AUTHOR INFORMATION

Section 1 of 11

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; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; 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

Section 2 of 11

Background: Argininosuccinate (ASA) lyase deficiency results in defective cleavage of ASA, which leads to accumulation in cells and excessive excretion in urine. In virtually all respects, this disorder shares the characteristics of each of the family of urea cycle defects. This deficiency's most important characteristic is its propensity to cause hyperammonemia in the affected individual.

Pathophysiology: The hepatic urea cycle is the major route for waste nitrogen disposal; generation of nitrogen is 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. A portion of the cycle is mitochondrial in nature; 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 rate-limiting step is carbamyl phosphate synthetase (CPS) disposal of waste nitrogen. In cases of genetic deficiency of an additional enzyme beyond CPS in the cycle, however, the deficient enzyme becomes rate limiting. This is the situation in argininosuccinic aciduria, despite the fact that formation of this substance ensures incorporation of the 2 waste nitrogen molecules normally found in urea. Although failure to release the arginine limits the cycle rate and slows hepatic regeneration of the distal intermediates of the cycle, this is unlikely to entirely explain the clinical findings, because ASA is excreted by the kidney at a rate practically equivalent to the glomerular filtration rate (GFR).

Whether ASA itself may cause a degree of toxicity due to hepatocellular accumulation is unknown; such an effect could help explain hyperammonemia development in affected individuals. In any case, the rapid clearance of ASA in urine has given the name to the disease, although elevations of ASA can be found in plasma. Hyperammonemia in this disease manifests with the typical findings and has all of the attendant consequences seen in the other diseases of this category.

Frequency:

• In the US: ASA lyase deficiency is a rare condition. As with other disorders in this category, this deficiency can manifest in the neonate or later in life, and true incidence cannot be cited without population screening data.

Mortality/Morbidity: ASA lyase deficiency is associated with high mortality and morbidity.

Sex: Inherited as an autosomal recessive trait, argininosuccinic aciduria affects both sexes equally.

CLINICAL

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History:

• Newborn presentation is consistent with the clinical manifestations of hyperammonemia. The multiple primary causes of hyperammonemia, specifically due to urea cycle enzyme deficiencies, vary in manifestation, diagnostic features, and management. For these reasons, the family of urea cycle defects are considered individually in this text; however, the common denominator, hyperammonemia, can manifest 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)
  
  
  
• The most striking clinical findings of each individual urea cycle disorder consequently relate to the foregoing constellation of symptoms and their temporal sequence.



• Delayed development and mental retardation are certain long-term consequences in survivors who do not receive proper treatment.

Physical:

• General


• • Signs of severe hyperammonemia may be present.

  • Poor growth may be evident.
  
  
  
• Head, ears, eyes, nose, and throat: 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 is common.



• Neurologic


• • Poor coordination

  • Dysdiadochokinesia

  • Hypotonia or hypertonia

  • Ataxia

  • Tremor

  • Seizures and hypothermia

  • Lethargy progressing to combativeness to obtundation to coma

  • Decorticate or decerebrate posturing
  
  
  
• A distinguishing feature in the newborn period, singular among the urea cycle defects, is the presence of trichorrhexis nodosa (friable hair). This may be seen clinically and is identifiable by microscopic examination. Trichorrhexis nodosa is likely to be much more apparent in the older infant in whom a choreoathetotic movement disorder may also be seen.



• Failure to suspect hyperammonemia and to obtain a blood ammonia level results in certain morbidity and, likely, death of the infant, because routine laboratory testing is unrevealing.

Causes:

• ASA lyase deficiency is an autosomal recessive genetic disorder. The gene for ASA lyase deficiency is located on chromosome 7 and has been mapped to the locus 7q11.2. The normal gene has been cloned and comprises approximately 35 kilobases and 16 exons. In contrast to other urea cycle defects, few mutational variants have been reported.



• Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in waste nitrogen metabolism. These enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms.

DIFFERENTIALS

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Arginase 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

WORKUP

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Lab Studies:

• No routine laboratory data assist diagnosis.


• • The BUN test is subject to a number of different factors aside from the rate of production via the urea cycle. Among the most obvious is the state of hydration, which may frequently cause an artifactual increase to a normal concentration in a very sick infant.
  
  
  
  • A very low BUN level is suggestive but must never be relied upon as a diagnostic indicator.
  
  
  
• As in all other urea cycle disorders, clinical suspicion is essential to obtaining a blood ammonia level, which is elevated significantly in the symptomatic patient. This finding should lead to an immediate blood and urine amino acid quantitation, which confirms presence of argininosuccinic acid in both fluids. In addition, increased blood citrulline, glutamine, alanine, and lysine levels may be observed. Argininosuccinic acid lyase may be assayed in cultured fibroblasts, providing the definitive biochemical diagnosis. The urine orotic acid level is elevated.

TREATMENT

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Medical Care:

• Immediate temporary withdrawal of protein is indicated in all cases of newly discovered hyperammonemia. Increase nonprotein caloric sources to avoid catabolism of muscle protein for energy.


• • IV benzoate, arginine, and phenylacetate may be indicated as initial therapy for hyperammonemia, but such combined therapy is appropriate only prior to specific diagnosis. Hemodialysis, if available, is a more efficient and rapid method for reduction of blood ammonia.
  
  
  
• Long-term therapy should involve a low-protein diet and arginine supplementation. This diet helps produce equivalent quantities of ornithine for enhancement of urea cycle activity up to the point of ASA lyase and, thus, enhances waste nitrogen incorporation.

Consultations:

• Medical genetics and/or metabolic-disease specialist



• Pediatric critical care specialist



• Dietitian

MEDICATION

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Because the enzyme defect interrupts the urea cycle, alternative means of waste nitrogen disposal are required. Medications assist in excreting nitrogen and serve as an alternative to urea to reduce waste nitrogen levels. Administer only in a large medical facility with close laboratory monitoring available.

Drug Category: Diagnostic agents, pituitary function -- These are used in management of severe, uncompensated metabolic alkalosis.

Drug Name	Arginine HCl (R-Gene) -- Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and argininosuccinate.
Pediatric Dose	Hyperammonemic crisis: 0.66 g/kg IV over 24 h, diluted in 25-35 mL 10% dextrose Maintenance treatment of a stable child: 0.4-0.7 g/kg/d PO administered as free base
Contraindications	Documented hypersensitivity; renal or hepatic failure
Interactions	Increased toxicity of estrogen-progesterone combinations due to growth hormone response and glucagon and insulin effects; spironolactone may cause potentially fatal hyperkalemia
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause mild-to-moderate metabolic acidosis; may cause nausea, vomiting, headache, hyperkalemia, hyperglycemia, or venous irritation during IV administration

Drug Name	Sodium phenylacetate and sodium benzoate (Ammonul) -- Benzoate combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. Phenylacetate conjugates (via acetylation) glutamine in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. The nitrogen content of phenylacetylglutamine per mol is identical to that of urea (two mols of nitrogen). Ammonul must be administered with arginine for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL) deficiencies. Indicated as adjunctive treatment of acute hyperammonemia associated with encephalopathy caused by urea cycle enzyme deficiencies. Serves as an alternative to urea to reduce waste nitrogen levels.
Adult Dose	Ammonul: Loading: 55 mL (5.5 g)/m2 IV over 90-120 min via central line Maintenance: 55 mL (5.5 g)/m2/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration
Pediatric Dose	Ammonul: <20 kg: Loading: 2.5 mL (250 mg)/kg IV over 90-120 min via central line Maintenance: 2.5 mL (250 mg)/kg/d IV over 24 h via central line Must dilute IV dose in at least 25 mL/kg of dextrose 10% before administration >20 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Penicillin may decrease effects of sodium benzoate/sodium phenylacetate; probenecid may inhibit renal excretion of products of sodium benzoate and sodium phenylacetate; valproate may antagonize efficacy of sodium benzoate and sodium phenylacetate corticosteroids may increase body protein metabolism, thereby increasing plasma ammonia levels; do not use concomitantly with oral sodium phenylbutyrate (Buphenyl) due to additive effects
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 giving to patients with congestive heart failure, severe renal dysfunction, and sodium retention with edema; common side effects include nausea, vomiting, tinnitus, and visual disturbance; IV 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)

FOLLOW-UP

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Further Outpatient Care:

• Under no circumstances should a patient with a urea cycle defect be cared for exclusively by a primary care provider.

• Provide care for a patient with ASA lyase deficiency under the guidance of a biochemical geneticist/metabolic-disease specialist who is skilled in therapy of urea cycle diseases.



• Especially in the growing infant, frequent dietary and medication adjustments are essential and should be made only with quantitative monitoring of plasma amino acids.



• Close attention to dietary intake and adjustments is a critical part of management and should involve the help of a highly trained nutritionist.

Complications:

• Untreated, patients may develop cerebral edema and die. Death can occur in some cases despite treatment.

• Mental retardation is a common sequela.

Prognosis:

• Prognosis is guarded.



• While intellectual impairment is the general rule, even among patients who receive excellent and timely treatment, some patients with ASA lyase deficiency reportedly have normal development.

Patient Education:

• Advise parents of an affected infant that they are obligate heterozygotes, because the disease is inherited as an autosomal recessive trait. This trait leads to a recurrence risk of 1:4 (25%) with each subsequent pregnancy.



• Prenatal diagnosis is available for ASA lyase deficiency, though the involved diagnostic procedures are not trivial. Even in cases in which elective abortion is not an option, parents should be prepared for an affected infant in order to avoid early hyperammonemia.



• Advise parents to follow the dietary and medication instructions scrupulously and to seek early medical attention for all intercurrent illnesses.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to suspect and/or detect hyperammonemia is likely to result in irreversible brain damage or death.



• Inadequate treatment may stabilize the patient clinically but permit ongoing brain damage.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is not true of argininosuccinic aciduria?

A: May manifest chronically in older infants
B: Can be associated with abnormalities of the hair shaft
C: Can cause choreoathetotic movement disorder
D: Results in very high plasma concentrations of argininosuccinate (ASA)
E: Causes developmental delay

The correct answer is D: Argininosuccinate is excreted by the kidney at a rate equivalent to the glomerular filtration rate (GFR), so plasma accumulation is minimal. Plasma ASA concentration is elevated but not to an extensive degree.

CME Question 2: Which of the following is not a diagnostic criterion for argininosuccinate (ASA) lyase deficiency?

A: Hyperammonemia
B: Low blood urea nitrogen (BUN) concentration
C: Increased urinary excretion of ASA
D: Mental retardation
E: Trichorrhexis nodosa

The correct answer is B: The BUN level is subject to a number of different factors aside from the rate of production via the urea cycle. Among the most obvious is the state of hydration, which may frequently cause an artifactual increase to a normal concentration in a very sick infant. Thus, a very low BUN level is suggestive but must never be relied upon as a diagnostic indicator.

Pearl Question 1 (T/F): Since argininosuccinate (ASA) synthesis results in incorporation of a second waste nitrogen, the disease process associated with inability to proceed to urea synthesis is moderated.

The correct answer is False: Despite the incorporation of the second nitrogen, clinical disease associated with ASA lyase deficiency is as severe as in other inherited disorders of urea synthesis. Assume that ASA itself is cytotoxic; an inability to further metabolize this compound leads to cell injury in the hepatocyte and inhibition of other urea cycle enzymes.

Pearl Question 2 (T/F): The liver is the only tissue that normally expresses the argininosuccinate (ASA) lyase gene.

The correct answer is False: As in the case of ASA synthase, an extrahepatic gene expression of ASA lyase exists. For this reason, definitive diagnosis by enzyme assay is relatively facile.

Pearl Question 3 (T/F): Appropriate long-term treatment of ASA lyase deficiency includes removal of protein from the diet.

The correct answer is False: Removal of all or essential minimal protein from the diet results in muscle catabolism and in hyperammonemia as severe as that caused by overfeeding.

Pearl Question 4 (T/F): Urine is the body fluid in which ASA is most easily demonstrated in the affected infant.

The correct answer is True: ASA is cleared rapidly by the kidney at a rate approximating the glomerular filtration rate (GFR), creating a very high urine/blood ratio of ASA concentration.

BIBLIOGRAPHY

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• Berry GT, Steiner RD: Long-term management of patients with urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S56-S62.
• Brusilow SW, Batshaw ML: Arginine therapy of argininosuccinase deficiency. Lancet 1979 Jan 20; 1(8108): 124-7[Medline].
• Collins FS, Summer GK, Schwartz RP: Neonatal argininosuccinic aciduria-survival after early diagnosis and dietary management. J Pediatr 1980 Mar; 96(3 Pt 1): 429-31[Medline].
• Glick NR, Snodgrass PJ, Schafer IA: Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity. Am J Hum Genet 1976 Jan; 28(01): 22-30[Medline].
• Linnebank M, Tschiedel E, Haberle J: Argininosuccinate lyase(ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet 2002; 111: 350-359.
• Reid Sutton V, Pan Y, Davis EC, Craigen WJ: A mouse model of argininosuccinic aciduria: biochemical characterization. Mol Genet Metab 2003 Jan; 78(1): 11-6[Medline].
• Stadler S, Gempel K, Bieger I: Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry. J Inherit Metab Dis 2001; 24: 370-378.
• Steiner RD, Cederbaum SD: Laboratory evaluation of urea cycle disorders. J Pediatr 2001 Jan; 138(1 Pt 2): S21-S29.
• Widhalm K, Koch S, Scheibenreiter S: Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics 1992 Jun; 89(6 Pt 2): 1182-4[Medline].

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