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PubMed2003

The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms.

Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1.

Amino Acid Transport Systems, Basic↗

PubMed2002

Late diagnosis of ornithine transcarbamylase defect in three related female patients: polymorphic presentations.

OBJECTIVE: To describe three female patients of one family with different phenotypes of the same mutation of the ornithine transcarbamylase gene. X-linked inherited ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. Many of the hemizygous males die during the neonatal period. Women, who are mostly healthy carriers, can also develop symptomatic hyperammonemia. DESIGN: Case study. SETTING: Intensive care unit and internal medicine unit at a university hospital. PATIENTS: The 20-yr-old female propositus was hospitalized for unexplained coma. She had a history of headaches, recurrent vomiting, specific anorexia for high-protein foods, and an acute neurologic crisis with alleged food poisoning 8 yrs before. The present episode began with psychiatric symptoms and seizures treated by diazepam and valproate. This unexplained coma, associated with respiratory alkalosis and major brain swelling on brain computed tomography scan, revealed hyperammonemia leading to the diagnosis of ornithine transcarbamylase deficiency. Continuous venovenous hemodiafiltration and treatment with sodium benzoate and phenylbutyrate improved the situation. However, the patient had some neurologic sequelae. DNA studies have disclosed a pathogenic mutation in the ornithine transcarbamylase gene of the patient, her mother, and her sister. For the mother, the disease was overlooked despite the onset of unusual headaches and neurologic signs that mimicked a cerebral tumor 12 yrs before. The 28-yr-old sister of the propositus has always been asymptomatic, even during pregnancy. CONCLUSIONS: Diagnosis of urea cycle disorder should be considered in any patient with unexplained neurologic and psychiatric disorders with selective anorexia, even in adulthood. Unexplained coma with cerebral edema and respiratory alkalosis requires urgent measurement of ammonemia and metabolic work-up.

Adult↗

PubMed2001

A pediatric patient with classical citrullinemia who underwent living-related partial liver transplantation.

Patients with inborn errors of metabolism undergo liver transplantation, but the effect of transplanting the liver of healthy carriers of these conditions has not been fully clarified. A 6-year-old girl with classical citrullinemia, who repeatedly suffered from hyperammonemia, underwent living-related liver transplantation by using a segment of the liver of her mother, who was a heterozygote carrier for classical citrullinemia. Hyperammonemia alleviated in the patient after the transplantation, thereby dramatically improving her quality of life. Although the levels of plasma and urinary citrulline remained high postoperatively, there was no marked difference in the level of plasma citrulline up to 1 month after surgery when compared with that of previously reported orthotopic liver transplantation cases with classical citrullinemia.

Child↗

PubMed2006

Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid.

OBJECTIVES: The aims of this report are to 1) present a rare case of fatal cerebral edema associated with late-onset ornithine transcarbamylase (OTC) deficiency in a juvenile male patient receiving valproic acid and 2) review the neuropathologic changes associated with the hyperammonemia. DESIGN: Case report. SETTING: A community hospital and a tertiary pediatric critical care unit. INTERVENTIONS: Carbohydrate administration, intravenous nitrogen excretion cocktail, and high-flux hemodialysis. MEASUREMENTS AND MAIN RESULTS: Despite aggressive therapy for presumed late-onset OTC deficiency, the patient rapidly developed fatal cerebral edema with tonsillar herniation. A liver biopsy confirmed OTC deficiency with approximately 3% of residual hepatic enzyme activity. Chromosomal analysis showed a normal male karyotype. A thorough molecular analysis of the coding region in the OTC gene Xp21.1 was completed, but mutations were not identified, suggesting an upstream or downstream abnormality. Severe brain swelling was evident on neuropathology, and histopathology showed Alzheimer type II astrocytes, neuronal cytoplasmic changes, and hypertrophy and eosinophilia of the small arterial walls. CONCLUSIONS: OTC deficiency is the most common urea cycle defect causing hyperammonemia. Late-onset presentations of OTC are infrequent, primarily affecting female patients. We present a rare case of a late-onset OTC deficiency in a juvenile male patient receiving valproic acid therapy who developed fatal cerebral edema. Valproic acid exacerbates acute elevations in ammonia and may contribute synergistically with ammonia to cerebral mitochondrial dysfunction.

Adolescent↗

PubMed2006

Successful portal-systemic shunt occlusion with balloon-occluded retrograde transvenous obliteration for portosystemic encephalopathy without liver cirrhosis.

A 68-year-old woman was admitted to the authors' hospital for hepatic encephalopathy. Her laboratory data and computed tomography findings were not suggestive of liver cirrhosis. Superior mesenteric angiography revealed an extrahepatic portal-systemic shunt with a main cause of hepatic encephalopathy. Despite treatment with branched-chain amino acid, lactulose, and kanamycin, hyperammonemia was prolonged, and the portal-systemic shunt was therefore treated with balloon-occluded retrograde transvenous obliteration. After the procedure, hyperammonemia was improved, and there were no signs of recurrent portal-systemic encephalopathy.

Aged↗

PubMed2003

Ammonia induced encephalopathy from valproic acid in a bipolar patient: case report.

Valproic acid is widely used as a mood stabilizer. We report a case of an adult with bipolar disorder taking therapeutic doses of valproic acid, who presented to the emergency department with coma related to hyperammonemia as a complication of valproic acid treatment. Valproic acid was discontinued which resulted in rapid clinical recovery. Valproic acid induced coma was likely related to a urea cycle enzymopathy. Clinicians should consider hyperammonemia in all patients who present with coma and other mental status changes while on valproic acid. In such patients, ammonia level should be obtained in addition to liver function tests.

Adult↗

PubMedDate not supplied

Long-term results of modified distal splenorenal shunts for the treatment of esophageal varices.

BACKGROUND/AIMS: Long-term results were compared for 3 types of distal splenorenal shunt for the treatment of esophageal varices. METHODOLOGY: Between July 1983 and December 1997, 45 patients with esophageal varices underwent distal splenorenal shunt. Group 1 underwent standard distal splenorenal shunt (n = 11). Group 2 underwent distal splenorenal shunt with splenopancreatic disconnection (n = 11). Group 3 underwent distal splenorenal shunt with splenopancreatic disconnection and gastric transection (n = 23). RESULTS: Additional treatment for recurrent varices was required in group 1, (n = 1, 9.1%), group 2 (n = 2, 18.2%), and group 3 (n = 1, 4.3%). All of the patients with recurrent varices developed a shunt stenosis within the 1st year after distal splenorenal shunt. The prevalence of hyperammonemia in group 1 was 40.0% at 1, 5, and 10 years. In group 2, the prevalence was 14.3% at 1 year, 31.4% at 5 years, and 54.3% at 10 years. In group 3, the prevalence was 0% at 1 year, and 9.1% at 5 and 10 years. The differences between group 3 and groups 1 and 2 were significant (P < 0.01). The cumulative survival rates at 1 year were 90.9%, 63.6%, and 95.7% for groups 1, 2, and 3, respectively. At 10 years, the cumulative survivals rates were 70.7%, 63.6%, and 69.4% for groups 1, 2, and 3, respectively. There were no significant differences in survival between the 3 groups. CONCLUSIONS: Distal splenorenal shunt with splenopancreatic disconnection and gastric transection may reduce the incidence of postoperative hyperammonemia.

Adult↗

PubMed2002

L-carnitine administration reverses acute mental status changes in a chronic hemodialysis patient with hepatitis C infection.

A chronic hemodialysis patient presented with elevated serum ammonia concentration (189 micromol/l) and acutely altered mental status. He had been adequately dialyzed over the prior months and had no evidence of liver dysfunction, despite serological evidence for hepatitis C virus infection. His mental status deteriorated to coma despite vitamin replenishment, intensive hemodialysis, lactulose treatment, and blood pressure control over a 3-day period. Blood free L-carnitine concentration was depressed, and total carnitine concentrations was normal. Three hours after a single 2 g dose of L-carnitine was administered intravenously, the mental status reverted to normal. Hyperammonemia resolved over a 5-week period. We suspect that subclinical liver dysfunction and dialysis status in tandem contributed to the carnitine deficiency, hyperammonemia, and confusion and that the L-carnitine administration reversed these biochemical and clinical abnormalities.

Carnitine↗

PubMed2002

[Liver failure and neurotransmitters of central nervous system].

There is increasing evidence that alternations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of hyperammonemia in liver failure. Concentrations of ammonium ion are increased and it leads to uncontrolled production of glutamine from these ions, so it is responsible for damage of the brain. Increasing concentrations of glutamine in the brain have a direct effect on glutamatergic neurotransmission, because number of binding sites for glutamatergic receptors changes. A number of binding sites for glutamatergic receptors: non-NMDA, AMPA and kainate is decreased in hippocampus, cerebral cortex, hypothalamus and cerebellum, while the binding sites for the NMDA receptor were within normal limits. Diminished expression of glutamatergic receptors leads to hypofunction of these receptors. So we can say about correlation between hyperammonemia in liver failure to distribution and activity of glutamine and glutamate as a neurotransmitter of CNS.

Central Nervous System Diseases↗

PubMed2004

[Valproate-induced hyperammonemic encephalopathy in a patient with Sjögren's syndrome].

We describe a 56-year-old woman with hyperammonemic encephalopathy caused by side effect of valproic acid (VPA). Ten months before the admission to our hospital, she had the first attack of convulsive seizure. Diagnosis of epilepsy was made, and the oral administration of VPA (800mg/day) was started at another hospital. Seizure was well controlled by VPA, until the recurrence of attack forced her to visit our hospital. Convulsive seizure disappeared immediately after intravenous administration of diazepam, but consciousness disturbance was prolonged for a few days. Since laboratory examinations revealed hyperammonemia without liver dysfunction, VPA was discontinued. Subsequently, her consciousness completely recovered. Other laboratory findings, including positive antinuclear antibody, antibodies to Sjögren's syndrome A, reduced lacrimal secretion in Schirmer's test, and cell infiltration in the salivary gland on lip biopsy specimen, suggested the presence of Sjögren's syndrome. The hyperammonemia occurs by the side effect of VPA, often has basal disease or drug interactions. It was, however, especially in patients with basal disease or other drugs, obscure whether (and how) Sjögren's syndrome contributed to the development of hyperammonemic encephalopathy in this case, since she took only VPA.

Anticonvulsants↗

PubMed1980

Tissue lipids in hyperammonemic encephalopathies of childhood.

Cholesterol, triglyceride, free fatty acid, and phospholipid concentrations were measured in 33 brain, liver, and adipose tissue samples obtained from 17 children who died of an acute encephalopathy associated with liver dysfunction and hyperammonemia (hyperammonemic encephalopathy). Eleven patients had Reye's syndrome, three had acute "toxic" encephalopathy (without fatty liver), two had glycogen storage disease type 1, and one had congenital hyperammonemia type 2. Hepatic triglyceride concentrations were markedly increased in Reye's syndrome, but varied from normal to increased concentrations in other hyperammonemic encephalopathies. In contrast, the acute encephalopathy could not be differentiated on the basis of clinical, laboratory, or pathologic features and the brain lipid profiles were remarkably similar among all patients studied.

Adipose Tissue↗

PubMed1999

Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation.

BACKGROUND: Lethal hyperammonemic coma has been reported in 2 adults after lung transplantation. It was associated with a massive elevation of brain glutamine levels, while plasma glutamine levels were normal or only slightly elevated. In liver tissue, glutamine synthetase activity was markedly reduced, and the histologic findings resembled those of Reye syndrome. The adequacy of therapy commonly used for inherited disorders of the urea cycle has not been adequately evaluated in patients with this form of secondary hyperammonemia. OBJECTIVE: To determine whether hemodialysis, in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy, would be efficacious in a patient with hyperammonemic coma after solid-organ transplantation. DESIGN: Case report. SETTING: A children's hospital. PATIENT: A 41-year-old woman with congenital heart disease developed a hyperammonemic coma with brain edema 19 days after undergoing a combined heart and lung transplantation. METHODS: Ammonium was measured in plasma. Amino acids were quantitated in plasma and cerebrospinal fluid by column chromatography. The effectiveness of therapy was assessed by measuring plasma ammonium levels and intracranial pressure and performing sequential neurological examinations. RESULTS: The patient had the anomalous combination of increased cerebrospinal fluid and decreased plasma glutamine levels. To our knowledge, she is the first patient with this complication after solid-organ transplantation to survive after combined therapy with sodium phenylacetate, sodium benzoate, arginine hydrochloride, and hemodialysis. Complications of the acute coma included focal motor seizures, which were controlled with carbamazepine, and difficulty with short-term memory. CONCLUSIONS: The aggressive use of hemodialysis in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy may allow survival in patients after solid-organ transplantation. An acute acquired derangement in extra-central nervous system glutamine metabolism may play a role in the production of hyperammonemia in this illness that resembles Reye syndrome, and, as in other hyperammonemic disorders, the duration and degree of elevation of brain glutamine levels may be the important determining factors in responsiveness to therapy.

Adult↗

PubMed1999

Neurologic nonmetabolic presentation of propionic acidemia.

BACKGROUND: Patients with propionic acidemia usually present in the neonatal period with life-threatening ketoacidosis, often complicated by hyperammonemia. It was thought that the neurologic abnormalities seen in this disease were exclusively the consequences of these acute crises. Experience with 2 patients with propionic acidemia indicates that this disease may present first with prominent neurologic disease without the life-threatening episodes of ketoacidosis that usually serve as the alerting signals for a diagnosis of an organic acidemia. OBJECTIVE: To examine the clinical and metabolic aspects of 2 patients with a phenotype that suggested disease of the basal ganglia. DESIGN: Examination of patterns of organic acids of the urine and enzyme assay for propionyl-CoA carboxylase in fibroblasts and lymphocytes. SETTING: Referral population to a biochemical genetics laboratory. PATIENTS: Two patients whose prominent features were hypotonia followed by spastic quadriparesis and choreoathetosis. Both had seizures. One patient was mildly mentally retarded but grew normally physically. The other had profound mental retardation and failure to thrive; he also self-mutilated his lower lip. Self-injurious behavior has not been reported in this disease. MAIN OUTCOME MEASURES: Clinical description, blood ammonia levels, organic acid levels in the urine, and enzyme activity. RESULTS: Excretion of metabolites, including methylcitrate, was typical. Residual activity of propionyl-CoA carboxylase approximated 5% of the control in each patient. CONCLUSIONS: Propionic acidemia can present as a pure neurologic disease without acute episodes of massive ketoacidosis. Hyperammonemia may occur after infancy in some patients, presenting as Reye syndrome.

Adult↗

PubMed2002

Facial appearance in persistent hyperinsulinemic hypoglycemia.

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.

ATP-Binding Cassette Transporters↗

PubMed2006

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency.

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Urea cycle disorders are a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia and hyperglutaminemia. Deficiencies of all of the enzymes of the cycle have been described and although each specific disorder results in the accumulation of different precursors, hyperammonemia and hyperglutaminemia are common biochemical hallmarks of these disorders. Arginase is the enzyme involved in the last step of the urea cycle. It catalyzes the conversion of arginine to urea and ornithine. The latter reenters the mitochondrion to continue the cycle. Hyperargininemia is an autosomal recessive disorder caused by a defect in the arginase I enzyme. Unlike other urea cycle disorders, this condition is not generally associated with a hyperammonemic encephalopathy in the neonatal period. It typically presents later in childhood between 2 and 4 years of age with predominantly neurological features. If untreated, it progresses with gradual developmental regression. A favorable outcome can be achieved if dietary treatment and alternative pathway therapy are instituted early in the disease course. With this approach, further neurological deterioration is prevented and partial recovery of skills ensues. Early diagnosis of this disorder through newborn screening programs may lead to a better outcome. This review article summarizes the clinical characterization of this disorder; as well as its biochemical, enzymatic, and molecular features. Treatment, prenatal diagnosis and diagnosis through newborn screening are also discussed.

Animals↗

PubMed1984

Clinical features of carbamyl phosphate synthetase-I deficiency in an adult.

Carbamyl phosphate synthetase-I (CPS-I) catalyzes the first reaction required for the conversion of ammonia to urea through the urea cycle. Severe CPS-I deficiency causes marked hyperammonemia with encephalopathy in infancy and usually results in death within the first few months of life. We describe a 33-year-old woman whose CPS-I activity is less than 5% of normal. She has had mild, intermittent symptoms throughout life but has never experienced severe encephalopathy. Although mildly retarded, she has no major neurological deficits. Therapy with a low-protein diet, lactulose, and sodium benzoate has prevented recurrence of hyperammonemia and symptoms. Cranial computed tomographic scans demonstrate prominent lucency of cerebral white matter, and cerebral evoked potential recordings indicate slowed central conduction. These findings suggest that the metabolic disturbances in this patient may have adversely affected central myelin formation or maintenance. This woman represents, to our knowledge, the oldest reported patient with CPS-I deficiency, and the case illustrates the need to consider urea cycle disorders in the differential diagnosis of intermittent neurological symptoms regardless of the patient's age.

Adult↗

PubMed1996

Transplantation of conditionally immortalized hepatocytes to treat hepatic encephalopathy.

Transplantation of hepatocytes has been shown to provide metabolic support during liver failure in experimental models. The potential clinical application of hepatocyte transplantation, however, is limited by the need for readily available, well-characterized cells, and a worldwide shortage of donor organs. A clonal hepatocyte cell line that could be grown economically in vitro and would exhibit a differentiated, nontransformed phenotype following transplantation would be an attractive solution to this problem. To test this alternative, primary Lewis rat hepatocytes were conditionally immortalized by retroviral transduction with a thermolabile mutant Simian virus 40 (SV40) large T antigen. The cloned immortalized cells proliferate in culture at 33 degrees C and stop growing at 37 degrees C to 39 degrees C. Transplanted into normal livers, these hepatocytes integrate normally into liver cords. When transplanted into the spleens of portacaval-shunted rats, they protect recipients from hyperammonemia-induced hepatic encephalopathy. The cells engrafted in the spleen exhibit normal morphology, secrete bile, and express albumin messenger RNA. The protection from hyperammonemia is reversed by splenectomy. These studies show that hepatocytes can be conditionally immortalized, expanded in culture, and are capable of providing metabolic support in chronic liver insufficiency. Safeguards that could make these cells clinically useful can be accomplished using currently available technology.

Animals↗

PubMed1997

Focal glycogenosis of the liver in disorders of ureagenesis: its occurrence and diagnostic significance.

Metabolic disorders of ureagenesis can cause a Reye-like syndrome with potentially fatal hyperammonemia in children. A mechanistically heterogeneous subset of these disorders shares the biochemical end-result of impaired mitochondrial citrulline production. These include deficiencies of the mitochondrial enzymes, ornithine transcarbamylase (OTC) and carbamyl-phosphate synthase (CPS), as well as dibasic aminoacidurias hyperammonemia-hyperornithinemia-homocitrullinuria (HHH) and lysinuric protein intolerance (LPI). In this report, we present histopathology of the liver in 10 children with defects of ureagenesis, including 6 with OTC deficiency, 3 with CPS deficiency, and 1 with HHH. The liver showed diffuse microvesicular steatosis, marked periportal nuclear glycogen, and variable portal fibrosis with occasional delicate portal-to-portal bridging. Discrete aggregates of distended hepatocytes with central nuclei and nonvacuolated clear cytoplasm were present in 5 of the 10 children, including two 2 OTC deficiency, 2 with CPS deficiency, and 1 with HHH. Similar aggregates had been previously noted in the liver of some children with OTC deficiency or LPI, but their nature and diagnostic significance had so far remained unknown. Using special stains on frozen tissue sections and electron microscopy, we show that the hepatocytes in these aggregates have little or no cytoplasmic neutral fat, but contain excessive free cytoplasmic glycogen, morphologically mimicking a glycogen storage disease. In our experience, hepatocellular aggregates of this nature do not occur in Reye syndrome or in any of its metabolic mimics other than the subset of defects listed above. Identification of these aggregates on liver biopsy can potentially narrow the differential diagnosis of a Reye-like syndrome with diffuse hepatocellular steatosis.

Adolescent↗