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16 recordsLinked to original sources
PubMed1984

Electroencephalographic findings in urea-cycle disorders.

Eleven electroencephalograms in 4 infants with urea-cycle disorders were reviewed. All infants had one or more abnormal EEGs. The abnormalities consisted mainly of multiareal spikes, spike-waves, or sharp-and-slow-wave activity. In addition, one patient, a term infant, exhibited exaggerated spindle-delta bursts. This infant, and also one other at a similar age, had monorhythmic paroxysmal theta activity. Clinically, all patients had seizures shortly preceding abnormal EEGs. EEG alterations were encountered over a wide range of elevated serum ammonia levels. Normal EEGs occurred in the face of slightly elevated levels. It is concluded that epileptiform EEG alterations may be a characteristic manifestation of urea-cycle disorders.

Amino Acid Metabolism, Inborn Errors↗
PubMed2002

Urea-cycle disorders as a paradigm for inborn errors of hepatocyte metabolism.

Urea-cycle disorders (UCDs) are a group of inborn errors of hepatocyte metabolism that are caused by the loss of enzymes involved in the process of transferring nitrogen from ammonia to urea, via the urea cycle (UC). Recent genetic analyses of inherited disorders that present with hyperammonemia demonstrate the function of cellular transporters that regulate the availability of UC intermediates. The regulation of UC intermediates, such as arginine, could have far reaching implications on nitric-oxide synthesis and vascular tone. Hence, each UCD and UC-related disorder constitutes a unique gene-nutrient interaction that is crucial for postnatal homeostasis. Recent advances in the diagnosis and management of UCDs include the application of in vivo metabolic-flux measurements. Cumulative morbidity is still high despite dietary and pharmacological therapies and, hence, both cell and gene therapies are being pursued as possible long-term corrective treatments. Although gene-replacement therapy has suffered recent clinical setbacks, new vector developments offer hope for the treatment of cell-autonomous defects of hepatocyte metabolism.

Cell- and Tissue-Based Therapy↗
PubMed2025

Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.

Carbamoyl phosphate synthetase 1 (CPS1) deficiency, a urea-cycle disorder, results in hyperammonemia initiating a sequence of adverse events that can lead to coma and death if not treated rapidly. There is a high unmet need for an effective therapeutic for this disorder, especially in early neonatal patients where mortality is excessive. However, development of an adeno-associated virus (AAV)-based approach is hampered by large cDNA size and high protein requirement. We developed an oversized AAV vector as a gene therapy to treat CPS1 deficiency. In order to constrain genome size, we utilized small liver-specific promoter/enhancers and a minimal polyadenylation signal. Long-term survival (9 months, end of study) with ammonia control was achieved in AAV8.CPS1-administered Cps1flox/flox mice, while all null vector-injected controls died with marked hyperammonemia; female mice demonstrated improved survival over treated males. While glutamine remained elevated compared to controls, ammonia was controlled in surviving animals. Mice maintained their weights and were not sarcopenic. While drinking water did contain carglumic acid, no nitrogen scavengers were administered. Although there were concerns with vector genomic integrity, these findings demonstrate proof of concept for an oversized gene-therapy approach for a challenging urea-cycle disorder where high-level hepatic protein is essential for survival.

MT: Delivery Strategies↗
PubMed1999

Dialysis in neonates with inborn errors of metabolism.

BACKGROUND: Certain inborn errors of metabolism become manifest during the neonatal period by acute accumulation of neurotoxic metabolites leading to coma and death or irreversible neurological damage. Outcome critically depends on the immediate elimination of the accumulated neurotoxins. Recent technological progress provides improved tools to optimize the efficacy of neonatal dialysis. METHODS: We report our experience with continuous venovenous haemodialysis (CVVHD) in six neonates with hyperammonaemic coma due to urea-cycle disorders or propionic acidaemia and in one child with leucine accumulation due to maple-syrup urine disease (MSUD), in comparison with five patients managed by peritoneal dialysis (PD) (2 hyperammonaemia, 3 MSUD). Application of a new extracorporeal device specifically designed for use in small children permitted the establishment of stable blood circuits utilizing small-sized catheters, and the tight control of balanced dialysate flows over wide flow ranges. RESULTS: Plasma ammonia or leucine levels were reduced by 50% within 7.1 +/- 4.1 h by CVVHD and within 17.9 +/- 12.4 h by PD (P<0.05). Also, total dialysis time was shorter with CVVHD (25 +/- 21 h) than with PD (73 +/- 35 h, P<0.02). A comparison of the CVVHD results with published literature confirmed superior metabolite removal compared to PD, and suggested comparable efficacy as achieved with continuous haemofiltration techniques. Apart from accidental pericardial tamponade during catheter insertion in one case, no major complications were noted with CVVHD. In three of the five PD patients, dialysis was compromised by mechanical complications. None of the MSUD patients but four children with urea-cycle disorders died, two during the acute period and two later during the first year of life, with signs of severe mental delay. Of the eight children presenting with hyperammonaemic coma, the four with the most rapid dialytic ammonia removal rate (50% reduction in < 7 h) survived with no or moderate mental retardation, whereas slower toxin removal was always associated with a lethal outcome. Simulation studies showed that the efficacy of neonatal CVVHD is limited mainly by blood-flow restrictions. CONCLUSIONS: While CVVHD is the potentially most efficacious dialytic technique for treating acute metabolic crises in neonates, utmost care must be taken to provide an adequately sized vascular access.

Humans↗
PubMed1999

Hepatocyte gene therapy in a large animal: a neonatal bovine model of citrullinemia.

The development of gene-replacement therapy for inborn errors of metabolism has been hindered by the limited number of suitable large-animal models of these diseases and by inadequate methods of assessing the efficacy of treatment. Such methods should provide sensitive detection of expression in vivo and should be unaffected by concurrent pharmacologic and dietary regimens. We present the results of studies in a neonatal bovine model of citrullinemia, an inborn error of urea-cycle metabolism characterized by deficiency of argininosuccinate synthetase and consequent life-threatening hyperammonemia. Measurements of the flux of nitrogen from orally administered 15NH4 to [15N]urea were used to determine urea-cycle activity in vivo. In control animals, these isotopic measurements proved to be unaffected by pharmacologic treatments. Systemic administration of a first-generation E1-deleted adenoviral vector expressing human argininosuccinate synthetase resulted in transduction of hepatocytes and partial correction of the enzyme defect. The isotopic method showed significant restoration of urea synthesis. Moreover, the calves showed clinical improvement and normalization of plasma glutamine levels after treatment. The results show the clinical efficacy of treating a large-animal model of an inborn error of hepatocyte metabolism in conjunction with a method for sensitively measuring correction in vivo. These studies will be applicable to human trials of the treatment of this disorder and other related urea-cycle disorders.

Adenoviridae↗
PubMedDate not supplied

Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders.

We present brain MR images in three patients with neonatal-onset hyperammonemic encephalopathy resulting from urea-cycle disorders (two sisters with deficiency of the carbamyl phosphate synthetase I reaction step and one boy with an ornithine transcarbamylase deficiency). MR imaging revealed almost identical findings of injury to the bilateral lentiform nuclei and the deep sulci of the insular and perirolandic regions; to our knowledge, this pattern has not been previously reported. We hypothesize that these lesions presumably reflect the distribution of brain injury due to hypoperfusion secondary to hyperammonemia and hyperglutaminemia in the neonatal period.

Atrophy↗
PubMed1992

Ornithine carbamoyl transferase deficiency: findings, models and problems.

The initial clinical symptoms of ornithine carbamoyl transferase deficiency depend on the age of onset. Respiratory distress on the first day of life does not allow exclusion of OCT deficiency in the individual patient. The acid-base status is not useful as a discriminant between urea-cycle disorders and organic acidurias. Beyond the neonatal age, a second period of increased risk for often lethal hyperammonaemic crises is found between 12 and 15 years of age. For definite diagnosis (pre- and postnatal) of heterozygotes the quantity of tissue obtained should be sufficient to obtain a representative sample for a mosaic structure. Experimental work gives some clues for the interpretation of reversible symptoms of hyperammonaemia. The increased transport of tryptophan at the blood-brain barrier in presence of increased glutamine concentration in tissue appears to depend on intact gammaglutamyl transpeptidase in brain microvessels and involves at least in part the L-carrier. Animal research on the mechanisms leading to irreversible damage in hyperammonaemia should be encouraged in order to define reliable predictive criteria for clinical decisions.

Adolescent↗
PubMed1992

Allopurinol challenge test in children.

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n = 14), 9.3 (n = 14), and 10.2 (n = 16) mumol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1 +/- 2.7 mumol/mmol creatinine (mean +/- SD, n = 44). This allopurinol challenge test was also performed in six children with urea-cycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26-134 mumol/mmol creatinine) following allopurinol ingestion.

Adolescent↗
PubMed1995

Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial.

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta-thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

Adult↗
PubMed1983

Structural investigations on pharmaceutical enzymes. Ornithine transcarbamylase (OCT) from bovine liver.

Ornithine transcarbamylase (OCT) is one of the urea-cycle enzymes in mitochondria which is involved in metabolic disorders in man. Reye's syndrome, characterized by encephalopathy and fatty infiltration of the liver, is one of such diseases. During this syndrome a reduction of OCT specific activity was observed, probably due to increased proteolytic degradation or to alteration in the enzyme conformation. It has recently been found that OCT administration to patients with liver disorders, contributes to illness resolution. Since the therapeutic properties of the enzymes are usually related to their structure, this paper reports some findings obtained by spectroscopic measurements on OCT structure and conformation stability in solution.

Animals↗
PubMed1988

Hepatic detoxification and hepatic function in chronic active hepatitis with and without cirrhosis.

The detoxification capacity of the liver in chronic active hepatitis (CAH) without liver cirrhosis (LC) is not sufficiently known. Therefore, we examined, in 156 patients with morphologically proven CAH of different stages, plasma ammonia, free phenols, indican, glucuronic acid and urea synthesis rate as parameters for liver detoxification. We found a significant increase of ammonia, phenols, and indican and a significant decrease of glucuronic acid and urea synthesis rate parallel to the stage of CAH without LC. In 34 CAH patients with complete recovery, a retrospective 10-year follow-up was possible. Parallel to the normalization of liver morphology and general liver tests, detoxification parameters also normalized. However, the detoxification disorders in CAH without LC are mild in nature and do not produce hepatic encephalopathy. Probably, they are caused by a reduced synthesis of the urea-cycle enzymes and of glucuronyltransferase in the liver.

Ammonia↗
PubMed2004

Analysis of pyrimidine synthesis "de novo" intermediates in urine and dried urine filter- paper strips with HPLC-electrospray tandem mass spectrometry.

BACKGROUND: The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the pyrimidine de novo pathway or a urea-cycle defect. Until now, no procedure was available that allowed the analysis of all of these metabolites in a single analytical run. We describe a rapid, specific method to measure these metabolites by HPLC-tandem mass spectrometry. METHODS: Urine or urine-soaked filter-paper strips were used to measure N-carbamyl-aspartate, dihydroorotate, orotate, orotidine, uridine, and uracil. Reversed-phase HPLC was combined with electrospray ionization tandem mass spectrometry, and detection was performed by multiple-reaction monitoring. Stable-isotope-labeled reference compounds were used as internal standards. RESULTS: All pyrimidine de novo metabolites and their degradation products were measured within a single analytical run of 14 min with lower limits of detection of 0.4-3 micromol/L. The intra- and interassay variation for urine with added compounds was 1.2-5% for urines and 2-9% for filter-paper extracts of the urines. Recoveries of the added metabolites were 97-106% for urine samples and 97-115% for filter-paper extracts of the urines. Analysis of urine samples from patients with a urea-cycle defect or pyrimidine degradation defect showed an aberrant metabolic profile when compared with controls. CONCLUSION: HPLC with electrospray ionization tandem mass spectrometry allows rapid testing for disorders affecting the pyrimidine de novo pathway. The use of filter-paper strips could facilitate collection, transport, and storage of urine samples.

Argininosuccinic Aciduria↗
PubMed2003

N-acetylglutamate and its changing role through evolution.

N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined. In humans, inherited NAGS deficiency is an autosomal recessive disorder causing hyperammonaemia and a phenotype similar to CPSI deficiency. Several mutations have been recently identified in the NAGS genes of families affected with this disorder.

Amino Acid Sequence↗
PubMed1982

Interactions of aspirin and other potential etiologic factors in an animal model of Reye syndrome.

Recent studies of Reye syndrome (RS) patients have suggested aspirin treatment as a possible factor in the etiology of this often fatal childhood disorder. the relationship of aspirin treatment to other factors that have been strongly implicated (influenza, ammonia toxicity) cannot be examined directly in patients because aspirin treatment is usually initiated by family members in the prodromal period before RS is diagnosed. In this report we describe the use of an animal model for RS in examining the interactions of these several potential etiological factors. Hyperammonemia and coma were produced in young male ferrets by a brief feeding of an arginine-deficient diet. The effects of influenza infection or aspirin treatment (or both) of control and hyperammonemic ferrets on their serum levels of ammonia, glutamic-oxaloacetic transaminase (GOT;L-aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1), ornithine carbamoyltransferase (OCT; carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3), bilirubin, and salicylate were studied. Liver levels of lipids, proteins, and several urea-cycle enzymes were also determined in the comatose ferrets and compared with those of untreated controls and of controls treated with influenza or aspirin, or both. Synergism of these three factors (hyperammonemia, influenza infection, and aspirin treatment) in causing RS-like alterations in these parameters was observed.

Ammonia↗
PubMed1975

Reye syndrome. A correlated electron-microscopic, viral, and biochemical observation.

Liver biopsy specimens of two patients with Reye syndrome were examined for ultrastructural features, viral isolation, and urea-cycle enzyme activity. Concurrent presence of herpes-like virus and myxovirus/paramyxovirus was demonstrated by electron microscopy, and viral infections were confirmed by isolation or serologic tests. A concomitant hepatic ornithine transcarbamoylase deficiency was also noted. The pathogenesis in these instances seems to consist of an initial synergistic insult on the liver by mixed types of viruses and subsequent breakdown of urea cycle, Krebs cycle, and possible other hepatic functions. An exodus of glycogen granules into the hepatic spaces of Disse and sinusoids suggests that the viruses have injured the plasma membranes as well as the mitochondria of hepatocytes. Since Kapila et al reported similar disorders five years before Reye et al, the name of Kapila-Reye disease is suggested.

Adolescent↗