sodium-benzoate and Hyperammonemia

Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.

Topics: Arginine; Carnitine; Child; Child, Preschool; Continuous Renal Replacement Therapy; Delphi Technique; Diet, Protein-Restricted; Humans; Hybrid Renal Replacement Therapy; Hyperammonemia; Infant; Infant, Newborn; Parenteral Nutrition; Peritoneal Dialysis; Phenylacetates; Phenylbutyrates; Practice Guidelines as Topic; Renal Dialysis; Sodium Benzoate; Urea Cycle Disorders, Inborn; Vitamin B Complex

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCDs), a group of inborn errors of hepatic metabolism that often result in life-threatening hyperammonemia. Argininosuccinate lyase (ASL) catalyzes the fourth reaction in this cycle, resulting in the breakdown of argininosuccinic acid to arginine and fumarate. ASL deficiency (ASLD) is the second most common UCD, with a prevalence of ~1 in 70,000 live births. ASLD can manifest as either a severe neonatal-onset form with hyperammonemia within the first few days after birth or as a late-onset form with episodic hyperammonemia and/or long-term complications that include liver dysfunction, neurocognitive deficits, and hypertension. These long-term complications can occur in the absence of hyperammonemic episodes, implying that ASL has functions outside of its role in ureagenesis and the tissue-specific lack of ASL may be responsible for these manifestations. The biochemical diagnosis of ASLD is typically established with elevation of plasma citrulline together with elevated argininosuccinic acid in the plasma or urine. Molecular genetic testing of ASL and assay of ASL enzyme activity are helpful when the biochemical findings are equivocal. However, there is no correlation between the genotype or enzyme activity and clinical outcome. Treatment of acute metabolic decompensations with hyperammonemia involves discontinuing oral protein intake, supplementing oral intake with intravenous lipids and/or glucose, and use of intravenous arginine and nitrogen-scavenging therapy. Dietary restriction of protein and dietary supplementation with arginine are the mainstays in long-term management. Orthotopic liver transplantation (OLT) is best considered only in patients with recurrent hyperammonemia or metabolic decompensations resistant to conventional medical therapy.

Topics: Arginine; Argininosuccinate Lyase; Argininosuccinic Acid; Argininosuccinic Aciduria; Child, Preschool; Citrulline; Cognition Disorders; Diet, Protein-Restricted; Fumarates; Genetic Testing; Glucose; Humans; Hyperammonemia; Hypertension; Infant; Infant, Newborn; Lipids; Liver Diseases; Liver Transplantation; Neonatal Screening; Phenylbutyrates; Sodium Benzoate

Hepatic encephalopathy complicates the course of both acute and chronic liver disease and its treatment remains an unmet clinical need. Ammonia is thought to be central in its pathogenesis and remains an important target of current and future therapeutic approaches. In liver failure, the main detoxification pathway of ammonia metabolism is compromised leading to hyperammonaemia. In this situation, the other ammonia-regulating pathways in multiple organs assume important significance. The present review focuses upon interorgan ammonia metabolism in health and disease describing the role of the key enzymes, glutamine synthase and glutaminase. Better understanding of these alternative pathways are leading to the development of new therapeutic approaches.

Topics: Adipose Tissue; Amino Acids; Ammonia; Arginine; Brain; Dipeptides; Glutamate-Ammonia Ligase; Glutaminase; Hepatic Encephalopathy; Humans; Hyperammonemia; Intestinal Mucosa; Kidney; Liver; Liver Failure; Lung; Muscles; Phenylbutyrates; Sodium Benzoate

Ornithine transcarbamylase deficiency is the most common inherited urea cycle disorder. Its clinical manifestations as lethargy, vomites, coma and cerebral edema are the effect of the higher concentration of the ammonia in plasma. Hyperammonemia, caused by mutation in ornithine transcarbamylase gene, is often considered as a reason of coma by pediatricians but skipped by internist, although it is the third reason of hepatic coma in adults. This article is the recapitulation of published studies and their implication on everyday clinical practice.

Topics: Amino Acid Metabolism, Inborn Errors; Brain Diseases, Metabolic; Coma; Female; Humans; Hyperammonemia; Male; Ornithine Carbamoyltransferase Deficiency Disease; Phenylbutazone; Sodium Benzoate; Urea

The symptoms and signs of ornithine transcarbamylase deficiency are discussed. When the condition occurs among males in the neonatal period it is likely to be lethal. Pathological findings are non-specific. The diagnosis should be considered if coma with cerebral oedema and respiratory alkalosis occurs for no obvious reason. When hyperammonaemia is found, enzyme assay on a liver biopsy should be considered. A useful clue in an asymptomatic patient is a voluntary adoption of a vegetarian diet. Provocative tests, such as the allopurinol test can be used, but the method most frequently applied is mutation analysis. In the case of prenatal diagnosis this is possible on a chorionic villus sample. The prognosis of ornithine transcarbamylase deficiency is better for those with an onset after infancy, but morbidity from brain damage does not appear to be linked to the number of episodes of hyperammonaemia that have occurred. The syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase which catalyses the conversion of ornithine and carbamoyl phosphate to citrulline. The gene responsible for this enzyme is located on Xp21.1, and is expressed in the liver and gut. Mutations can be divided into two groups: those with neonatal onset with all enzyme activity abolished, and those with later onset with partial and varying enzyme deficiency. There can be a variety of precipitating causes, for example sodium valproate. Treatment can be given with a low protein diet, and with alternate pathway drugs such as sodium benzoate and phenylbutyrate. Liver transplant can be considered when symptoms are life-threatening, although there may be severe complications.Gene replacement therapy is the hope of the future.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Food Preservatives; Humans; Hyperammonemia; Infant, Newborn; Male; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Phenylbutazone; Sodium Benzoate

Alternative pathway therapy is currently an accepted treatment approach for inborn errors of the urea cycle. This involves the long-term use of oral sodium phenylbutyrate, arginine supplements, or both, depending on the specific enzyme deficiency, and treatment of acute hyperammonemic crises with intravenous sodium benzoate/sodium phenylacetate plus arginine. A review of 20 years of experience with this approach illustrates the strengths and limitations of this treatment. It has clearly decreased the mortality and morbidity from these disorders, but they remain unacceptably high. The medications are generally well tolerated, but severe accidental overdosage has been reported because of the infrequent use of the medication. There is also a difference in their metabolism between newborns and older children that must be addressed in determining dosage. To avoid these complications it is recommended that drug levels in blood be monitored routinely and that very specific treatment protocols and oversight be followed to avoid overdoses. Finally, it must be acknowledged that alternative pathway therapy has limited effectiveness in preventing hyperammonemia and must be combined with effective dietary management. Therefore in children with neonatal-onset disease or in those with very poor metabolic control, liver transplantation should be considered. There should also be the continued search for innovative therapies that may offer a more permanent and complete correction, such as gene therapy.

Topics: Amino Acid Metabolism, Inborn Errors; Animals; Arginine; Humans; Hyperammonemia; Phenylacetates; Phenylbutyrates; Sodium Benzoate; Urea

Sodium benzoate is widely used in the Alimentary Industry at low doses for its antimicrobial action. It has also been used as a liver function test. The principle is to evaluate the liver capacity for conjugation of glycine to benzoic acid and to form hippuric acid which is excreted in the urine. In hyperammonemic syndromes, secondary to enzymatic deficiency of the urea cicle, sodium benzoate has the property to act as an alternative way of nitrogen excretion to urinary hippurate instead of urea. Recently, it has been proposed as a therapeutic alternative in cirrhotic patients with portal systemic encephalopathy. Historical, biochemical and clinical data which constitute the principles to validate its clinical application in Hepatology are reviewed in this manuscript.

Topics: Acetates; Adult; Animals; Child; Clinical Trials as Topic; Drug Evaluation, Preclinical; Glycine; Hepatic Encephalopathy; Hippurates; Humans; Hyperammonemia; Liver Cirrhosis; Liver Function Tests; Male; Metabolism, Inborn Errors; Mice; Molecular Structure; Rats; Sodium Benzoate; Urea

The management of hepatic encephalopathy should be considered accordingly with the precipitating factor and the type of encephalopathy. Ideally the therapeutic approach must be useful for both acute and chronic forms of encephalopathy. Current treatment of hepatic encephalopathy consists of certain well-established measures attempting to identify and treat the precipitating factors, and to reduce the intestinal nitrogenous compounds formation and absorption by dietary restriction or bowel-cleansing with catartics or antibiotics such as neomycin, metronidazol, etc. This review describes briefly several therapeutic modalities.

Topics: Bromocriptine; Clinical Trials as Topic; Colon; Dietary Proteins; Disaccharides; Double-Blind Method; Enema; GABA Antagonists; Gastrointestinal Hemorrhage; Hepatic Encephalopathy; Humans; Hyperammonemia; Laxatives; Levodopa; Liver Cirrhosis; Malnutrition; Metabolic Networks and Pathways; Plant Proteins, Dietary; Sodium Benzoate; Zinc

The objective was to evaluate the efficacy and safety of sodium benzoate in the management of hyperammonemia and hepatic encephalopathy (HE) in decompensated chronic liver disease.. It was a prospective, interventional, double-blinded randomized controlled trial conducted from August 2017 to December 2018. Children with decompensated chronic liver disease and hyperammonemia were included in the study. Those with ammonia >400 μg/dL, already receiving sodium benzoate or with grade III ascites were excluded. Group A received sodium benzoate (400 mg/kg loading dose followed by 200 mg · kg · daymaintenance for 5 days) along with the standard medical therapy. Group B received standard medical therapy with placebo.. A total of 108 episodes of hyperammonemia occurred in 86 patients of whom 16 were excluded. The final analysis included 46 episodes in each group. The median decrease in ammonia from baseline to day 5 was 52 μg/dL in group A versus 42 μg/dL in group B (P = 0.321). There was a significant decrease in ammonia on days 1 and 2 in group A as compared to group B, but not on subsequent days. There was no significant difference in the resolution of HE (57.1% vs 50%; P = 1), but there was higher, albeit insignificant increase in ascites in group A (15.9% vs 4.5%).. Addition of sodium benzoate significantly reduced the ammonia levels on the first 2 days of therapy but the effect was not sustained till day 5. The effect of sodium benzoate would probably be more sustained, if higher dosage (400 mg · kg · day) could be used under monitoring of benzoate levels. There was no effect on resolution of HE. Sodium benzoate caused an increasing trend of adverse events with no effect on short-term survival.

Topics: Ammonia; Child; Double-Blind Method; Hepatic Encephalopathy; Humans; Hyperammonemia; Prospective Studies; Sodium Benzoate

Hyperammonemia can result in hepatic encephalopathy, which in severe cases eventually can lead to coma and death. In dogs, congenital portosystemic shunts (CPSS) are the most common cause for hyperammonemia. Conservative treatment consists of a protein modified diet, nonabsorbable disaccharides, antibiotics, or some combinations of these. Sodium benzoate (SB) and sodium phenylbutyrate (SPB) both are used in the acute and long-term treatment of humans with hyperammonemia caused by urea cycle enzyme deficiencies. Both treatments are believed to lower blood ammonia concentrations by promoting excretion of excess nitrogen via alternative pathways.. To evaluate the efficacy and safety of PO treatment with SB and SPB on hyperammonemia and clinical signs in CPSS dogs.. Randomized, double-blind, placebo-controlled crossover trial. Concentrations of blood ammonia and bile acids were measured in CPSS dogs before and after a 5-day treatment with SB, SPB, and placebo. A wash-out period of 3 days was used between treatments. A standard questionnaire was developed and distributed to owners to evaluate clinical signs before and after each treatment.. Blood ammonia concentrations were not influenced by any of the treatments and were comparable to those observed during placebo treatment. In addition, SB and SPB treatment did not result in improvement of clinical signs. Adverse effects during treatment included anorexia, vomiting, and lethargy.. Based on our results, we conclude that SB or SPB are not useful in the conservative treatment of hyperammonemia in dogs with CPSS.

Topics: Ammonia; Animals; Bile Acids and Salts; Cross-Over Studies; Dogs; Double-Blind Method; Female; Hyperammonemia; Male; Phenylbutyrates; Portal Vein; Random Allocation; Sodium Benzoate; Vascular Malformations

The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.. We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.. Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.. Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.

Topics: Adolescent; Adult; Age Factors; Age of Onset; Amino Acid Metabolism, Inborn Errors; Ammonia; Carbamoyl-Phosphate Synthase I Deficiency Disease; Child; Child, Preschool; Citrullinemia; Female; Humans; Hyperammonemia; Infant; Infant, Newborn; Male; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Sodium Benzoate; Survival Analysis; Urea

To investigate the therapeutic efficacy of sodium benzoate (SB) in a cirrotic population with chronic portal systemic encepalopathy (PSE), we performed a double blind, randomised, multicentric, clinical trial, comparing SB versus a standard therapy of lactitol (LA). To perform the study blind, syrups containing the two drugs were prepared. To date 27 patients have been studied. Of these, 12 received SB (5.6 g/day) and 15 received LA (29 g/day). Standard PSE parameters were assessed and hippurate urinary excretion was measured before and after the trial. For the SB group, basal and final PSE index were 0.39 +/- 0.16 and 0.17 +/- 0.1 respectively (p < 0.001). The Group on LA had a PSE index of 0.40 + 0.1 and 0.23 +/- 0.18 (basal and final respectively) (p < 0.001). The final hippurate excretion for SB group was 2498.9 mg/24 h. The hippurate excretion for the LA group suffer no changes (traces). No serious side effects were observed with either therapy. We suggested that SB is a safe, efficacious and comfortable alternate treatment for PSE.

Topics: Adult; Aged; Double-Blind Method; Female; Hepatic Encephalopathy; Hippurates; Humans; Hyperammonemia; Liver Cirrhosis; Male; Middle Aged; Neuropsychological Tests; Severity of Illness Index; Sodium Benzoate; Treatment Outcome

Topics: Adult; Benzoates; Child; East Asian People; Healthy Volunteers; Humans; Hyperammonemia; Infant; Phenylacetates; Sodium Benzoate

Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.

Topics: Ammonia; Antineoplastic Agents; Asparaginase; Child; Glutamine; Humans; Hyperammonemia; Phenylbutyrates; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sodium Benzoate; Treatment Outcome

A case of a 19-year-old female with low-risk acute myeloid leukemia is presented who was diagnosed with idiopathic hyperammonemic encephalopathy following the development of abrupt neurologic decline, respiratory alkalosis, and elevated plasma ammonia levels of unknown etiology. Delayed symptom recognition of this exceedingly rare condition contributes to the often fatal outcomes of idiopathic hyperammonemic encephalopathy. As illustrated by this case, prompt diagnosis and utilization of a variety of ammonia-modulating treatment modalities can result in remarkable clinical recovery. This case provides guidance to clinicians in counseling families about the possibility of neurologic recovery in similar clinical scenarios.

Topics: Adult; Brain Diseases; Female; Humans; Hyperammonemia; Leukemia, Myeloid, Acute; Neurotoxicity Syndromes; Phenylbutyrates; Prognosis; Sodium Benzoate; Survival Rate; Young Adult

To determine the local effects of peripheral Ammonul infusion on the skin and the subcutaneous tissues.  Methods: This retrospective study was conducted at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. All children less than 16 years of age admitted between December 2015 and October 2018 with hyperammonemia and received Ammonul infusion for treatment were recruited. Results: Twenty-one patients received the Ammonul infusion. They were admitted 58 times with acute hyperammonemia during the study period, with an average of 2.8 admissions per patient. The mean age of the included patients was 49.5 months. The most frequent underlying diagnoses were propionic acidemia (n=9), urea cycle disorders (n=5), and intrinsic liver disease (n=3). All participants received Ammonul through peripheral lines except 3 who received it through central lines. No extravasation, burns, or other local side effects were observed in this cohort.. This data indicate that the use of Ammonul through a peripheral venous route appears to be safe and not associated with infusion-related local adverse effects.

Topics: Acute Disease; Adolescent; Child; Drug Combinations; Female; Humans; Hyperammonemia; Infusions, Intravenous; Male; Phenylacetates; Retrospective Studies; Saudi Arabia; Sodium Benzoate; Tertiary Care Centers

Topics: Benzoates; Child; Double-Blind Method; Humans; Hyperammonemia; Liver Diseases; Sodium Benzoate

Long-term survival of patients with neonatal-onset carbamoyl-phosphate synthetase 1 deficiency (CPS1D), an autosomal recessive disorder characterized by repeated, life-threatening hyperammonemia, is rare. We describe the diagnosis and clinical management of a teenager with neonatal-onset CPS1D who did not undergo therapeutic liver transplantation.. Following emergent neonatal therapy, the patient was diagnosed with CPS1D based on clinical, radiological, biochemical and genetic analyses. Her clinical course, neurobehavioral development and therapeutic interventions are presented and discussed.. Born from nonconsanguineous parents, the proband underwent phototherapy for neonatal jaundice, associated with acute encephalopathy, apnea and cerebral edema. Based on blood and urinary biochemical abnormalities, neonatal-onset CPS1D was diagnosed. Her hyperammonemia was corrected by hemodialysis, followed by sodium benzoate, L-arginine, levocarnitine and protein-free diet therapy. Because of a relapse and persistent neurobehavioral regression by age 1, a planned liver transplantation was cancelled. At age 10, sodium phenylbutyrate was substituted as ammonia scavenger. Genetic testing revealed compound heterozygote c.2359C>T (R787X) and c.236+6T>C variants of CPS1, confirming her diagnosis. Despite severe neurological sequelae, the patient is 16 and in stable condition.. Our case suggests that early hemodialysis and pharmacologic interventions for acute neonatal hyperammonemia can improve the prognosis of patients with neonatal-onset CPS1D.

Topics: Arginine; Brain Diseases, Metabolic; Carbamoyl-Phosphate Synthase I Deficiency Disease; Carnitine; Female; Humans; Hyperammonemia; Infant, Newborn; Phenylbutyrates; Renal Dialysis; Sodium Benzoate

Hyperammonaemia is a metabolic disturbance characterized by accumulation of ammonia in the blood. Entry of ammonia into the brain via the blood-brain barrier leads to hyperammonaemic encephalopathy. The causes of hyperammonaemia in paediatric patients vary. We present 3 cases of hyperammonaemia in critically ill children in whom an inborn metabolic disorder was identified and provide insights into the phenotypes, diagnostic approaches and management. In children with acute overwhelming illness and progressive neurological deterioration plasma ammonia measurement should be included in the urgent diagnostic work-up. We here raise the awareness that hyperammonaemia is a metabolic emergency requiring prompt recognition and treatment to avoid subsequent complications.

Topics: Ammonia; Arginine; Biomarkers; Brain Diseases, Metabolic, Inborn; Carnitine; Critical Illness; Diet, Protein-Restricted; Early Diagnosis; Emergencies; Female; Humans; Hyperammonemia; Infant; Infant, Newborn; Male; Phenylbutyrates; Sodium Benzoate; Treatment Outcome

The purpose of the study was to evaluate the influence of establishing a protocol for the use of combined sodium benzoate and sodium phenylacetate (SBSP) (Ammonul®) to treat acute hyperammonemia. This was a retrospective, single-center study in a 24-bed medical and surgical pediatric intensive care unit (PICU) in a tertiary care teaching maternal-child hospital in Canada. Inclusion criteria were age < 18 years, PICU admission between 1 January 2000 and 30 June 2016, and SBSP treatment. An SBSP delivery protocol was implemented in our hospital on 30 August 2008 in order to improve management of acute hyperammonemia. Patients were assigned to one of the two groups, without or with protocol, depending on date of admission. SBSP was ordered 34 times during the study period, and 23 orders were considered for analysis (14 with and 9 without protocol). Patient characteristics were similar between groups. The median time from diagnosis to prescription was significantly shorter in the protocol group [40 min (21-82) vs 100 min (70-150), p = 0.03)] but the median time from diagnosis to administration of the treatment was equivalent [144 min (90-220) vs 195 (143-274), (p = 0.2)]. Other clinical outcomes did not differ. This study is the first to compare two SBSP delivery strategies in the treatment of acute hyperammonemia in this PICU setting. Implementation of a delivery protocol shortened the time from diagnosis of hyperammonemia to prescription of SBSP and helped us identify other parameters that can be improved to optimize treatment delivery.

Topics: Acute Disease; Ammonia; Canada; Child; Child, Preschool; Female; Humans; Hyperammonemia; Infant; Infant, Newborn; Infusions, Intravenous; Intensive Care Units, Pediatric; Male; Phenylacetates; Retrospective Studies; Sodium Benzoate

Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.. Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.. Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.. Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Topics: Ammonia; Drug Combinations; Female; Glutamine; Humans; Hyperammonemia; Infant, Newborn; Male; Mutation; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Pregnancy; Prenatal Care; Prenatal Diagnosis; Sodium Benzoate; Treatment Outcome; Urea

Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N-carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate. Improvement in mental status mirrored brain glutamine levels, as coma persisted for 48h after plasma ammonia normalized. We hypothesize that the slower clearance for brain glutamine levels accounts for the delay in improvement following initiation of treatment in cases of chronic hyperammonemia. We propose MRS to monitor brain glutamine as a noninvasive approach to be utilized for diagnostic and therapeutic monitoring purposes in adult patients presenting with idiopathic hyperammonemia.

Topics: Brain; Coma; Female; Gastric Bypass; Glutamates; Glutamine; Humans; Hyperammonemia; Magnetic Resonance Spectroscopy; Middle Aged; Phenylacetates; Sodium Benzoate; Treatment Outcome

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.

Topics: Animals; Dogs; Female; Hyperammonemia; Male; Nitrogen; Phenylacetates; Random Allocation; Saline Waters; Sodium Benzoate

Hyperammonemia is a rare, often fatal complication after transplantation. The etiology is unknown, but recognition and rapid treatment may help to improve the survival of this unusual syndrome. We present the largest case series to date of hyperammonemia after lung transplantation (LTx) and discuss a treatment protocol that has been developed at our institution.. We conducted a retrospective cohort series of patients who underwent LTx between January 1, 2000, and December 31, 2013. Patients who developed hyperammonemia syndrome in the posttransplantation period, which was defined as symptoms of encephalopathy and plasma ammonia level exceeding 200 μmol/L on at least 1 occasion, were included. Data including demographics, antimicrobial and immunosuppression regimens, ammonia levels and other pertinent laboratory data, treatments administered, and outcomes were recorded.. Eight of 807 lung transplant recipients developed hyperammonemia syndrome postoperatively during this time period. Median time to onset was 9.0 days, and median peak ammonia level was 370 μmol/L. All 8 patients were treated with hemodialysis, 7 of 8 patients were treated with bowel decontamination, and 5 of 8 patients were treated with nitrogen scavenging agents. Six of the 8 patients died.. The incidence of hyperammonemia syndrome in LTx patients was approximately 1%. Future research is needed to determine the efficacy of treatment, including hemodialysis, bowel decontamination, antibiotics, and the use of nitrogen scavenging agents in lung recipients with hyperammonemia.

Topics: Aged; Ammonia; Arginine; Biomarkers; Carnitine; Combined Modality Therapy; Decontamination; Female; Humans; Hyperammonemia; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Missouri; Phenylacetates; Protective Agents; Renal Dialysis; Retrospective Studies; Sodium Benzoate; Syndrome; Time Factors; Treatment Outcome; Up-Regulation

Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS).. Data of 63 patients were collected (27 patients with ASS deficiency, 23 patients with OTC deficiency, and 12 patients with CPS1 deficiency, one patient definite diagnosis not documented). The majority of patients (43/63, 68 %) had an initial ammonia concentration exceeding 500 μmol/L (normal < 100), of which most (26/43, 60.5 %) were also encephalopathic and were treated with hemodialysis. In patients surviving the initial crisis, recurrence of hyperammonemic events within the first 1.5 years of life occurred frequently (mean 3.6 events, range 0-20). Of all patients, 16 (25.4 %) died during or immediately after the neonatal period.. We observed in this cohort of neonatal onset UCD patients a high rate of initial life-threatening hyperammonemia and a high risk of recurrence of severe hyperammonemic crises. These corresponded to a high mortality rate during the entire study period (30.2 %) despite the fact that patients were treated in leading European metabolic centers. This underlines the need to critically re-evaluate the current treatment strategies in these patients.

Topics: Arginine; Child, Preschool; Female; Humans; Hyperammonemia; Infant; Kaplan-Meier Estimate; Liver Transplantation; Male; Ornithine Carbamoyltransferase Deficiency Disease; Prognosis; Retrospective Studies; Sodium Benzoate; Urea Cycle Disorders, Inborn

Topics: Ammonia; Arginine; Child; Clinical Chemistry Tests; Diagnostic Errors; Fatigue; Female; Fever; Headache; Humans; Hyperammonemia; Phenylacetates; Reference Values; Sodium Benzoate

To evaluate the therapeutic agents used during metabolic crises and in long-term management of patients with propionic acidemia (PA).. The records of PA patients were retrospectively evaluated.. The study group consisted of 30 patients with 141 admissions. During metabolic crises, hyperammonemia was found in 130 (92%) admissions and almost all patients were managed with normal saline, ≥ 10% dextrose, and restriction of protein intake. In 56 (40%) admissions, management was done in intensive care unit, 31 (22%) with mechanical ventilation, 10 (7%) with haemodialysis, 16 (11%) with vasopressor agents, and 12 (9%) with insulin. In the rescue procedure, L-carnitine was used in 135 (96%) patients, sodium bicarbonate in 116 (82%), sodium benzoate in 76 (54%), and metronidazole in 10 (7%), biotin in about one-quarter, L-arginine in one third, and antibiotics in three-quarter of the admissions. Blood/packed RBCs were used in 28 (20%) patients, platelets in 26 (18%), fresh frozen plasma in 8 (6%), and granulocyte-colony stimulating factors in 10 (7%) admissions. All patients were managed completely/partially with medical nutrition formula plus amino acid mixture, vitamins and minerals. For long-term management 24 (80%) patients were on L-carnitine, 22 (73%) on sodium benzoate, 6 (20%) on biotin, one half on alkaline therapy and 4 (13%) on regular metronidazole use. Almost all patients were on medical formula and regular follow-up.. Aggressive and adequate management of acute metabolic crises with restriction of protein intake, stabilization of patient, reversal of catabolism, and removal of toxic metabolites are essential steps. Concerted efforts to ensure adequate nutrition, to minimize the risk of acute decompensation and additional therapeutic advances are imperative to improve the outcome of PA patients.

Topics: Adolescent; Anti-Infective Agents; Biotin; Carnitine; Child; Child, Preschool; Diet, Protein-Restricted; Female; Humans; Hyperammonemia; Infant; Infant, Newborn; Long-Term Care; Male; Metronidazole; Nutrition Therapy; Propionic Acidemia; Retrospective Studies; Sodium Benzoate; Sodium Bicarbonate; Vitamin B Complex

Topics: Ammonia; Arginine; Argininosuccinate Lyase; Argininosuccinic Aciduria; Breast Feeding; Combined Modality Therapy; Diet, Protein-Restricted; DNA Mutational Analysis; Female; Hemofiltration; Humans; Hyperammonemia; Infant Formula; Infant, Newborn; Lactic Acid; Sodium Benzoate

Ornithine carbamoyltransferase (OTC) deficiency is a urea cycle disorder that causes the accumulation of ammonia, which can lead to encephalopathy. Adults presenting with hyperammonemia who are subsequently diagnosed with urea cycle disorders are rare. Herein, we report a case of a late-onset OTC deficient patient who was successfully treated with arginine, benzoate and hemodialysis. A 59-yr-old man was admitted to our hospital with progressive lethargy and confusion. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. A plasma amino acid and urine organic acid analysis revealed OTC deficiency. Despite the administration of a lactulose enema, the patient's serum ammonia level increased and he remained confused, leading us to initiate acute hemodialysis. After treatment with arginine, sodium benzoate and hemodialysis, the patient's serum ammonia level stabilized and his mental status returned to normal.

Topics: Age of Onset; Ammonia; Arginine; Citrulline; Humans; Hyperammonemia; Male; Middle Aged; Ornithine; Ornithine Carbamoyltransferase Deficiency Disease; Pedigree; Renal Dialysis; Sodium Benzoate

Topics: Adult; Brain Edema; Carbohydrates; Enteral Nutrition; Glucose; Humans; Hyperammonemia; Insulin; Male; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Renal Dialysis; Sodium Benzoate

4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate.

Topics: Adenosine Triphosphatases; Adolescent; Arginine; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Child, Preschool; Diet, Protein-Restricted; Female; Humans; Hyperammonemia; Liver; Ornithine Carbamoyltransferase Deficiency Disease; Phenylacetates; Receptors, Cytoplasmic and Nuclear; Retrospective Studies; RNA, Messenger; Sodium Benzoate

Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.

Topics: Alleles; Animals; Arginine; Argininosuccinate Synthase; Blotting, Western; Cell Movement; Cerebellum; Citrullinemia; Developmental Disabilities; Disease Models, Animal; Female; Growth Disorders; Humans; Hyperammonemia; Immunoenzyme Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mutation, Missense; Nitric Oxide; Phenotype; Sodium Benzoate; Syndrome

Reports on citrullinemia usually describe the imaging findings in the adult form of the disease. However, neuroimaging findings of neonatal cases are seldom reported. We report on the diffusion-weighted magnetic resonance imaging (MRI) findings of a one-year old infant with neonatal citrullinemia during an acute episode and discuss possible underlying mechanisms for abnormal diffusion findings.

Topics: Brain; Cerebral Cortex; Citrullinemia; Diffusion Magnetic Resonance Imaging; Epilepsy, Tonic-Clonic; Fatal Outcome; Humans; Hyperammonemia; Infant; Male; Sodium Benzoate

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by mutations in ORNT1 gene that encodes a mitochondrial ornithine transporter. It has variable clinical presentations with episodic hyperammonemia, liver dysfunction, and chronic neurological manifestations. In this work, we report the findings of HHH syndrome in 3 Saudi siblings. The 4-year-old proband presented with recurrent Reye-like episodes, hypotonia, and multiple stroke-like lesions on brain MRI. Biochemical and molecular analysis confirmed that she had HHH syndrome. She significantly improved on protein restriction and sodium benzoate. Her two older siblings have milder phenotypes with protein intolerance and learning problems. In comparison to their sister, their homocitrulline and orotic acid were only mildly elevated even before treatment. The three patients were homozygous for a novel mutation in ORNT1 with a Gly220Arg change. In view of the CNS lesions, which initially were felt to be suggestive of MELAS, we sequenced the entire mtDNA genome and no potential pathogenic mutations were detected. Analysis of ORNT2 did not provide explanation of the clinical and biochemical variability. This work presents a yet unreported CNS involvement pattern, notably multiple supratentorial stroke-like lesions in association with HHH syndrome. Moreover, it illustrates considerable clinical/biochemical correlation, and describes a novel mutation. We suggest including HHH syndrome in the differential diagnosis of patients found to have stroke-like lesions on brain MRI.

Topics: Adolescent; Amino Acid Metabolism, Inborn Errors; Amino Acid Transport Systems, Basic; Brain; Brain Diseases, Metabolic, Inborn; Child; Child, Preschool; Citrulline; DNA Mutational Analysis; Female; Food, Formulated; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Hyperammonemia; Magnetic Resonance Imaging; Male; Mitochondrial Membrane Transport Proteins; Mutation; Ornithine; Pedigree; Saudi Arabia; Sodium Benzoate; Stroke

Deficiency of any of the 5 enzymes in the urea cycle results in the accumulation of ammonia, leading to encephalopathy; which if untreated, can be lethal and produce devastating neurologic sequelae in long-term survivors. We hereby present an interesting case that presented with hyperammonemia and encephalopathy; later found to have an urea cycle defect.

Topics: Diagnosis, Differential; Glucocorticoids; Hepatic Encephalopathy; Humans; Hyperammonemia; Male; Metabolism, Inborn Errors; Middle Aged; Phenylbutyrates; Prednisone; Sodium Benzoate; Urea

An infant with a suspected inborn metabolism error was treated with a metabolic cocktail of intravenous sodium phenylacetate (NaPh) and sodium benzoate (NaBz) for hyperammonemia. Sequential hemodialysis (HD) then hemofiltration (HF) was performed due to hyperammonemia. Dialytic and convective clearance (K; ml/min) of ammonia, NaPh, and NaBz was measured. The K of ammonia was 57 and 37 for HD and HF, respectively. The K of NaBz was 37 and 12 for HD and HF, respectively. The K of NaPh was 38 and 14 ml/min for HD and HF, respectively. Despite high clearance of both NaPh and NaBz by HD and HF, the hyperammonemia was corrected.

Topics: Ammonia; Hemofiltration; Humans; Hyperammonemia; Infant, Newborn; Phenylacetates; Renal Dialysis; Sodium Benzoate

Topics: Amino Acid Metabolism, Inborn Errors; Humans; Hyperammonemia; Phenylacetates; Sodium Benzoate; Urea

Ammunol (sodium phenylacetate/sodium benzoate) is an intravenously administered, investigational drug used for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. A pharmacokinetic study of sodium phenylacetate/sodium benzoate (NAPA/NABZ) was performed in two groups of normal healthy volunteers, following the dosing regimen used to treat hyperammonemia.. The first group of subjects (n = 3) received a bolus dose of 5.5 g/m2 of NAPA/NABZ, over a period of 1.5 h. Following a seven-day washout, subjects then received the same bolus dose, followed by a continuous infusion of 5.5 g/m2 over 24h. A second group of different subjects (n = 17) received the same treatment regimen, but using doses of 3.75 g/m2. Phenylacetate (PA) and benzoate (BZ), and their respective metabolites, phenylacetylglutamine (PAG), and hippurate (HIP) were measured over a 24-h period. An HPLC method was used for the measurement of all analyte concentrations. Non-compartmental analysis and modeling was performed using WinNonlin Professional.. Both BZ and PA displayed saturable, non-linear elimination, with a decrease in clearance with increased dose. During the bolus dose with continuous infusion regimen, plasma levels of both BZ and PA peaked at the end of the priming dose, and PA levels remained near peak for 5-9h. In contrast, BZ plasma levels immediately fell following the priming dose, and became undetectable at 14.1+/-4.2 and 26.8+/-2.3h in the low- and high-dose group, respectively. The formation of HIP occurred more rapidly than that of PAG. For both PA and BZ, metabolite formation increased in a linear fashion with the dose.. These data describe the pharmacokinetics of PA and BZ, and their respective metabolites, as observed in healthy adult volunteers, with the higher dose studied equivalent to that used to treat hyperammonemia. Dose optimization is required to maximize nitrogen removal, while minimizing the risk of toxicity, especially due to PA. Because of the slower elimination of PA, and the non-linear pharmacokinetic behavior displayed by both PA and BZ, only investigational protocol-specific doses should be used, and higher doses should be avoided unless blood level monitoring can be done promptly and frequently.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hyperammonemia; Infusions, Intravenous; Molecular Structure; Phenylacetates; Prospective Studies; Sodium Benzoate; Time Factors

Topics: Adult; Anesthesia, General; Epilepsy; Fasting; Female; Humans; Hyperammonemia; Intellectual Disability; Oral Surgical Procedures; Ornithine Carbamoyltransferase Deficiency Disease; Postoperative Complications; Preoperative Care; Proteins; Sodium Benzoate; Substance Withdrawal Syndrome; Urea

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.. Case study.. Intensive care unit and internal medicine unit at a university hospital.. 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.. 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.

Topics: Adult; Coma; Female; Hemofiltration; Humans; Hyperammonemia; Middle Aged; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Phenylbutazone; Sodium Benzoate

The treatment of newborns with urea cycle disorders has evolved over the years into a complex multidisciplinary effort. The complexity derives from the number of issues that must be addressed simultaneously. At the Urea Cycle Disorders Consensus Meeting held in Washington, D.C., a panel of physicians and other professionals with extensive experience in this field was assembled to bring some systematization to this task. This manuscript is a condensation of the collective opinion and experience of that group. The outcome of untreated or poorly treated patients with urea cycle disorders is universally bad. Although a favorable outcome is not always feasible, even with the best therapy, the methods outlined here should help treat such a patient by drawing on the experience of others who have treated patients with urea cycle disorders. This article does not purport to be the final word in treating children with these disorders. However, by establishing some common ground, new methods can be tried and compared with existing ones. In a future that holds the prospect of gene therapy "cures" for these diseases, striving for the best possible outcome in the critical newborn period is a worthy goal.

Topics: Algorithms; Amino Acid Metabolism, Inborn Errors; Antimetabolites, Antineoplastic; Arginine; Dialysis; Extracorporeal Membrane Oxygenation; Humans; Hyperammonemia; Infant, Newborn; Phenylacetates; Sodium Benzoate; Urea

Topics: Amino Acid Metabolism, Inborn Errors; Arginine; Argininosuccinate Lyase; Argininosuccinic Acid; Argininosuccinic Aciduria; Child, Preschool; Hepatomegaly; Humans; Hyperammonemia; Point Mutation; Psychomotor Disorders; RNA Splicing; Sodium Benzoate