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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Karl S Roth is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Editors: Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
argininemia, familial argininemia, hyperargininemia, urea cycle disorder, arginase type I deficiency, arginase type II, dietary protein intolerance, hyperammonemia, hepatic arginase activity, arginase deficiency, N-acetylglutamate synthesis, arginine, spastic diplegia, protein intolerance, spasticity, urea cycle enzyme deficiencies
Background
Arginase deficiency is thought to be the least common of the urea cycle disorders. This entity also manifests itself in a fashion somewhat different from other disorders in the group (see Physical). Two separate isozymes of the enzyme arginase have been reported. Type I is found in the liver and contributes the vast majority of hepatic arginase activity, whereas type II is inducible and found in extrahepatic tissues. The disease is caused by a deficiency of arginase type I in the liver.
Pathophysiology
The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle takes place in mitochondria; mitochondrial dysfunction may impair urea production and result in hyperammonemia (see Hyperammonemia). Overall, the rate of synthesis of N-acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle, regulates the activity of the cycle. The reaction normally mediated by arginase is the terminal step in the urea cycle, which liberates urea with regeneration of ornithine (Image 1). Consequently, as in argininosuccinic aciduria, both waste nitrogen molecules normally eliminated by the urea cycle are incorporated into the arginine substrate molecule in the reaction. The severe hyperammonemia observed in other urea cycle defects is rarely observed in patients with arginase deficiency for at least 2 identifiable reasons. The first reason is that formed arginine, which contains 2 waste nitrogen molecules, can be released from the hepatocyte and excreted in urine. The second reason may be attributed to the inducibility of the type II isozyme in peripheral tissues, which can attack the arginine released by the hepatocyte and produce urea and ornithine. The ornithine returns to the liver for use in the urea cycle, while the urea is excreted. A 4-fold increase in renal type II arginase has been demonstrated in an affected patient.
The distinct tendency to develop spastic diplegia in patients with arginase deficiency, as compared with patients with other urea cycle disorders, suggests a specific pathogenic mechanism at the CNS level, apart from the generalized toxicity of hyperammonemia. The nature of this mechanism remains unelucidated, but some workers have pointed to an accumulation of guanidino compounds that could interfere with GABAergic transmission. These compounds have also been shown to inhibit the cerebral cortical sodium-potassium adenosine triphosphatase (ATPase) of rats at concentrations comparable with those seen in affected humans. The ATPase is essential to maintenance of the electrochemical gradient of neurons, and its inhibition may be involved in the pathogenesis of the seizure disorder associated with this disease.
Frequency
United States
Incidence cannot be cited because of the absence of any population screening data.
Mortality/Morbidity
Morbidity is high, but the rarity of the condition makes it impossible to cite statistics. Death from arginase deficiency appears to be relatively infrequent, but reliable statistics are not available.
Sex
As an autosomal recessive trait, the disease equally affects both genders.
Age
As an inherited disorder, the age of onset is typically during the neonatal period. Because of its atypical manifestation, the disease may easily be missed in the neonatal period and only recognized in later infancy or early childhood. Some cases likely go undiagnosed, with clinical symptomatology attributed to cerebral palsy.
History
- A history of delayed development, protein intolerance, and spasticity is suggestive of arginase deficiency.
- Although a catastrophic neonatal presentation is uncommon in patients with arginase deficiency, surmising that onset is at birth and that progression is relatively slow compared with other urea cycle disorders is reasonable. Specifically, dietary protein intolerance is an early sign and should not be overlooked.
- The typical presentation is that of an older infant whose development is delayed, who has occasional episodes of vomiting and somnolence without apparent cause, who is protein intolerant, and who shows evidence of long-tract neurological impairment.
- A common clinical feature in this disorder is spasticity, and the disease is likely underdiagnosed because many affected children are diagnosed with cerebral palsy without effort to diagnose arginase deficiency.
- The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, disorders in the urea cycle defect family are individually considered in this article; however, hyperammonemia is a common denominator and can present with some or all of the following symptoms:
- Anorexia
- Irritability
- Heavy or rapid breathing
- Lethargy
- Vomiting
- Disorientation
- Somnolence
- Asterixis (rare)
- Combativeness
- Obtundation
- Coma
- Cerebral edema
- Death (if treatment is not forthcoming or effective)
- As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to the constellation of symptoms of hyperammonemia and rough temporal sequence of events.
- Arginase deficiency may have a somewhat different manifestation for reasons cited above.
Physical
- General
- Signs of severe hyperammonemia may be present.
- Poor growth may be observed.
- Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
- Pulmonary
- Tachypnea or hyperpnea may be present.
- Apnea and respiratory failure may occur in latter stages.
- Abdominal: Hepatomegaly may be present and is usually mild.
- Neurologic
- Poor coordination and spasticity
- Hyperreflexia
- Dysdiadochokinesia
- Hypotonia or hypertonia
- Ataxia
- Tremor
- Seizures and hypothermia
- Lethargy progressing to combativeness to obtundation to coma; decorticate or decerebrate posturing if profound hyperammonemia present
Causes
- The gene for liver arginase has been cloned and is located on chromosome 6. It has been mapped to locus 6q23, consists of 11.5 kilobases, and comprises 8 exons. A mouse "knockout" model for arginase I deficiency has been produced. These animals die within 10-12 days of birth of severe hyperammonemia, whereas animals deficient in arginase II have no identifiable phenotype, except for impaired fertility in the male.
- Approximately 20 mutational variants have been identified.
Argininosuccinate Lyase Deficiency
Carbamoyl Phosphate Synthetase Deficiency
Citrullinemia
Hyperammonemia
Hyperammonemia-Hyperornithinemia-Homocitrullinemia Syndrome
Hyperinsulinemia
Methylmalonic Acidemia
N-Acetylglutamate Synthetase Deficiency
Ornithine Transcarbamylase Deficiency
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)
Other Problems to be Considered
Organic acid disorders (eg, isovaleric acidemia)
Lysinuric protein intolerance
Transient hyperammonemia of the newborn
Hepatic insufficiency/dysfunction
Mitochondrial diseases and pyruvate carboxylase deficiency
Valproate ingestion
L-asparaginase ingestion
Reye syndrome
Sepsis
Lab Studies
- Beyond the inherent problems in diagnosis of any urea cycle disorder, this entity is somewhat difficult to diagnose.
- The typical crisis associated with hyperammonemia is rarely observed, and random measurement of blood ammonia levels during periods of clinical stability is not helpful.
- Arginine excretion in urine is usually not massively increased because of isozyme induction; however, a urinary amino acid excretion pattern can be observed. The excretion pattern is similar to that found in cystinuria, with increased arginine, ornithine, lysine, and, possibly, cystine. It can be observed because of competitive inhibition of dibasic amino acid reabsorption by elevated arginine in the renal proximal tubule.
- Plasma arginine levels may not be greatly increased in cases of self-restriction of protein intake; therefore, even experienced clinicians may fail to diagnose the disease. Urine orotic acid is usually mildly increased. Plasma ammonia levels may be mildly increased or normal.
- When mild-to-moderate elevated plasma arginine levels are observed in association with developmental delay and spasticity, a red cell arginase assay is indicated for definitive biochemical diagnosis.
Medical Care
- Protein intake is restricted. A carefully monitored diet plan is necessary.
- Because severe hyperammonemia is unusual, the need for intravenous therapy or hemodialysis is unlikely. In the event that intravenous therapy or hemodialysis is required, the need to omit intravenous arginine from the treatment regimen should be obvious.
- Long-term therapy rests upon provision of a low-protein diet and, possibly, oral sodium benzoate or sodium phenylbutyrate. A metabolic disease expert should guide the treatment of this rare condition.
Consultations
- Medical geneticist
- Metabolic disease specialist
- Dietitian
Drug Category: Endocrine and metabolic agents
The use of benzoate and phenylacetate is based on the need to provide alternate routes for disposition of waste nitrogen. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl coenzyme A (CoA) and then conjugated with glutamine to form phenylacetylglutamine. These 2 pathways result in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.
| Drug Name | Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul) |
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| Description | Sodium benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol nitrogen. Sodium phenylacetate converted to phenylacetylglutamine, thereby taking up 1 mol per mol of free ammonia. The oral (Ucephan) and IV (Ammonul) products contain a combination of sodium benzoate 10 g/100 mL and sodium phenylacetate 10 g/100 mL (100 mg of each/mL). |
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| Pediatric Dose | Ammonul 10% injection (100 mg/mL)
Loading dose: 250 mg/kg IV infused over 90 min via central line
Maintenance dose: 250 mg/kg IV infused over 24 h via central line
Dilute IV dose in 30 mL/kg of dextrose 10%
Ucephan oral
Oral maintenance dose: 375 mg/kg/d PO divide tid/qid in conjunction with a low-protein diet |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); because of sodium content, exercise caution when administering to patients with CHF, severe renal dysfunction, and sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbances; IV dose must be diluted with dextrose 10% and administered via central line; phenylacetate may cause neurotoxicity; typically administered with antiemetic to prevent common occurrence of nausea and vomiting; caution in severe congestive heart failure or severe renal insufficiency since it contains large amount of sodium (30.5 mg/mL in undiluted IV product); only perform administration in a large medical facility with close laboratory monitoring available |
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| Drug Name | Sodium phenylbutyrate (Buphenyl) |
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| Description | Prodrug rapidly converted orally to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste. |
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| Pediatric Dose | 0.5 g/kg/d PO divided tid pc |
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| Contraindications | Documented hypersensitivity, severe hypertension, heart failure, renal dysfunction, acute hyperammonemia |
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| Interactions | Valproate and haloperidol may increase ammonia levels |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema |
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Further Outpatient Care
- A biochemical geneticist, a metabolic disease specialist, or both should guide the management of arginase deficiency, as with all urea cycle disorders.
- Nutritional management is the mainstay of treatment and should be carried out under the scrutiny of a highly trained nutritionist.
- Closely monitor affected individuals for growth and plasma amino acid levels; under no circumstances should a child with arginase deficiency be cared for by a primary care provider alone.
Deterrence/Prevention
- Prenatal diagnosis can be performed using DNA analysis.
- Recent experience with tandem mass spectrometric newborn screening technique has permitted early identification and treatment. Infants treated in this fashion have thus far done well and remained healthy.
Prognosis
- In view of the relatively subtle and progressive presentation, patient rarely escape irreversible damage to the CNS. Nonetheless, early diagnosis in the clinical course allows for improved outcome. Even in patients who receive a late diagnosis, treatment from birth in a subsequent infant of an affected family should prevent the developmental delay and the spasticity, based on more recent experience.
Patient Education
- Advise parents of an affected child of their obligate heterozygote status.
- Adherence to a low-protein diet is imperative; stress the importance to long-term outcome.
- Seek early medical attention for intercurrent illnesses because hyperammonemic crisis, although uncommon in this disease, can occur.
- Prenatal diagnosis is possible with an enzyme assay using fetal RBCs; arginase mutations have been identified in skin fibroblasts from amniotic fluid and specimens from chorionic villus biopsies.
Medical/Legal Pitfalls
- As with all urea cycle disorders, failure to recognize hyperammonemia results in a missed diagnosis. However, unlike other urea cycle disorders, arginase deficiency often does not manifest acutely and may instead appear as slowly progressive cerebral palsy and mental retardation without other apparent explanation. Early signs of dietary protein intolerance, especially frequent vomiting and postprandial irritability, may be helpful. Thus, examine all such patients for hyperammonemia.
| Media file 1:
Compounds that comprise the urea cycle are sequentially numbered, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS), in this step. Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase. |
 |  View Full Size Image | |
Media type: Graph
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Arginase Deficiency excerpt Article Last Updated: Jun 8, 2007
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