Congenital Hyperammonemia Research Articles

S100B Protein but Not 3-Nitrotyrosine Positively Correlates with Plasma Ammonia in Patients with Inherited Hyperammonemias: A New Promising Diagnostic Tool?

Individuals with inherited hyperammonemias often present developmental and intellectual deficiencies which are likely to be exaggerated by hyperammonemia episodes in long-term outcomes. In order to find a new, systemic marker common to the course of congenital hyperammonemias, we decided to measure the plasma level of S100 calcium-binding protein B (S100B), which is associated with cerebral impairment. Further, we analyzed three mechanistically diverged but linked with oxidative-nitrosative stress biochemical parameters: 3-nitrotyrosine (3-NT), a measure of plasma proteins' nitration; advanced oxidation protein products (AOPP), a measure of protein oxidation; and glutathione peroxidase (GPx) activity, a measure of anti-oxidative enzymatic capacity. The plasma biomarkers listed above were determined for the first time in congenital hyperammonemia. Also, the level of pro- and anti-inflammatory mediators (i.e., IL-12, IL-6, IL-8, TNF-α, IL-1β, and IL-10) and chemokines (IP-10, MCP-1, MIG, and RANTES) were quantified. S100B was positively correlated with plasma ammonia level, while noticeable levels of circulating 3-NT in some of the patients' plasma did not correlate with ammonia concentration. Overall, the linear correlation between ammonia and S100B but not standard oxidative stress-related markers offers a unique perspective for the future identification and monitoring of neurological deficits risk-linked with hyperammonemia episodes in patients with inherited hyperammonemias. The S100B measure may support the development of therapeutic targets and clinical monitoring in these disorders.

Clinical and biochemical characteristics of patients with ornithine transcarbamylase deficiency

BackgroundOrnithine transcarbamylase deficiency (OTCD) is pleomorphic congenital hyperammonemia, in which the prognosis of the patient is determined both by genotype and environmental factors. This study investigated the clinical and biochemical characteristics of OTCD patients with different prognosis. MethodOf 35 OTCD patients, six males deceased at the first disease-onset, 17 males survived and had controllable ammonia levels after treatment, and 12 females survived through the first disease-onset but had intractable hyperammonemia and high mortality. Fasting blood samples from patients collected at three disease stages were used for the analysis of amino acid (AA) profile, acylcarnitine profile, and micronutrients. Differences in profiles between patients and healthy controls and within patient groups were studied. ResultsAll OTCD patients had accumulation of glutamine, homocitrulline, lysine, glutamate, cystathionine, and pipecolic acid, as well as deficiency of citrulline, tryptophan, threonine, and carnitine. For male non-survivors, most other AAs and long-chain acylcarnitines were elevated at disease onset, of which the levels of creatine, N-acetylaspartic acid, and homoarginine were remarkably high. Male survivors and female patients had most other AAs at low to normal levels. Compared with male survivors, female patients had much lower protein-intolerance, as indicated by significantly lower levels of protein consumption indicators, including essential AAs, 1-methylhistidine, acylcarnitines et al., but high levels of ammonia. Female patients still had significantly higher levels of citrulline, homocitrulline, and citrulline/arginine compared to male survivors. ConclusionUnique profiles were observed in each group of OTCD patients, indicating specific physiological changes that happened to them.

Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency

Genetic defects in ammonia metabolism can produce irreversible damage of the developing CNS causing an impairment of cognitive and motor functions. We investigated alterations in behavior, synaptic plasticity and gene expression in the hippocampus and dorsal striatum of transgenic mice with systemic hyperammonemia resulting from conditional knockout of hepatic glutamine synthetase (LGS-ko). These mice showed reduced exploratory activity and delayed habituation to a novel environment. Field potential recordings from LGS-ko brain slices revealed significantly reduced magnitude of electrically-induced long-term potentiation (LTP) in both CA3-CA1 hippocampal and corticostriatal synaptic transmission. Corticostriatal but not hippocampal slices from LGS-ko brains demonstrated also significant alterations in long-lasting effects evoked by pharmacological activation of glutamate receptors. Real-time RT-PCR revealed distinct patterns of dysregulated gene expression in the hippocampus and striatum of LGS-ko mice: LGS-ko hippocampus showed significantly modified expression of mRNAs for mGluR1, GluN2B subunit of NMDAR, and A1 adenosine receptors while altered expression of mRNAs for D1 dopamine receptors, the M1 cholinoreceptor and the acetylcholine-synthetizing enzyme choline-acetyltransferase was observed in LGS-ko striatum. Thus, inborn systemic hyperammonemia resulted in significant deficits in novelty acquisition and disturbed synaptic plasticity in corticostriatal and hippocampal pathways involved in learning and goal-directed behavior.

Urea Cycle Defects Causing Acute Cerebral Failure in Children: case report

A clinical case, that illustrates the specifics of acute cerebral insufficiency of metabolic genesis due to congenital defects of the urea cycle, is reported. A diagnostics and differential diagnostics algorithm for congenital hyperammonemia is presented and current recommendations for correction of this disease are described. Particular attention is paid to the necessity of the earliest diagnostics possible and targeted pathogenetic treatment.

Early treatment of a child with NAGS deficiency using N-carbamyl glutamate results in a normal neurological outcome

Acute hyperammonemia has a variety of etiologies and clinical manifestations. If not treated early in neonates, it leads to irreversible brain damage or death. We present a 7-day-old female patient who was brought to the emergency department with drownsiness and vomiting. Metabolic work-up revealed a blood ammonia level of 290 μmol/L (normal <100 μmol/L in neonates) with a compensated respiratory alkalosis, normal glycaemia and lactate and absence of urinary ketones. Oral feeding was stopped, an infusion of 20 % glucose was started, and sodium benzoate and arginine hydrochloride were given. After a drop of ammonemia within 12 h of treatment, it started rising again. N-carbamylglutamate (NCG) was added resulting in a rapid normalisation of ammonemia. Feedings were progressively reintroduced, the ammonia levels remained low. The results of the metabolic work-up were compatible with carbamyl phosphate synthase 1 (CPS1) or N-acetyl glutamate synthase (NAGS) deficiency. Genetic analysis confirmed the latter diagnosis with a homozygous mutation c. 1450T > C (p.W484R) in exon 6 of the NAGS gene in the patient and a carrier state in both parents. At the age of 9 months, the child is growing well with normal neurological development, under treatment with NCG 100 mg/kg/day and a normal diet. Conclusion: This case highlights the importance of keeping a high index of suspicion and early testing for ammonia levels in neonates/children with unexplained encephalopathy. In neonates with congenital hyperammonemia, NCG should always be started together with the standard management of hyperammonemia until all laboratory investigations are complete or indicate another disease.

Genetic ablation of Rhbg in the mouse does not impair renal ammonium excretion

NH(4)(+) transport by the distal nephron and NH(4)(+) detoxification by the liver are critical for achieving regulation of acid-base balance and to avoid hyperammonemic hepatic encephalopathy, respectively. Therefore, it has been proposed that rhesus type B glycoprotein (Rhbg), a member of the Mep/Amt/Rh NH(3) channel superfamily, may be involved in some forms of distal tubular acidosis and congenital hyperammonemia. We have tested this hypothesis by inactivating the RHbg gene in the mouse by insertional mutagenesis. Histochemical studies analyses confirmed that RHbg knockout (KO) mice did not express Rhbg protein. Under basal conditions, the KO mice did not exhibit encephalopathy and survived well. They did not exhibit hallmarks of distal tubular acidosis because neither acid-base status, serum potassium concentration, nor bone mineral density was altered by RHbg disruption. They did not have hyperammonemia or disturbed hepatic NH(3) metabolism. Moreover, the KO mice adapted to a chronic acid-loading challenge by increasing urinary NH(4)(+) excretion as well as their wild-type controls. Finally, transepithelial NH(3) diffusive permeability, or NH(3) and NH(4)(+) entry across the basolateral membrane of cortical collecting duct cells, measured by in vitro microperfusion of collecting duct from KO and wild-type mice, was identical with no apparent effect of the absence of Rhbg protein. We conclude that Rhbg is not a critical determinant of NH(4)(+) excretion by the kidney and of NH(4)(+) detoxification by the liver in vivo.

Direct and indirect enhancement of GABAergic neurotransmission by ammonia: implications for the pathogenesis of hyperammonemic syndromes

Experimental evidence indicates that ammonia causes neuroexcitation and seizures. This contrasts with the lethargy, confusion and other manifestations of global CNS depression commonly considered to be major components of hyperammonemic encephalopathies. Substantial data now indicates that ammonia can modulate GABAergic neurotransmission through direct and indirect mechanisms. This modulation consists of an enhancement of GABAergic neurotransmission at concentrations commonly encountered in hyperammonemic states and precedes the suppression of inhibitory neuronal function observed at higher (>1 mM) ammonia concentrations. Not only is this increase in GABAergic neurotransmission consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia, but it also provides a mechanism for testing new therapeutic modalities for the treatment of hyperammonemic encephalopathy.

Reduction in the MK-801 binding sites of the NMDA sub-type of glutamate receptor in a mouse model of congenital hyperammonemia: prevention by acetyl- l-carnitine

Our earlier studies on the pharmacotherapeutic effects of acetyl- l-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl- d-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [ 3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca 2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [ 3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca 2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.

Restoration of Hepatic Cytochrome c Oxidase Activity and Expression with Acetyl- l-carnitine Treatment in spf Mice with an Ornithine Transcarbamylase Deficiency

The sparse fur (spf) mutant mouse, with an X-linked ornithine transcarbamylase deficiency, is a model of congenital hyperammonemia in children. Our earlier studies indicated a deficiency of hepatic carnitine, CoA-SH, acetyl CoA, and ATP in spf mice. We have now studied the effects of a 7-day treatment with acetyl- l-carnitine (ALCAR) in the spf/Y mice on the activity and expression of the respiratory chain enzyme cytochrome c oxidase (COX; EC 1.9.3.1). We found decreased hepatic activity and expression of COX in the untreated hyperammonemic spf/Y mice, which was restored upon ALCAR treatment. Because COX is a mitochondrial membrane protein, we also carried out studies to explain the mechanism of ALCAR through its effect on membrane stability. Our results indicate a decrease of the mitochondrial membrane cholesterol/phospholipid molar ratio (CHOL/PL ratio) with the activity and expression of COX in untreated spf/Y mice. While ALCAR treatment normalized the ratios, it also restored the hepatic ATP production to normal. To study further if there was any effect of ALCAR on the mitochondrial matrix urea cycle enzymes, we measured the activity and expression of mutant ornithine transcarbamylase (OTC; EC 2.1.3.3) and normal carbamyl phosphate synthase-I (CPS-I; EC 6.3.4.16) in spf/Y mice. There was no general effect on the specific activities of the matrix enzymes upon ALCAR treatment, although their mRNA levels were enhanced. Our studies point towards the feasibility of an ALCAR treatment in conjunction with other treatment modalities, e.g. sodium benzoate and/or arginine, to improve the availability of cellular ATP and to counteract the effects of hereditary hyperammonemic syndromes in children.

Differential inhibition by hyperammonemia of the electron transport chain enzymes in synaptosomes and non-synaptic mitochondria in ornithine transcarbamylase-deficient spf-mice: restoration by acetyl-L-carnitine.

Sparse-fur (spf) mouse is the ideal animal model to study the neuropathology of congenital ornithine transcarbamylase (OTC) deficiency. Our current hypothesis implies that an ammonia-induced depletion of energy metabolism in the spf mouse, could be due to a reduction in the activities of the enzymes of the electron transport chain and a treatment with acetyl-L-carnitine could normalize this abnormality. We also hypothesized that there might be a differential degree of inhibition in synaptosomal and non-synaptic mitochondria, for the enzymes of the electron transport chain, caused by congenital hyperammonemia. We have therefore measured the activities of NADH-cytochrome C oxidoreductase, succinate cytochrome C oxidoreductase and cytochrome C oxidase in synaptosomes and non-synaptic mitochondria, isolated from spf mice and CD-1 controls with and without acetyl-L-carnitine treatment. Our results indicate a significant reduction (19-34%) in the activities of these complexes in synaptosomes in untreated spf mice, whereas in non-synaptic mitochondria, there was a tendency for the activities to decrease. Acetyl-L-carnitine treatment enhanced these activities (15-64%) for all the three enzyme complexes and its effect was more prominent on succinate cytochrome C oxidoreductase activity (64%). These studies point out that: (a) ammonia-induced disturbances in the energy metabolism could be more pronounced in neuronal mitochondria, and (b) the effect of acetyl-L-carnitine on the restoration of cerebral ATP in hyperammonemia could be through an enhancement of the activities of various electron transport chain enzymes.

Developmental study of hepatic glutamine synthetase in a mouse model of congenital hyperammonemia

The development of hepatic glutamine synthetase (GS; EC 6.3.1.2) activity and expression was studied in 1 to 112 day old sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase (OTC, EC 2.1.3.3.) deficiency. The spf/Y mutant mice were found to have a smaller body weight (p < 0.01) yet possessed a larger liver (p < 0.01-0.05) in comparison to normal male mice (+/Y). The neonatal hepatic GS activity was retarded in the spf/Y mice (p < 0.01) but reached normal values by the 28th day of age, after which it increased as compared to the control CD-I mice (p < 0.01). The spf GS activity remained constant from 28 to 56 days, whereas the CD-I GS activity decreased. A further significant increase in the spf GS activity was observed from 56 day to 112 day indicating its adaptation. The decrease of GS mRNA in the spf/Y mice from 28 to 112 days of age (3.72 +/- 0.25 vs 1.68 +/- 0.32, p < 0.01) suggests translational and post-translational modifications in the regulation of GS activity. The changes in the activity and expression patterns of GS could be due to an effect of the OTC mutation on the hepatic ammonia metabolism. This may be indicative of the adaptational processes in the spf mutant mice, which may play a specific role in this animal model to help it to survive with its hyperammonemia.

Direct enhancement of GABA-ergic neurotransmission by ammonia.

Ammonia (NH4 +) has been implicated since the 1950’s as the primary pathogenic agent contributing to the encephalopathies associated with hepatic failure1. NH4 + is clearly neurotoxic, but the molecular mechanisms by which ammonia exerts its toxic actions remain the subject of active investigation. Because the primary neurologic manifestations of these encephalopathies are consistent with central nervous system depression, increased activity of neuronal pathways using the principle inhibitory neurotransmitter, γ-aminobutyric acid (GABA) appeared likely to contribute to the pathogenesis of these syndromes. Despite ample evidence for the presence of both increased GABAergic neurotransmission and elevated NH4 + concentrations in the brain during hepatic failure, these two pathogenic mechanisms appear to be mutually exclusive. However, recent investigations suggest that these two pathogenic mechanisms are linked, in that NH4 + may enhance GABAergic neurotransmission by directly interacting with the GABAA receptor at pathophysiologically relevant concentrations. These new findings not only have important implications for the mechanisms contributing to the encephalopathies associated with hepatic failure and congenital hyperammonemia syndromes, but may provide a locus for the development of new treatment modalities.KeywordsHepatic EncephalopathyAmmonium SaltGABAergic NeurotransmissionAmmonium TartrateCentral Nervous System DepressionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Sparse-fur (spf) mouse as a model of hyperammonemia: alterations in the neurotransmitter systems.

Literature on sparse-fur (spf) mutant mouse, as an animal model of congenital hyperammonemia has been reviewed earlierl,4. Our current estimates indicate that over one hundred full-fledged articles have been published on spf mice since 1976, when the X-linked hepatic ornithine transcarbamylase (OTC; E.C. 2.1.3.3.) deficiency associated with the sparse-fur mutation was described for the first time5. An allelic form, the spfash (abnormal skin and hair) mutation, having a somewhat different phenotype to spf mouse, was also shown to have a quantitative deficiency of the hepatic OTC6. These publications have covered various aspects of the expression of the spf gene, including the clinical pathology, neurochemical pathology, behavior, experimental carcinogenesis and pharmacogenetics. Moreover, the spf mouse is now established as an animal model to study the effects of transgenic and viral-mediated gene therapy7,12. As indicated in Figure. 1, this has brought in a dramatic increase in new research studies on the spf and spfash mice, a big majority of which were initiated from our laboratory. It can be said that the spf mouse is now established as the most appropriate model to study the pathology and therapy of chronic hyperammonemic encephalopathy, particularly of hereditary origin. In the following text, we shall briefly review the nature and expression of the spf mutation, at the hepatic and intestinal levels, and its similarity to the human OTC deficiency. Particular emphasis shall be given to the neurochemical pathology in the spf mouse, from the point of view of metabolic and neurotransmitter abnormalities.

Tyrosine uptake and regional brain monoamine metabolites in a rat model resembling congenital hyperammonemia.

Hyperammonemia found in congenital disorders has a toxic effect on the central nervous system. Disturbances of brain neurotransmitter metabolism have been proposed, such as an increased transport of tryptophan into the brain and an increased flux through the serotonin pathway. Results concerning the catecholamine pathway are, however, contradictory. We therefore studied whether hyperammonermia increases brain uptake of the neurotransmitter precursor amino acid tyrosine and whether these changes affect the concentration of neurotransmitters and their metabolites in different brain areas (frontal cortex, caudatus-putamen, thalamus, hypothalamus, hippocampus/substantia nigra, brainstem) of rats made hyperammonemic with urease. The brain uptake of tyrosine was measured in the forebrain, brainstem, and cerebellum. The brain areas were analyzed for dopamine, 3,4-hydroxyphenylacetic acid; homovanillic acid, norepinephrine, and vanillylmandelic acid. The brain uptake index of tyrosine was increased in the forebrain and brainstem of the hyperammonemic rats with concomitantly elevated concentrations in the forebrain of tyrosine, phenylalanine, and tryptophan. The homovanillic acid content was significantly increased in the hypothalamus, hippocampus/substantia nigra and brainstem. The concentrations of norepinephrine, dopamine, and 3, 4-hydroxyphenylacetic acid were not significantly changed. Vanillylmandellic acid was decreased in the caudatus-putamen, thalamus, and hypothalamus. The data indicate an undisturbed neurotransmitter synthesis and, taken with the augmented tyrosine uptake at the blood-brain barrier, an increased flux through the dopamine pathway. These changes observed in the hyperammonemic animal model could contribute to the understanding of the pathogenic mechanisms and offer an explanation for the neuropsychiatric disturbances observed in children with congenital hyperammonemia.

Modulation of ligand binding to components of the GABA A receptor complex by ammonia: implications for the pathogenesis of hyperammonemic syndromes

The effects of 5-500 μM concentrations of neutral ammonium salts on the binding of ligands to components of the GABA A receptor complex were investigated. [ 3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (10–500 μM), but not sodium tartrate with EC 50 = 98 μM and E max = 31%. Further increasing ammonium tartrate concentrations (500–2500 μM) decreased [ 3H]flunitrazepam binding to control levels. The ammonium tartrate-induced increase in [ 3H]flunitrazepam binding was manifested as a 50% decrease in K d. Furthermore, GABA increased the potency of ammonium tartrate in enhancing [ 3H]flunitrazepam binding by 63%. [ 3H]Ro 15-1788 and [ 3H]Ro 15-4513 binding to the benzodiazepine receptor was not significantly enhanced by ammonium tartrate ( E max ≈ 13%). Ammonium tartrate also increased, then decreased the binding of 500 nM [ 3H]muscimol to the GABA A receptor (EC 50 = 52 μM, E max = 30%) in a concentration-dependent manner, but had no effect on [ 3H]SR 95-531 binding ( E max < 16%). The ammonium tartrate-induced alterations in [ 3H]muscimol binding were demonstrated in saturation assays as the loss of the high affinity binding site and a 27% increase in the B max of the low affinity binding site. These results indicate that ammonia biphasically enhances, then returns ligand binding to both the GABA and benzodiazepine receptor components of the GABA A receptor complex to control levels in a barbiturate-like fashion. This suggests that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, an event preceding the suppression of inhibitory neuronal function observed at higher ( > 1 mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia.

Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia.

Human MutationVolume 8, Issue 1 p. 74-76 Mutations in Brief Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia Brigitte Gilbert-Dussardier, Brigitte Gilbert-Dussardier Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, France Service Pédiatrie 1, CHRU Dupuytren, 87042 Limoges-Cedex, France; Fax: 33-1-4734-8514Search for more papers by this authorBertrand Segues, Bertrand Segues Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorJean-Michel Rozet, Jean-Michel Rozet Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorDaniel Rabier, Daniel Rabier Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorPatrick Calvas, Patrick Calvas Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorLionel de Lumley, Lionel de Lumley Service Pédiatrie 1, CHRU Dupuytren, 87042 Limoges-Cedex, France; Fax: 33-1-4734-8514Search for more papers by this authorJean-Paul Bonnefond, Jean-Paul Bonnefond Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorArnold Munnich, Corresponding Author Arnold Munnich Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceUnité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this author Brigitte Gilbert-Dussardier, Brigitte Gilbert-Dussardier Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, France Service Pédiatrie 1, CHRU Dupuytren, 87042 Limoges-Cedex, France; Fax: 33-1-4734-8514Search for more papers by this authorBertrand Segues, Bertrand Segues Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorJean-Michel Rozet, Jean-Michel Rozet Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorDaniel Rabier, Daniel Rabier Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorPatrick Calvas, Patrick Calvas Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorLionel de Lumley, Lionel de Lumley Service Pédiatrie 1, CHRU Dupuytren, 87042 Limoges-Cedex, France; Fax: 33-1-4734-8514Search for more papers by this authorJean-Paul Bonnefond, Jean-Paul Bonnefond Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this authorArnold Munnich, Corresponding Author Arnold Munnich Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceUnité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U 393, Department of Genetics, Hôpital des Enfants Malades, 75743 Paris-Cedex 15, FranceSearch for more papers by this author First published: 1996 https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<74::AID-HUMU11>3.0.CO;2-OCitations: 10AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume8, Issue11996Pages 74-76 RelatedInformation

Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia

Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia

Na +,K +-ATPase activities are increased in brain in both congenital and acquired hyperammonemic syndromes

Activities of Na +,K +-ATPase were measured in brain regions of experimental animals with either congenital or acquired hyperammonemic. In the sparse-fur (spf) mutant mouse, with a genetic X-linked deficiency of ornithine transcarbamylase, an animal model of congenital hyperammonemia, Na +,K +-ATPase was increased in frontal cortex (by 57%, P < 0.001), cerebellum (by 61%, P < 0.001), brainstem (by 71 %, P < 0.001) and striatum (by 48%, P < 0.01). Four weeks following portacaval anastomosis in the rat, Na +,K +-ATPase activities were increased in cerebellum and striatum (by 19%, P < 0.01) and in brainstem (by 28%, P < 0.01). Stimulation of Na +,K +-ATPase and the subsequent alteration of neuronal excitability could contribute to the CNS dysfunction characteristic of chronic hyperammonemic syndromes.

Neurotransmitter alterations in congenital hyperammonemia

AbstractInborn errors of metabolism are associated with a significant risk of mental retardation and other developmental disabilities. Only rarely, is the mechanism of the neural injury clearly understood. This is particularly true for those inborn errors of metabolism associated with hyperammonemia, principally urea cycle disorders and organic acidemias. Previously, it was assumed that elevated ammonia levels alone could account for the brain injury. However, in vitro studies suggest that ammonia is not particularly toxic to intact neurons. Furthermore, there does not appear to be a direct linkage between the peak blood ammonia level during hyperammonemic coma and subsequent neurodevelopmental outcome. There is, however, a correlation between duration of hyperammonemic coma and outcome, suggesting a secondary, time‐influenced mechanism of neural injury. Recent research has focused on excitotoxicity as a possible inducer of neural injury in congenital hyperammonemia. In addition to developmental disabilities, affected children exhibit behavioral abnormalities. An alteration in serotonin metabolism has been proposed as an explanation for these aberrant behaviors during less severe episodes of hyperammonemia. This review focuses on the neurotransmitter abnormalities occuring in congenital hyperammonemia and on new approaches to protecting the brain during hyperammonemic crises. © 1995 Wiley‐Liss, Inc.

Tissue-specific alterations of binding sites for peripheral-type benzodiazepine receptor ligand [3H]PK11195 in rats following portacaval anastomosis

Kinetics of binding of [3H]PK11195, an antagonist ligand with high selectivity for the peripheral-type (mitochondrial) benzodiazepine receptor (PTBR), was studied in homogenates of cerebral cortex, kidney, heart, and testis of portacaval shunted rats and sham-operated controls. Portacaval anastomosis resulted in a significant two- to threefold increase in the number of [3H]PK11195 binding sites in cerebral cortex and kidney. A reduction in the number of [3H]PK11195 binding sites was observed in testis preparations, while the number of binding sites in the heart remained unaltered. These differences in the response of PTBRs to portacaval anastomosis, in different organs suggest that the physiological function of these receptors and the factors regulating them are modulated by distinct mechanisms. The finding of increased densities of [3H]PK11195 binding sites in brain and kidney following portacaval anastomosis parallels the cellular hypertrophy in these tissues and, together with previous observations of similar increases of these binding sites in brain and kidney in congenital hyperammonemia, suggest a pathophysiologic role for ammonia in these changes. In contrast, the significant loss of [3H]PK11195 binding sites in testicular preparations following portacaval anastomosis together with the known effects of steroid hormones on these sites suggests a role for PTBRs in the pathogenesis of testicular atrophy in chronic liver disease.