eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Arginase Deficiency

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

Updated: Mar 2, 2009

Introduction

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.¹ 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 (see Media file 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 citing statistics impossible. 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.²

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.³

Clinical

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.

Differential Diagnoses

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

Laboratory Studies

Beyond the inherent problems in diagnosis of any urea cycle disorder, arginase deficiency is somewhat difficult to diagnose.

• The typical crisis associated with hyperammonemia is rare, and random measurement of blood ammonia levels during periods of clinical stability is not helpful.
• Arginine excretion in urine is not usually 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.⁴ 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.

Treatment

Medical Care

• Protein intake is restricted in patients with arginase deficiency. 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 on 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

Medication

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.

Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)

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 PO (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).

Dosing

Adult

Pediatric

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 PO
PO maintenance dose: 375 mg/kg/d PO divide tid/qid in conjunction with a low-protein diet

Interactions

Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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 because 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

Sodium phenylbutyrate (Buphenyl)

Prodrug rapidly converted PO 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.

Dosing

Adult

Pediatric

0.5 g/kg/d PO divided tid pc

Interactions

Valproate and haloperidol may increase ammonia levels

Contraindications

Documented hypersensitivity, severe hypertension, heart failure, renal dysfunction, acute hyperammonemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Because of sodium content, avoid in patients with CHF, severe renal dysfunction, and sodium retention with edema

Follow-up

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.⁵
• 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.

Miscellaneous

Medicolegal 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.

Multimedia

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.

References

1. Cederbaum SD, Yu H, Grody WW, et al. Arginases I and II: do their functions overlap?. Mol Genet Metab. Apr 2004;81 Suppl 1:S38-44. [Medline].

2. Ash DE, Scolnick LR, Kanyo ZF, et al. Molecular basis of hyperargininemia: structure-function consequences of mutations in human liver arginase. Mol Genet Metab. Aug 1998;64(4):243-9. [Medline].

3. Scheuerle AE, McVie R, Beaudet AL, Shapira SK. Arginase deficiency presenting as cerebral palsy. Pediatrics. May 1993;91(5):995-6. [Medline].

4. Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr. Jun 2007;137(6 Suppl 2):1656S-1661S. [Medline].

5. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Pt 2):S56-S62. [Medline].

6. Cederbaum SD, Shaw KN, Valente M. Hyperargininemia. J Pediatr. Apr 1977;90(4):569-73. [Medline].

7. Cowley DM, Bowling FG, McGill JJ, et al. Adult-onset arginase deficiency. J Inherit Metab Dis. Aug 1998;21(6):677-8. [Medline].

8. Crombez EA, Cederbaum SD. Hyperargininemia due to liver arginase deficiency. Mol Genet Metab. Mar 2005;84(3):243-51. [Medline].

9. Haberle J, Koch HG. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat Diagn. May 2004;24(5):378-383. [Medline].

10. Iyer R, Jenkinson CP, Vockley JG, et al. The human arginases and arginase deficiency. J Inherit Metab Dis. 1998;21 Suppl 1:86-100. [Medline].

11. Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. Oct 2008;97(10):1412-9. [Medline].

12. Korman SH, Gutman A, Stemmer E, Kay BS, Ben-Neriah Z, Zeigler M. Prenatal diagnosis fro arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis. Prenat Diagn. Nov 2004;24(11):857-60. [Medline].

13. Picker JD, Puga AC, Levy HL, et al. Arginase deficiency with lethal neonatal expression: evidence for the glutamine hypothesis of cerebral edema. J Pediatr. Mar 2003;142(3):349-52. [Medline].

14. Qureshi IA, Letarte J, Ouellet R, Batshaw ML, et al. Treatment of hyperargininemia with sodium benzoate and arginine- restricted diet. J Pediatr. Mar 1984;104(3):473-6. [Medline].

15. Saudubray JM, Rabier D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J Nutr. Jun 2007;137(6 Suppl 2):1669S-1672S. [Medline].

16. Scaglia F, Lee B. Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency. Am J Med Genet C Semin Med Genet. May 15 2006;142(2):113-20. [Medline].

17. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].

Keywords

argininemia, familial argininemia, hyperargininemia, urea cycle disorder, arginase type I deficiency, arginase type II, dietary protein intolerance, hyperammonemia, hepatic arginase activity, arginase deficiency, -acetylglutamate synthesis, arginine, spastic diplegia, protein intolerance, spasticity, urea cycle enzyme deficiencies

Contributor Information and Disclosures

Author

Karl S Roth, MD, Professor and Chair, 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 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
Disclosure: Nothing to disclose.

Medical Editor

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
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

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
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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