AUTHOR INFORMATION

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Authored by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Advancement of Science, 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

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Karl S Roth, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, July 7 2005, VOLUME 6, Number 7

INTRODUCTION

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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 the other members of the group (see Physical). Two separate isozymes of the enzyme arginase exist. Type I is found in the liver and contributes the vast majority of hepatic arginase activity, while type II is inducible and found in extrahepatic tissues. The disease is caused by deficiency of arginase type I in the liver.

Pathophysiology: The hepatic urea cycle is the major route for waste nitrogen disposal, which is generated chiefly from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal as well. A portion of the cycle takes place in mitochondria; mitochondrial dysfunction may impair urea production and result in Hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N-acetylglutamate, the enzyme activator that initiates incorporation of ammonia into 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 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 attributable 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.

Frequency:

• In the US: 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 affects each gender equally.

Age: As an inherited disorder, the age of onset is typically during the neonatal period. Because of its atypical form of manifestation, the disease may be easily 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.

CLINICAL

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History:

• The history of delayed development, protein intolerance, and spasticity should direct the clinician's attention to arginase deficiency.


• • Although a catastrophic neonatal presentation is very uncommon in arginase deficiency, surmising that onset is at birth and progression is relatively slow in comparison to other members of this family of 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, has occasional episodes of vomiting and somnolence without apparent cause, is protein intolerant, and shows evidence of long-tract neurological impairment.
  
  
  
  • A common clinical feature in this disorder is spasticity, and it is likely that the disease is 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, are somewhat variable in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually in this textbook; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following:


• • 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, for reasons cited above, may have a somewhat different manifestation.

Physical:

• General


• • Signs of severe hyperammonemia may be present.
  
  
  
  • Poor growth may be evident.
  
  
  
• 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 if present.



• 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.

DIFFERENTIALS

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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

WORKUP

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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 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, similar to that found in cystinuria with increased arginine, ornithine, lysine, and, possibly, cystine, 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 the experienced clinician may fail to diagnose the disease. Urine orotic acid is usually mildly increased. Plasma ammonia levels may be mildly increased or normal.
  
  
  
  • When demonstration of mild-to-moderate elevated plasma arginine is observed in association with developmental delay and spasticity, a red cell arginase assay is indicated for definitive biochemical diagnosis.
  
  
  

TREATMENT

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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 very rare condition.

Consultations:

• Medical genetics and/or metabolic-disease specialist



• Dietitian

MEDICATION

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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 CoA and then conjugated with glutamine to form phenylacetylglutamine. Each of these 2 pathways results 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) -- Combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes l mol nitrogen. The oral product Ucephan is a combination of sodium benzoate 10 g and sodium phenylacetate 10 g per 100 mL (100 mg of each/mL). The IV preparation is currently investigational.
Pediatric Dose	Loading dose: 250 mg/kg IV infused over 90 min Maintenance dose: 250 mg/kg IV infused over 24 h Dilute IV dose in 30 mL/kg of dextrose 10% Oral maintenance dose: 375 mg/kg/d PO divide tid/qid in conjunction with a low-protein diet
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	Sodium phenylbutyrate (Buphenyl) -- 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.
Pediatric Dose	0.5 g/kg/d PO divided tid pc
Contraindications	Documented hypersensitivity, severe hypertension, heart failure, renal dysfunction, acute hyperammonemia
Interactions	Valproate and haloperidol may increase ammonia levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema

Drug Name	Sodium phenylacetate -- Converted to phenylacetylglutamine, thereby taking up 1 mol per mol of free ammonia. Only perform administration in a large medical facility with close laboratory monitoring available.
Pediatric Dose	For IV dosages please see Citrullinemia For maintenance treatment in a stable child: the use of phenylbutyrate (see above) is preferred
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal impairment; diagnostic aid not intended for therapeutic use

FOLLOW-UP

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Further Outpatient Care:

• A biochemical genetics/metabolic-disease expert should guide the management of arginase deficiency, as with all of the 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 so treated have thus far done well and remained normal.

Prognosis:

• In view of the relatively subtle and progressive presentation, an affected patient escaping irreversible damage to the CNS is unlikely. Nonetheless, early diagnosis in the clinical course allows for improved outcome. Even in a case of a late diagnosis, treatment from birth in a subsequent infant of an affected family should prevent the developmental delay and the spasticity, based upon 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, though uncommon in this disease, can occur.



• Prenatal diagnosis is possible by enzyme assay using fetal red blood cells; arginase mutations have been identified in skin fibroblasts from amniotic fluid and specimens from chorionic villus biopsies.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• As with all urea cycle disorders, failure to recognize hyperammonemia results in a missed diagnosis. Unique among this group of 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.

TEST QUESTIONS

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CME Question 1: Which of the following is not a part of the neonatal presentation of arginase deficiency?

A: Catastrophic onset
B: Increased urinary amino acid excretion pattern similar to that of cystinuria
C: Early feeding intolerance
D: Irritability
E: Normal routine blood laboratory values

The correct answer is A: Catastrophic illness due to arginase deficiency is not usual because extrahepatic isozyme induction by arginine accumulation leads to cleavage of arginine outside of the liver.

CME Question 2: Which of the following is a characteristically associated finding in older infants with arginase deficiency?

A: Diarrhea
B: Abnormal liver function
C: Abnormal renal function
D: Spastic diplegia
E: Blindness

The correct answer is D: Spastic diplegia consistent with the nonspecific diagnosis of cerebral palsy is very frequently associated with arginase deficiency; therefore, argininemia must always be considered in the differential diagnosis of cerebral palsy.

Pearl Question 1 (T/F): Arginase-deficient children are unlikely to be susceptible to a hyperammonemic crisis.

The correct answer is True: Arginase is an enzyme that is expressed in an inducible isozyme form (arginase II) in several extrahepatic tissues. Therefore, when failure to cleave arginine in the hepatocyte leads to release of arginine into blood, induction of and increase in arginase II activity is present in other tissues This completes the final step in the urea cycle.

Pearl Question 2 (T/F): Plasma arginine concentrations are always very high in arginase deficiency.

The correct answer is False: Plasma arginine concentrations may not always be greatly increased in arginase deficiency. The patient may self-restrict protein intake, thus reducing the waste nitrogen load on the urea cycle and causing less arginine synthesis. The lower arginine synthetic rate can be handled more easily by the inducible arginase II system in other tissues. This maintains a lower circulating level in the blood.

Pearl Question 3 (T/F): The role of treatment with sodium benzoate or sodium phenylbutyrate is to enhance the excretion of waste nitrogen.

The correct answer is True: By further reducing the load on the urea cycle for waste nitrogen through alternative disposal routes, conjugation of benzoate with glycine to form hippuric acid or of phenylacetate to phenylacetylglutamine may lead to enhanced excretion.

Pearl Question 4 (T/F): Clinical presentation and a red blood cell arginase assay can differentiate argininemia and cystinuria.

The correct answer is True: Arginase activity is easily assayable in the red blood cell. Cystinuria is a renal tubular transport disorder with no CNS implications.

PICTURES

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Caption: Picture 1. Arginase deficiency. Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; it also is at this step that N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamoyl phosphate synthetase (CPS). 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.
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BIBLIOGRAPHY

Section 12 of 12

• Ash DE, Scolnick LR, Kanyo ZF, Vockley JG, et al: Molecular basis of hyperargininemia: structure-function consequences of mutations in human liver arginase. Mol Genet Metab 1998 Aug; 64(4): 243-9[Medline].
• Berry GT, Steiner RD: Long-term management of patients with urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S56-S62[Medline].
• Cederbaum SD, Shaw KN, Valente M: Hyperargininemia. J Pediatr 1977 Apr; 90(4): 569-73[Medline].
• Cederbaum SD, Yu H, Grody WW: Arginases I and II: do their functions overlap? Mol Genet Metab 2004; 81Supplement 1: S38-S44.
• Cowley DM, Bowling FG, McGill JJ, van Dongen J, et al: Adult-onset arginase deficiency. J Inherit Metab Dis 1998 Aug; 21(6): 677-8[Medline].
• Crombez EA, Cederbaum SD: Hyperargininemia due to liver arginase deficiency. Mol Genet Metab 2005; 84: 243-251.
• Haberle J, Koch HG: Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn 2004; 24: 378-383.
• Iyer R, Jenkinson CP, Vockley JG, Kern RM, et al: The human arginases and arginase deficiency. J Inherit Metab Dis 1998; 21 Suppl 1: 86-100[Medline].
• Korman SH, Gutman A, Stemmer E: Prenatal diagnosis fro arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis. Prenat Diagn 2004; 24: 857-860.
• Picker JD, Puga AC, Levy HL, et al: Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr 2003 Mar; 142(3): 349-52[Medline].
• Qureshi IA, Letarte J, Ouellet R, Batshaw ML, et al: Treatment of hyperargininemia with sodium benzoate and arginine- restricted diet. J Pediatr 1984 Mar; 104(3): 473-6[Medline].
• Scheuerle AE, McVie R, Beaudet AL, Shapira SK: Arginase deficiency presenting as cerebral palsy. Pediatrics 1993 May; 91(5): 995-6[Medline].
• Steiner RD, Cederbaum SD: Laboratory evaluation of urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S21-S29[Medline].

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