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PubMed1985

Cerebral citric acid cycle enzymes in methionine sulfoximine toxicity.

The activity levels of pyruvate dehydrogenase, enzymes of the citric acid cycle, aspartate and alanine aminotransferases, and NADP+-isocitrate dehydrogenase were determined in the cerebral cortex, cerebellum, brain stem, corpus striatum, hippocampus, and midbrain regions of normal rats and rats injected with acute and subacute doses of methionine sulfoximine (MSI). In both conditions there was an elevation in the activities of pyruvate dehydrogenase and all the enzymes of the citric acid cycle except malate dehydrogenase, whereas the activities of aminotransferases and NADP+-isocitrate dehydrogenase were suppressed in all the cerebral regions. It is suggested that the operational rates of the citric acid cycle would be enhanced in MSI-induced hyperammonemia and that there might be a derangement in the transport of reducing equivalents across mitochondrial membranes. It has been suggested that the convulsant action of the drug is due to its effects on ionic gradients and may not be due to depletion of alpha-ketoglutarate from the citric acid cycle.

Animals↗

PubMed2005

Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University.

To address the current role of liver transplantation (LT) for urea cycle disorders (UCDs), we reviewed the worldwide English literature on the outcomes of LT for UCD as well as 13 of our own cases of living donor liver transplantation (LDLT) for UCD. The total number of cases was 51, including our 13 cases. The overall cumulative patient survival rate is presumed to be more than 90% at 5 years. Most of the surviving patients under consideration are currently doing well with satisfactory quality of life. One advantage of LDLT over deceased donor liver transplantation (DDLT) is the opportunity to schedule surgery, which beneficially affects neurological consequences. Auxiliary partial orthotopic liver transplantation (APOLT) is no longer considered significant for the establishment of gene therapies or hepatocyte transplantation but plays a significant role in improving living liver donor safety; this is achieved by reducing the extent of the hepatectomy, which avoids right liver donation. Employing heterozygous carriers of the UCDs as donors in LDLT was generally acceptable. However, male hemizygotes with ornithine transcarbamylase deficiency (OTCD) must be excluded from donor candidacy because of the potential risk of sudden-onset fatal hyperammonemia. Given this possibility as well as the necessity of identifying heterozygotes for other disorders, enzymatic and/or genetic assays of the liver tissues in cases of UCDs are essential to elucidate the impact of using heterozygous carrier donors on the risk or safety of LDLT donor-recipient pairs. In conclusion, LT should be considered to be the definitive treatment for UCDs at this stage, although some issues remain unresolved.

Adolescent↗

PubMed1998

The role of orthotopic liver transplantation in the treatment of ornithine transcarbamylase deficiency.

The purpose of this study was to combine our clinical experience with a review of the literature to determine the value of orthotopic liver transplantation in the treatment of both boys and girls with ornithine transcarbamylase deficiency. Three boys younger than 1 year of age with symptomatic ornithine transcarbamylase deficiency (median age, 116 days; range, 40 to 223 days) underwent orthotopic liver transplantation. The patients' growth, developmental progress, ammonia levels, and amino acid levels were analyzed pre- and post-liver transplantation. The clinical courses of the respective patients and the treatment modalities used were compared with published reports from 1978 through 1997. The median follow-up period in these 3 patients was 3.2 years (range, 9 months to 5.2 years). Orthotopic liver transplantation restored normal urea production and stabilized ammonia levels within 24 hours of surgery (median serum ammonia level 24 hours post-liver replacement, 43 micromol/L; range, 30 to 66 micromol/L). After liver replacement, arginine synthesis was normalized; however, plasma citrulline levels remained less than normal in all patients. Linear growth was evaluated in all 3 patients at the time of the most recent follow-up; median z scores for patient height and weight were -2.16 and -1.16, respectively. Standardized intelligence tests showed that 2 of the 3 patients continue to perform at age-appropriate levels. The third child was developmentally delayed pretransplantation at 4 months of age on presentation and continues to perform in a below-average fashion. Orthotopic liver transplantation results in the restoration of normal urea production and serum ammonia levels in the boy suffering from symptomatic ornithine transcarbamylase deficiency. Serum arginine, but not citrulline, levels are normalized, probably because of the persistent intestinal mucosa defect. Patient growth is similar to that in infants undergoing liver transplantation for other causes. When liver transplantation is performed before cognitive impairment occurs, intellectual development is normal, because the risk of additional episodes of hyperammonemia is elevated.

Amino Acid Metabolism, Inborn Errors↗

PubMedDate not supplied

Gas chromatographic-mass spectrometric urinary metabolome analysis to study mutations of inborn errors of metabolism.

Urine contains numerous metabolites, and can provide evidence for the screening or molecular diagnosis of many inborn errors of metabolism (IEMs). The metabolomic analysis of urine by the combined use of urease pretreatment, stable-isotope dilution, and capillary gas chromatography/mass spectrometry offers reliable and quantitative data for the simultaneous screening or molecular diagnosis of more than 130 IEMs. Those IEMs include hyperammonemias and lactic acidemias, and the IEMs of amino acids, pyrimidines, purines, carbohydrates, and others including primary hyperoxalurias, hereditary fructose intolerance, propionic acidemia, and methylmalonic acidemia. Metabolite analysis is comprehensive for mutant genotypes. Enzyme dysfunction-either by the abnormal structure of an enzyme/apoenzyme, the reduced quantity of a normal enzyme/apoenzyme, or the lack of a coenzyme-is involved. Enzyme dysfunction-either by an abnormal regulatory gene, abnormal sub-cellular localization, or by abnormal post-transcriptional or post-translational modification-is included. Mutations-either known or unknown, common or uncommon-are involved. If the urine metabolome approach can accurately observe quantitative abnormality for hundreds of metabolites, reflecting 100 different disease-causing reactions in a body, then it is possible to simultaneously detect different mutant genotypes of far more than tens of thousands.

DNA Mutational Analysis↗

PubMed1991

Localized 1H NMR spectroscopy in patients with chronic hepatic encephalopathy. Analysis of changes in cerebral glutamine, choline and inositols.

Localized, short echo 1H magnetic resonance spectra from an area in the parietal cortex of three patients suffering from chronic hepatic encephalopathy are compared with equivalent spectra obtained from healthy control subjects. Three significant differences are found: elevated glutamine, decreased inositol, and decreased choline peak intensities. The elevation of cerebral glutamine concentration is expected as a consequence of the presumed chronic hyperammonemia in this disease. The finding of a 50% change in the inositol peak is physiologically unexpected and so far unaccounted for. Data acquisition and processing parameters are described in detail. To further define spectral abnormalities, which were readily detected in untransformed spectra, a simple data analysis scheme has been used that consists of post-acquisition low-frequency filtering, a lineshape transformation, and a difference technique to clarify spectral changes.

Aged↗

PubMedDate not supplied

A 15N NMR study of in vivo cerebral glutamine synthesis in hyperammonemic rats.

Rats were given intravenous 15NH4+ infusion at a rate of 2.2 or 5.5 mmol/h/kg body wt to induce hyperammonemia, as animal models of hepatic encephalopathy. Its effect on cerebral amino acid metabolism was studied in vivo by 15N NMR spectroscopy at 20.27 MHz for 15N. Cerebral [gamma-15N]glutamine (present at a tissue concentration of 4-9 mumol/g) and [alpha-15N]glutamate/glutamine (6 mumol/g) were clearly observed in living rats within 9-18 min. In portacaval-shunted rats, final cerebral [gamma-15N]glutamine concentrations were higher than those in controls after the same infusion period, presumably because decreased 15NH4+ removal in the liver led to increased 15NH3 diffusion into the astrocytes. In control rats, cerebral [gamma-15N]glutamine pool increased at a rate of 1.7 mumol/h/g when blood ammonia concentration was 0.8 mM. 15N enrichment in gamma-15N was 71%. From these observations, in vivo activity of glutamine synthetase in rat brain was estimated to be 3.5 mumol/h/g. Comparison with reported optimum in vitro activity suggests that in situ concentrations of some substrates and cofactors limit the activity of glutamine synthetase in vivo.

Ammonia↗

PubMed2001

Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis.

We report a Japanese boy who died at Day 28 of life because of severe carbamoyl phosphate synthetase I (CPS1) deficiency that was proven by enzyme assay. By analysis of cDNA and genomic DNA, he was shown to be a compound heterozygote with two point mutations of the CPS1 gene, 840G>C leading to an aberrant splicing and 1123C>T (predicting Q375X). The 840G>C was a mutation described in another Japanese family. Since his parents carried each mutation heterozygously, we performed prenatal diagnosis at 16 weeks of his mother's next gestation by multiplex PCR and melting curve analysis in a single capillary containing two-color fluorescent (LC-Red 640 and LC-Red 705) probes on LightCycler. We analyzed genomic DNA extracted from amniotic cells and found that the fetus was homozygous for the wild-type alleles. At term a healthy girl was born without hyperammonemia.

Carbamoyl-Phosphate Synthase I Deficiency Disease↗

PubMed1998

N-carbamoyl-L-glutamate plus L-arginine can protect ammonia intoxication in rats with reduced functional liver mass.

We previously reported the protective effect of N-carbamoyl-L-glutamate plus L-arginine in rats given a lethal dose (LD99.9) of ammonium acetate (Kim, S. et al., Proc. Natl. Acad. Sci. 69, 3530-3533, 1971; ref.1). The present study was undertaken to find out whether the same compounds could also be effective even after the functional mass of the liver was significantly reduced. Thus, the protective effect of these compounds in 70% partial hepatectomized rats following the injection of sublethal dose of ammonium acetate was assessed. The mixture could significantly decrease blood ammonia level compared with PBS-injected control group. In addition, abnormal behaviors observed in the control rats were significantly improved. The protective effect on the behavioral change seemed to be closely related with their effect on blood ammonia level, showing a strong correlation between the blood ammonia level and the behavioral score. The findings provide a rational basis for the clinical use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia encountered in liver diseases.

Acetates↗

PubMed1993

A profile of cerebral and hepatic carnitine, ammonia, and energy metabolism in a model of organic aciduria: BALB/cByJ mouse with short-chain acyl-CoA dehydrogenase deficiency.

Spontaneous animal models of inborn errors of metabolism are valuable tools for defining the pathogenesis of these disorders and also the mechanism of various therapeutic approaches. In the present study, we have employed BALB/cByJ mice with an autosomal recessive deficiency of short-chain acyl-CoA dehydrogenase (SCAD). These animals were characterized by a marked urinary excretion of ethylmalonic and methylsuccinic acids along with butyrylglycine. Using adult homozygous mice we have studied the basic cerebral and hepatic profile of carnitine, ammonia, and energy metabolism. The effects of fasting and a short-term supplement of L-carnitine have been evaluated in comparison with control BALB/cJ mice. The mutant mice had low levels of acetyl-CoA and high levels of lactate compared to control mice. Fasting aggravated this condition by further decreasing acetyl-CoA and increasing lactate levels in the mutant mice. Free carnitine levels were significantly decreased in liver with fasting. Long-chain acylcarnitines were significantly lower in the brain of mutant mice. A short-term supplementation of L-carnitine resulted in general increases of carnitine levels in liver and muscle, but they still remained lower in mutant BALB/cByJ mice as compared to control BALB/cJ mice. L-Carnitine treatment increased cerebral CoA-SH levels and both hepatic and cerebral acetyl-CoA levels in mutant mice. Hyperammonemia which has been described frequently in acyl-CoA dehydrogenase deficiencies was not observed in adult BALB/cByJ mice. This could be due to a rapid conjugation of butyryl-CoA with glycine by an increased activity of glycine N-acyltransferase.

Acidosis↗

PubMed1993

Four new mutations in the ornithine transcarbamylase gene.

We characterized four new mutations in the ornithine transcarbamylase (OTC) gene in three male infants who died from acute neonatal hyperammonemia and one male infant with late onset disease. OTC enzymatic activity was undetectable in the livers of the three neonates, whereas residual enzymatic activity was present in the fourth patient. All 10 exons of the OTC gene were amplified by the polymerase chain reaction (PCR) from genomic DNA of the four patients. The amplified DNA was screened for abnormal gel electrophoretic migration patterns via single-strand conformational polymorphism (SSCP). One patient showed an abnormal SSCP pattern of exon 8 and exon 9, a second patient had an abnormal exon 6, a third had an abnormal exon 9, and the fourth patient revealed an abnormal exon 3. Sequencing of the abnormal exons revealed that the first patient had a deleterious mutation in exon 9 consisting of a G-->T transversion in codon 310 causing a Glu-->stop coding change. The abnormal exon 8 of this patient contained a common polymorphism consisting of an A-->G transition in codon 270 resulting in Gln-->Arg code change. The abnormal exon 6 of the second patient contained an A-->G transition in codon 183 causing a Tyr-->Cys change. Exon 9 of the third patient contained a deletion of a thymine nucleotide (base 882) resulting in a shift of the reading frame and a code for premature termination 28 codons downstream. The fourth patient with a "milder" clinical presentation had an A-->T transversion in exon 3 (codon 88) causing a Lys-->Asn change.

Ammonia↗

PubMed1996

Effects of short-chain acyl-CoA dehydrogenase deficiency on development expression of metabolic enzyme genes in the mouse.

Patients with an acyl-CoA dehydrogenase deficiency share the disease features of hypoglycemia, hyperammonemia, tissue fatty change, hypoketonemia, carnitine deficiency, and organic acidemia due to apparent disruption of normal fatty acid, glucose, and urea metabolism. Most of the acute clinical episodes occur in young children. These episodes are precipitated by fasting and are often fatal, with the in vivo mechanisms essentially unknown. Since the genes of the rate controlling enzymes of these pathways are tissue and developmentally regulated at the transcriptional level, we measured, throughout neonatal development, the steady-state mRNA levels of long-chain, medium-chain, and short-chain (SCAD) acyl-CoA dehydrogenases, pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), carbamyl phosphate synthetase I (CPS), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (AS) in fed or fasted SCAD-deficient BALB/ByJ mice compared to BALB/cBy controls. Overall, our results showed no major effects on expression of acyl-CoA dehydrogenases due to SCAD deficiency, regardless of age or fasting. In SCAD-deficient mice we found depressed mRNA expression and enzyme activity for the urea cycle enzymes CPS and AS at 6 days of age, and found no apparent effects on expression of gluconeogenic enzymes PC or PEPCK. There was a period of overall lower gene expression for most genes at 6 and 15 days, which appears to be in parallel with the developmental period when children with these diseases are most severely affected.

Acyl-CoA Dehydrogenase↗

PubMed1995

Genomic organization of the human gene (CA5) and pseudogene for mitochondrial carbonic anhydrase V and their localization to chromosomes 16q and 16p.

Carbonic anhydrase V (CA V) is expressed in mitochondrial matrix in liver and several other tissues. It is of interest for its putative roles in providing bicarbonate to carbamoyl phosphate synthetase for ureagenesis and to pyruvate carboxylase for gluconeogenesis and its possible importance in explaining certain inherited metabolic disorders with hyperammonemia and hypoglycemia. Following the recent characterization of the cDNA for human CA V, we report the isolation of the human gene from two lambda genomic libraries and its characterization. The CA V gene (CA5) is approximately 50 kb long and contains 7 exons and 6 introns. The exon-intron boundaries are found in positions identical to those determined for the previously described CA II, CA III, and CA VII genes. Like the CA VII gene, CA5 does not contain typical TATA and CAAT promoter elements in the 5' flanking region but does contain a TTTAA sequence 147 nucleotides upstream of the initiation codon. CA5 also contains a 12-bp GT-rich segment beginning 13 bp downstream of the polyadenylation signal in the 3' untranslated region of exon 7. FISH analysis allowed CA5 to be assigned to chromosome 16q24.3. An unprocessed pseudogene containing sequence homologous to exons 3-7 and introns 3-6 was also isolated and was assigned by FISH analysis to chromosome 16p11.2-p12.

Amino Acid Sequence↗

PubMed1994

Glutamine does not increase ammonia in systemically drained small bowel transplants.

Glutamine (Gln) enhances small bowel function and ameliorates acute injury, but its metabolism generates portal ammonia (NH4), which normally is detoxified by the liver. Its beneficial use in small bowel transplantation (SBTx) therefore, may be offset by hyperammonemia, since such grafts may be systemically drained. We tested the hypothesis that oral glutamine supplementation increases plasma NH4 in rats with systemically drained SBTx. Lewis rats with isologous SBTx had plasma NH4 and Gln assayed during isonitrogenous, isocaloric Gln dietary supplementation and were compared to controls. Plasma NH4 levels were higher in the SBTx group during all dietary manipulations, consistent with previous studies. A Gln-deficient diet (0%) caused plasma Gln levels to fall in both experimental and control animals, but had no consistent effect on NH4 levels. With Gln supplementation (12.5 and 25% of total protein) Gln levels returned to baseline but again, plasma NH4 levels did not significantly change. We conclude that oral glutamine supplementation given in an isonitrogenous manner does not increase ammonia beyond that which is usually seen in animals with systemically drained SBTx. This suggests that Gln-enriched diets are not specifically contraindicated in patients with systemically drained SBTx and may be beneficial.

Ammonia↗

PubMed1998

Cloning and characterization of the mouse and rat type II arginase genes.

Two forms of arginase, both catalyzing the hydrolysis of arginine to ornithine and urea, are found in animals ranging from amphibians to mammals. In humans, inherited deficiency of hepatic or type I arginase results in hyperargininemia, a syndrome characterized by periodic episodes of hyperammonemia, spasticity, and neurological deterioration. In these patients, a second extrahepatic or type II arginase activity is significantly increased, an induction that may partially compensate for the lack of AI activity and apparently mitigates some of the clinical effects of the condition. Cloning and characterization of the human AII cDNA was recently accomplished. The cloning, sequencing, and partial characterization of the mouse and rat AII cDNAs are reported herein. The DNA sequences predicted polypeptides of 354 amino acids, including a N-terminal mitochondrial import signal. Sequence homology to the human type II arginase, arginase activity data, and immunoprecipitation with an anti-AII antibody confirm the identity of these cloned genes as rodent extrahepatic type II arginases.

Amino Acid Sequence↗

PubMed2000

Evidence for a short-chain carnitine-acylcarnitine translocase in mitochondria specifically related to the metabolism of branched-chain amino acids.

Carnitine-acylcarnitine translocase (CATR) deficiency is a severe defect in fatty acid oxidation which presents early in life most frequently with hypoglycemia, hyperammonemia, and severe cardiac abnormalities. CATR exchanges acylcarnitines of various chain lengths for free carnitine across the mitochondrial membrane. In vitro studies in intact fibroblasts from patients with documented deficiency of CATR were probed with stable-isotope-labeled precursors and the resulting acylcarnitines were analyzed by tandem mass spectrometry. After a 72-h incubation with l-[(2)H(3)]carnitine the translocase-deficient cells produced acylcarnitines in which the deuterium was incorporated into short-chain acylcarnitines, C2-C5. Experiments with simultaneous incubation of l-[(2)H(3)]carnitine and l-[(13)C(6)]isoleucine produced [(13)C(5)]2-methylbutyryl-[(2)H(3)]carnitine and [(13)C(3)]propionyl-[(2)H(3)]carnitine indicating exchange of labeled acylcarnitine from inside the mitochondrial matrix with labeled free carnitine. These studies support the possible existence of a "branched-chain" carnitine-acylcarnitine translocator in mitochondria.

Amino Acids, Branched-Chain↗

PubMed2001

Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients.

Ornithine transcarbamylase deficiency is a very heterogeneous urea cycle disorder resulting in hyperammonemia with various presentations from the neonatal period through adulthood. We performed a retrospective study in nine patients (four male/five female, age at diagnosis ranging from 6 days to 14 years) to evaluate the safety and efficacy of sodium phenylbutyrate (Ammonaps) in long-term treatment. All patients were diagnosed by DNA mutational analysis and/or liver enzyme measurement. They had previously been treated with sodium benzoate (median dose 248 mg/kg/day; range 106-275) and low protein diet (median 0.84 g/kg/day) and were switched to sodium phenylbutyrate (median dose of 352 mg/kg/day) at 8.9 and 4.9 years of age (median) in males and females, respectively. We analyzed clinical and biochemical data and the median follow-up duration was 26 months. During that time, there were no hyperammonemic episodes requiring hospitalization. Median plasma ammonia and glutamine levels were 30 and 902 micromol/L, respectively. Total protein intake could be increased to 0.95 g/kg/day after 18 months. No side effects related to therapy were observed. Further prospective studies should be performed to define the optimal dosage of sodium phenylbutyrate and the requirements for protein diet at different ages.

Adolescent↗

PubMed2001

Carnitine/acylcarnitine translocase deficiency (neonatal phenotype): successful prenatal and postmortem diagnosis associated with a novel mutation in a single family.

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) deficiency is one of the most severe and usually lethal mitochondrial fat oxidation disorders characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. In this study, the proband was the daughter of consanguineous Hispanic parents. At 36 h of life, she had bradycardia and died at 4 days of age without a specific diagnosis. In a subsequent pregnancy, prenatal counseling and amniocentesis were provided. Incubation of the amniocytes from this pregnancy and fibroblasts (from the dead proband) with [16-(2)H(3)]palmitic acid and analysis by tandem mass spectrometry revealed an increasedconcentration of [16-(2)H(3)]palmitoylcarnitine, suggesting the diagnoses of either CACT or carnitine palmitoyltransferase II (CPT-II) deficiency. CACT enzyme activity was absent in both cell lines. Molecular investigation of cDNA from the dead proband and her affected sibling revealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation of these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a single nucleotide G deletion at the donor site in intron 3 which resulted in exon skipping and a 13-bp insertion. The proband and her affected sibling were homozygous for this deletion.

Base Sequence↗

PubMed2001

Carnitine transport by organic cation transporters and systemic carnitine deficiency.

The intracellular homeostasis is controlled by different membrane transporters. Organic cation transporters function primarily in the elimination of cationic drugs, endogenous amines, and other xenobiotics in tissues such as the kidney, intestine, and liver. Among these molecules, carnitine is an endogenous amine which is an essential cofactor for mitochondrial beta-oxidation. Recently, a new family of transporters, named OCT (organic cation transporters) has been described. In this minireview, we present the recent knowledge about OCT and focus on carnitine transport, more particularly by the OCTN2. The importance of this sodium-dependent carnitine cotransporter, OCTN2, comes from various recently reported mutations in the gene which give rise to the primary systemic carnitine deficiency (SCD; OMIM 212140). The SCD is an autosomal recessive disorder of fatty acid oxidation characterized by skeletal myopathy, progressive cardiomyopathy, hypoglycemia and hyperammonemia. Most of the OCTN2 mutations identified in humans with SCD result in loss of carnitine transport function. Identifying these mutations will allow an easy targeting of the SCD syndrome. The characteristics of the juvenile visceral steatosis (jvs) mouse, an animal model of SCD showing similar symptoms as humans having this genetic disorder, are also described. These mice have a mutation in the gene encoding the mouse carnitine transporter octn2. Although various OCTN carnitine transporters have been identified and functionally characterized, their membrane localization and regulation are still unknown and must be investigated. This knowledge will also help in designing new drugs that regulate carnitine transport activity.

Animals↗