Amino Acid Metabolism, Inborn Errors↗

PubMed2004

Management of movement disorders in glutaryl-CoA dehydrogenase deficiency: anticholinergic drugs and botulinum toxin as additional therapeutic options.

Glutaric aciduria type I is an inborn error of metabolism due to the deficiency of glutaryl-CoA dehydrogenase, an enzyme responsible for the catabolism of lysine, hydroxylysine and tryptophan. The most important neurological symptoms include dyskinesia and dystonia, which can be focal, segmental or generalized. Treatment of the extrapyramidal syndrome is often unsatisfactory. We report our experience in the treatment of generalized and focal dystonia with anticholinergic drugs and botulinum toxin type A, respectively. Both therapies proved beneficial.

Adolescent↗

PubMed1993

Regulation of orotic acid biosynthesis and excretion induced by oral glutamine administration in mice.

Glutamine, the most abundant amino acid in blood and tissues, is degraded by the renal and splanchnic tissues, especially the small intestinal mucosa. Due to the activity of glutaminase, it may be broken down in these tissues and contribute to ammoniagenicity. Glutamine, either directly or through ammonia production, may act as a nitrogenous source for pyrimidine biosynthesis. We have evaluated the effect of glutamine on orotate metabolism in mice, by gavaging (ig) L-glutamine, 1.0 to 4.0 mmol/100 g of body wt/day, during 6 weeks of experimentation. Glutamine at doses of 2.5 to 4.0 mmol/100 g of body wt caused a significant increase in plasma ammonia and urinary orotate. The regulation of the orotic acid biosynthesis and excretion was studied by testing the effects of various inhibitors in mice force-fed with glutamine (4 mmol/100 g of body wt, ig). The orotic aciduria was insensitive to acivicin (1 and 5 mg/100 g of body wt, ip), a specific inhibitor of the cytoplasmic carbamyl phosphate synthetase-II, thus pointing toward the mitochondrion as the principal source of carbamyl phosphate. Cycloheximide (15 and 100 mg/kg of body wt, ip) caused a significant decrease in urinary orotate indicating that the induction of orotate synthesis by glutamine may be associated with the translation of a specific protein. However, orotate excretion was significantly decreased by N-(phosphonoacetyl)-L-aspartate (PALA) (5 mg/100 g of body wt, ip) due to its inhibitory effect on the aspartate transcarbamylase activity. There was a significant increase of urinary orotate following ingestion of adenine supplemented diets (0.1% and 0.2%), suggesting the blockage of the utilization of orotate for nucleotide biosynthesis by glutamine. Since orotate synthesis may also be influenced by ornithine metabolism, we evaluated the effect of glutamine administration on various ornithine-metabolizing enzymes. There was a decrease in hepatic ornithine decarboxylase activity with no change in hepatic ornithine aminotransferase activity following the administration of glutamine. This observation indicates that an increased metabolic utilization of ornithine is not responsible for the increase in orotate excretion, which may be caused principally through an effect of glutamine on mitochondrial carbamyl phosphate synthesis.

Administration, Oral↗

PubMed2001

Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase.

Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

Aldehyde Oxidoreductases↗

PubMed2003

MLYCD mutation analysis: evidence for protein mistargeting as a cause of MLYCD deficiency.

Malonyl-CoA decarboxylase (MLYCD) deficiency is an autosomal recessive disorder characterized by malonic aciduria, developmental delay, seizure disorder, hypoglycemia, and cardiomyopathy. Genomic sequencing of MLYCD in nine unrelated patients identified 16 of 18 pathogenic alleles, which are documented in the newly created Human MLYCD Allelic Variant Database (http://mlycd.hgu.mrc.ac.uk/). Fibroblast cell lines were available from eight of these patients and two previously reported patients with homozygous MLYCD mutations. Western blot analysis using antisera raised to a C-terminal peptide detected a 66-kDa band that was absent in six patients and substantially reduced in three patients. One patient showed an increase in protein levels with a prominent smeary 68-l83-kDa band. Immunocytochemical analysis of MLYCD-expressing patient cell lines showed apparent intracellular mislocalization. An extreme N-terminal mutation c.8G>A (p.G3D) mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a four-amino acid conserved N-terminal motif. A 25-base deletion between the putative mitochondrial and peroxisomal initiating codons (M1 and M40) and a point mutation ablating the second of these (c.119T>C, p.M40T) both showed punctate perinuclear staining. As none of the three mislocalizing mutations are predicted to alter the catalytic function of the peptide, it seems likely that correct subcellular localization of MLYCD is critical for it to function normally.

Adolescent↗

PubMed2004

Photosensitive absence epilepsy with myoclonias and heterozygosity for succinic semialdehyde dehydrogenase (SSADH) deficiency.

OBJECTIVE: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a neurometabolic disorder characterized by excessive GABA levels and seizures. There has been no clinical phenotype described to date with heterozygosity for SSADH deficiency. METHODS: A patient heterozygous for SSADH deficiency presented with absence and myoclonic seizures. EEG monitoring and enzymatic, metabolic, and molecular studies for SSADH were obtained on the patient and family members. RESULTS: EEG recordings yielded generalized 3-4 Hz spike-wave paroxysms and trains of multiple spikes in the heterozygous patient, and photosensitivity in the heterozygous patient and parent as well as in the sibling with homozygous deficiency. The heterozygous patient and parents did not manifest 4-OH-butyric aciduria but SSADH levels were low and a splice site mutation of the SSADH gene was identified in each. CONCLUSIONS: Heterozygosity for SSADH deficiency may be associated with an epilepsy syndrome characterized by absence and myoclonic seizures, photoparoxysmal EEG and generalized epileptiform discharges SIGNIFICANCE: Heterozygous SSADH deficiency may be suspected, given an appropriate family history in the setting of an apparently idiopathic generalized epilepsy. Pathogenic explanations may relate to regional elevations in GABA or GHB concentrations.

Adolescent↗

PubMed1990

Methylmalonic aciduria due to a new defect in adenosylcobalamin accumulation by cells.

A child with methylmalonic aciduria due to failure to accumulate adocbl in mitochondria has a phenotype similar to cblA disease. Deficient utilization of labeled propionate by his fibroblasts is corrected by their fusion with those from cblA patients, indicating that he belongs to a different complementation class and probably is deficient in a different gene product. The defect appears not to be due to reduced affinity of enzymes for adocbl, or for ATP, and the minimal thiol required for adocbl synthesis is not different from that of extracts of normal cells.

Amino Acid Metabolism, Inborn Errors↗

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↗

PubMed1997

Urinary proton magnetic resonance studies of early ifosfamide-induced nephrotoxicity and encephalopathy.

Ifosfamide is an oxazophosphorine widely used in the treatment of cancer in children and adults. Nephrotoxicity and neurotoxicity are major side effects. The aim of this study was to use high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine to identify novel biochemical markers of ifosfamide-induced toxicity. Urine samples were collected from 10 nonencephalopathic patients (who had not previously received nephrotoxic chemotherapy) immediately prior to the first ifosfamide dose and at timed intervals for up to four treatment cycles. The findings were compared with those for urine samples collected from five patients during acute encephalopathic episodes. 1H NMR urinalysis identified a series of characteristic time-related changes in the excretion profiles of low molecular weight endogenous metabolites during ifosfamide therapy. These changes included a decreased excretion of hippurate and an increased excretion of glycine, histidine, glucose, lactate, and trimethylamine-N-oxide. Two nonencephalopathic patients had marked but transient glutaric or adipic aciduria during the second cycle of ifosfamide treatment. Urinary retinol-binding protein rose acutely after each treatment cycle but usually returned to baseline levels. Maximum renal toxicity was observed by the fourth treatment cycle. The ratio of the urinary excretion of the uroprotectant mesna (active form) to dimesna (inactive form) correlated with the degree of renal toxicity. For the encephalopathic patients, the ifosfamide-induced changes in the urinary low molecular weight metabolite profile were similar to those for the nonencephalopathic group. In contrast to previous reports, none of the encephalopathic group developed glutaric aciduria, and i.v. methylene blue did not reverse neurotoxicity in the two patients who received it. The results suggest that ifosfamide nephrotoxicity involves both cortical and medullary regions of the nephron and that the urinary mesna:dimesna ratio may be important in assessing the degree of cytoprotection. This study demonstrates that 1H NMR can provide novel biochemical information on ifosfamide-induced toxicity and will be of value in the optimization of ifosfamide therapy.

Adult↗