Urea Cycle Enzyme Deficiencies Research Articles

S3336 An Unusual Cause of Encephalopathy

Introduction: Hepatic encephalopathy, while common among cirrhosis patients, can occur without cirrhosis. In adults, 90% cases of hyperammonemia are due to cirrhosis. Ammonia is central to its pathophysiology produced by bacterial degradation in the gut from protein, urea, and glutamine. Ammonia acts as a neurotoxin which is metabolized by hepatocytes to urea for excretion via kidney and colon. Type B hepatic encephalopathy is due to portosystemic shunting without parenchymal liver disease. Case Description/Methods: A 69-year-old female with history of hepatoma with resection and chemoembolization in 1997, mucosa-associated lymphoid tissue, perforated diverticulitis status post colostomy and reversal in 2015 was in her usual state of health a day prior to admission when she presented with lethargy after episodes of nausea and vomiting. She was arousable and not able to follow commands. Her CT (computed tomography) of the brain with no acute changes followed by CT of abdomen showing dilated small intestine extending into ventral hernia with concern for obstruction. Blood tests revealed ammonia 141 umol/L, total bilirubin 4.1 mg/dL, direct bilirubin 1.5 mg/dL, international normalized ratio 1.2 and platelet 130 k/ul. Alkaline phosphatase, alanine and aspartate transaminases were within normal limits. Obstruction resolved with conservative management and she was started on rectal and oral lactulose with rifaximin via nasogastric tube. Her mentation improved significantly although the cause of her hepatic encephalopathy remained unclear. Then she underwent magnetic resonance imaging of the abdomen with contrast showing portal to hepatic vein shunt with stable postoperative changes. Shunt closure option was discussed and patient opted outpatient follow up. Discussion: Prompt diagnosis and treatment of hepatic encephalopathy is important to prevent cerebral edema. In patients with encephalopathy and elevated ammonia in absence of liver parenchymal disease, work-up for shunt and urea cycle enzyme deficiency should be done. In the absence of cirrhosis most portosystemic shunts are congenital or traumatic. This case brings a rare cause due to remote liver surgery and chemoembolization. The treatment of portosystemic shunts is evolving, balloon-occlusion retrograde transvenous obliteration is one such technique. In the absence of varices, bland embolization with ectopic coils and vascular plugs can be utilized. Endovascular treatment carries an improvement of hepatic encephalopathy by 50 to 80% at 18 to 24 months.

Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.

EE268 Budget Impact Analysis for the Use of Sodium Phenylacetate and Sodium Benzoate in the Treatment of Acute Hyperammonemia: Experience in a Saudi Setting

Sodium phenylacetate/Sodium benzoate injection combination is an orphan drug indicated as an adjunct therapy in treating acute Hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies. There is a lack of economic data on its use in the pediatric population, particularly in Saudi Arabia. This analysis aims to assess the budget impact of Sodium phenylacetate and Sodium benzoate injection combination in treating acute Hyperammonemia and associated encephalopathy in patients with urea cycle enzyme deficiencies compared to hemodialysis in the pediatric population.

Fatal Coma Secondary to Acute Onset of Hyperammonemia in a Non-Cirrhotic Adult Male Secondary to a Urea Cycle Enzyme Deficiency—a Rare Disease Case Report

Introduction Acute hyperammonemia in adult patients without liver disease is uncommon. Other etiologies are broad and can be difficult to rule out quickly. Urea cycle disorders such as ornithine transcarbamylase (OTC) deficiency are rare and often present in children. Adult-onset cases are rarer. This makes recognizing and treating late-onset urea cycle disorders challenging in the acute setting. Case Report We present the case of a 56-year-old male with a history of early onset coronary artery disease, chronic back pain, and heavy tobacco use who was found unconscious at home by a neighbor. He was found to have toxic levels of serum ammonia during further evaluation in the emergency department. Laboratory testing confirmed a diagnosis of OTC deficiency. Genetic analysis further showed a c.-106C>A variant of the OTC gene. Conclusion Although extremely rare, late-onset urea cycle disorders should be considered when patients present with altered mental status with hyperammonemia of unknown etiology. Furthermore, this case adds evidence that the c.-106C>A OTC gene variant has pathogenic significance.

2310 A Mysterious Case of Non-Cirrhotic Recurrent Severe Hyperammonemia: What Urea-lly Need to Know

INTRODUCTION: Ammonia is a well-known toxin, mostly studied in Hepatic encephalopathy. While, it is related to severe liver disease in 90% cases, the remaining 10% is constituted by disturbances in its excretion or related to over production from other etiologies. [1] Awareness of hyperammonemia in absence of severe hepatic disease may lead to lifesaving prompt diagnosis and treatment. We present a mysterious case of recurrent severe hyperammonemia without known liver disease. CASE DESCRIPTION/METHODS: A 53 year old male with prior history of well controlled hypertension presented to the emergency department with unresponsiveness. On exam, he was unconscious with occasional spontaneous eye opening and a left gaze preference. CT head and CT angiogram of neck did not reveal any acute abnormalities. Liver enzymes and Bilirubin were normal. Blood alcohol level was 0.089gm/dl%. EEG showed diffuse encephalopathy. Serum ammonia was 705 umol/L. He was started on lactulose. His mentation improved in a day and repeat serum ammonia was 25umol/L. Ultrasound liver and CT abdomen ruled out cirrhosis and gall bladder disease. He was discharged home with a prescription of lactulose. He returned to the ED with another episode of unresponsiveness a month later and was found to have elevated serum ammonia of 213 umol/L. Levetiracetam was started empirically with suspicion of recurrent seizures causing this unresponsiveness. He continued to have similar episodes of hyperammonemic encephalopathy. Orotic acid in urine was high (>200 mmol/mol creatinine ), clinching the diagnosis of ornithine transcarbamylase (OTC) deficiency. He was advised to consume a low protein diet and was prescribed L-carnitine along with lactulose. DISCUSSION: Ammonia directly affects neuronal electric activity by inhibiting the generation of both excitatory and inhibitory postsynaptic potentials. Secondary hyperammonemia occurs commonly in the presence of hepatic disorders leading to portosystemic encephalopathy. Less common causes include drugs like valproate, post-chemotherapy, gastric bypass surgery. Causes of primary hyperammonemia in adults include milder forms of urea cycle enzyme deficiencies like OTC, argininosuccinate lyase. Noncirrhotic hyperammonemia as a cause of altered mental status remains a diagnosis of exclusion and requires high index suspicion. Treatment options include lactulose, l-carnitine, and drugs to lower cerebral edema if patient has MRI findings. Liver transplantation is an important treatment modality in urea-cycle disorders.

PS-149-Recombinant glutamine synthetase: A novel strategy for the treatment of hyperammonemia and consequent hepatic encephalopathy in rodent model of cirrhosis and urea cycle enzyme deficiency

PS-149-Recombinant glutamine synthetase: A novel strategy for the treatment of hyperammonemia and consequent hepatic encephalopathy in rodent model of cirrhosis and urea cycle enzyme deficiency

Saline is as effective as nitrogen scavengers for treatment of hyperammonemia

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.

Hyperammonaemia‐induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress

Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia. We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+ /NADH ratio and ATP content. During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids. Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell-permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content. Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non-hepatic ammonia disposal. Non-hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α-ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+ /NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell-permeable ester of α-ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia-induced mitochondrial dysfunction is a novel therapeutic approach.

How much nutrition matters for children

Overweight/obesity is a growing epidemic in the Western world and a leading cause of morbidity and mortality, mainly from cardiovascular disease. Doctors are going to play a major role as they are being called on to adapt their practices to confront it. In particular, nutrition seems to be at the core of obesity in children. The ascending trend of this phenomenon in pediatric age, with inherent healthcare implications, was already reported in epidemiological studies of the mid '90s. Public health programs of primary prevention should be stimulated and recommended, with the aim of promoting diet and lifestyle changes in the general population. In addition, accurate anthropometric measurements should be performed for use by pediatricians, who should focus efforts on preventing obesity during infancy and childhood. Nutrition plays such a pivotal role that it may be considered a valuable treatment strategy for multiple pediatric conditions, including celiac disease, Crohn's disease, short bowel syndrome, galactosemia, congenital deficiency of urea cycle enzymes. In view of all this, it would be advisable that food science be given higher relevance in medical education.

Ammonia metabolism and hyperammonemic disorders.

Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic. Eventually most is excreted in urine as urea, together with ammonia used as a buffer. In extrahepatic tissues, ammonia is incorporated into nontoxic glutamine and released into blood. Large amounts are metabolized by the kidneys and small intestine. In the intestine, this yields ammonia, which is sequestered in portal blood and transported to the liver for ureagenesis, and citrulline, which is converted to arginine by the kidneys. The amazing developments in NMR imaging and spectroscopy and molecular biology have confirmed concepts derived from early studies in animals and cell cultures. The processes involved are exquisitely tuned. When they are faulty, ammonia accumulates. Severe acute hyperammonemia causes a rapidly progressive, often fatal, encephalopathy with brain edema. Chronic milder hyperammonemia causes a neuropsychiatric illness. Survivors of severe neonatal hyperammonemia have structural brain damage. Proposed explanations for brain edema are an increase in astrocyte osmolality, generally attributed to glutamine accumulation, and cytotoxic oxidative/nitrosative damage. However, ammonia neurotoxicity is multifactorial, with disturbances also in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium. Around 90% of hyperammonemic patients have liver disease. Inherited defects are rare. They are being recognized increasingly in adults. Deficiencies of urea cycle enzymes, citrin, and pyruvate carboxylase demonstrate the roles of isolated pathways in ammonia metabolism. Phenylbutyrate is used routinely to treat inherited urea cycle disorders, and its use for hepatic encephalopathy is under investigation.

GRP-074 Frequency of Valproic Acid-Induced Hyperammonemia in Adult Psychiatric Settings

BackgroundValproic acid (VPA) is widely prescribed by paediatric neurologists as an antiepileptic drug. VPA-induced hyperammonaemia can lead to encephalopathy and coma; it is well documented among the paediatric population. Severe...

A Rare Case of Hyperammonemia Complication of High‐Protein Parenteral Nutrition

Hyperammonemia is a metabolic derangement that can be potentially fatal. Primary hyperammonemia due to urea cycle enzyme deficiency is usually discovered in neonates but rarely can present in adulthood. Late-onset manifestations of urea cycle disorders can go unnoticed, until they become life threatening. The authors report a 28-year-old man who developed hyperammonemia in the hospital following parenteral nutrition (PN), leading to cerebral edema, which was fatal despite resolution of the hyperammonemia with cessation of PN and the use of continuous renal replacement therapy.

MRI findings in acute hyperammonemic encephalopathy resulting from decompensated chronic liver disease

Hyperammonemic encephalopathy is a type of metabolic encephalopathy with diversified etiology. Hyperammonemia is the end result of several metabolic disorders such as congenital deficiencies of urea cycle enzymes, hepatic encephalopathy, Reye's syndrome and other toxic encephalopathies. Non-specific clinical presentation poses a great challenge in early diagnosis of this entity. Irrespective of the underlying etiology, hyperammonemia causes a distinctive pattern of brain parenchymal injury. The cingulate gyrus and insular cortex are more vulnerable to this type of toxic insult. Characteristic magnetic resonance imaging findings in combination with laboratory parameters can help to differentiate this entity from other metabolic encephalopathy and thus aiding in early diagnosis and treatment.

A novel facet to consider for the effects of butyrate on its target cells. Focus on “The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein”

short-chain fatty acids (SCFAs), acetate, propionate, and butyrate are produced by bacterial fermentation of dietary fiber in the colonic lumen. In the normal human large intestine, SCFA concentrations range from 70 to 100 mM; these SCFAs account for ∼80% of the anions present in the lumen ([5][1

Headache and neuropsychic disorders in the puerperium: a case report with suspected deficiency of urea cycle enzymes

An enzymatic abnormality of the urea cycle is a metabolic disorder occasionally seen in adults, but particularly in the puerperium. The main risk is acute hyperammoniemic encephalopathy, leading to psychosis, coma and even death if not diagnosed promptly and treated appropriately. Headache is frequent in the puerperium normally manifesting between 3 and 6days after delivery. We describe here a 39-year-old woman, who 3days after delivery presented diffuse tension-type headache and depression, followed by behavioral disorders, psychomotor agitation, epileptic seizures, and finally coma 2days later. Pregnancy and normal delivery: routine blood chemistry findings, CT scan, MR imaging, angio-MR of the brain, and lumbar puncture were normal. EEG when seizures started, it showed diffuse slowing, as in the case of metabolic encephalopathy. This led us to assay blood ammonia, which was high at >400mmol. Liver function and abdominal US were normal; hence, we suspected a urea cycle enzymatic abnormality, and requested for genetic tests. These confirmed a congenital primary metabolic deficiency of arginine succinate synthetase, with high citrullinemia (type II, adult form). Dialysis was started promptly, with initially iv arginine, then orally, plus medical therapy for the hyperammoniemia and a low protein diet; plasma ammonia dropped swiftly to normal, and her state of consciousness gradually improved until all the clinical symptoms had resolved. Ammonia assay should always be considered in the first few days of the puerperium in women with headache and behavioral disorders, to exclude an inborn deficiency of the urea cycle, which may have gone unnoticed until then.

Risk of hyperammonemic coma in the puerperium: two cases of women with diagnosed and undiagnosed deficiency of urea cycle enzymes

Deficiencies of urea cycle enzymes are rare metabolic disorders. Inadequate function of these enzymes may in worst cases lead to hyperammonemic encephalopathy and death. The danger of urea cycle enzyme deficiencies is that previously healthy adults with no prior medical history suggesting these deficiencies may suddenly develop life-threatening complications during prolonged catabolic situations such as delivery or surgery. Since most of the metabolic disorders are diagnosed during childhood, it may sometimes be difficult to bear in mind these rare diseases as a cause of unconsciousness in adulthood. However, early diagnosis and prompt initiation of ammonia-lowering treatment are essential for survival of these patients. We present two pregnant women with urea cycle disorders: one with a known deficiency and an uncomplicated outcome, and another with a previously undiagnosed disorder and life-threatening course of the postpartum period.

Ammonia toxicity and its prevention in inherited defects of the urea cycle

The urea cycle is the final pathway for removal of surplus nitrogen from the body, and the major route in humans for detoxification of ammonia. The full complement of enzymes is expressed only in liver. Inherited deficiencies of urea cycle enzymes lead to hyperammonaemia, which causes brain damage. Severe defects present with hyperammonaemic crises in neonates. Equally devastating episodes may occur in previously asymptomatic adults with mild defects, most often X-linked ornithine transcarbamylase (OTC) deficiency. Several mechanisms probably contribute to pathogenesis. Treatment aims to reduce plasma ammonia quickly, reduce production of waste nitrogen, dispose of waste nitrogen using alternative pathways to the urea cycle and replace arginine. These therapies have increased survival and probably improve the neurological outcome. Arginine, sodium benzoate, sodium phenylbutyrate and, less often, sodium phenylacetate are used. Long-term correction is achieved by liver transplantation. Gene therapy for OTC deficiency is effective in animals, and work is ongoing to improve persistence and safety.

Les déficits du cycle de l’urée chez les patients adultes

Urea cycle disorders (UCD) usually present after 24 h to 48 h of life with failure to thrive, lethargy and coma leading to death, but milder forms may occur from infancy to adulthood. Survival of children with UCD has significantly improved and the need for transitional care to adulthood has emerged. Adult onset UCD present with chronic or acute neurological, psychiatric and digestive symptoms associated with protein avoidance. Ornithine transcarbamylase (OTC) deficiency, which is inherited as an X-linked disorder, is the most well-described UCD in adults. Acute decompensations associate the triad of encephalopathy, respiratory alkalosis and hyperammonemia. Acute encephalopathy is characterized by brain edema, which is life-threatening without treatment. Specific urea cycle enzyme deficiency can be suspected in the presence of abnormal plasma amino acids concentrations and urinary excretion of orotic acid. A measurement enzyme activity in appropriate tissue, or DNA analysis if available, is required for diagnosis. Treatment requires restriction of dietary protein intake and the use of alternative pathways of waste nitrogen excretion with sodium benzoate and sodium phenylbutyrate. Patients with acute forms may need hemodialysis or hemodiafiltration. Therapeutic goals for OTC deficiency are to maintain plasma ammonia<80 micromol/L, plasma glutamine<1,000 micromol/L, argininemia 80-150 micromol/L and branched chain amino acids within the normal range, in order to prevent episodes of potentially lethal acute hyperammonemia. Potentially fatal acute hyperammonemia may occur in male or female patients at any age. Ammonia should be measured promptly in case of acute neurological and psychiatric symptoms or coma.

Transient Hyperammonemia Due to Urea Cycle Enzyme Deficiency in Irish Wolfhounds

Background:Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6‐to 8‐wk‐old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3–4 months.Hypothesis:Transient hyperammonemia has a metabolic basis in Irish Wolfhounds.Animals:Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied.Methods:Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups.Results:Fasting venous ammonia concentrations were high (113–622 μg/dL, 65–345 μmol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine.Conclusions and Clinical Importance: Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.

Transient Hyperammonemia Due to Urea Cycle Enzyme Deficiency in Irish Wolfhounds

Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6- to 8-wk-old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3-4 months. Transient hyperammonemia has a metabolic basis in Irish Wolfhounds. Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied. Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups. Fasting venous ammonia concentrations were high (113-622 microg/dL, 65-345 micromol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine. Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.