Are You Confident of the Diagnosis?

What you should be alert for in the history
Characteristic findings on physical examination

Argininosuccinic aciduria is a disorder of the urea acid cycle. Although patients may present at any age, the onset is more typical in the neonatal period or late infancy.

The neonatal presentation is usually characterized by normal delivery followed by generalized hypotonia, lethargy, poor feeding with vomiting, hypothermia and hyperventilation leading to central respiratory alkalosis. The neonate develops progressive decreased consciousness leading to coma. The diagnosis should be suspected in any hypotonic neonate with failure to feed.

The enzyme deficiency leads to accumulation of argininosuccinic acid in all body fluids and progressive and severe hyperammonemia. The elevated of ammonia leads to ammonia-induced coma and serious central nervous system injury.

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The onset in late infancy is usually characterized by less severe symptoms including failure to thrive, gastroesophageal reflux and vomiting, variable degrees of irritability and behavioral or psychomotor retardation. Trichorrhexis nodosa is common, presenting as coarse, brittle hair and is the result of arginine deficiency (Figure 1) .

Figure 1.

Trichorrhexis nodosa. (Courtesy of Ph Abimelec, MD)

Expected results of diagnostic studies

Laboratory tests include measurement of plasma and urinary amino acids, urinary organic acids, electrolytes, lactate and pyruvate levels. These are essential to evaluate the neonate and other late onset presentations, but these are not specific to this diagnosis. Abnormal urinary organic acid levels suggest congenital lactic acidosis, organic acidemias and fatty acid oxidation defects. These are commonly associated with hyperammonemia. Urea cycle disorders often have normal urinary organic acid levels.

Determination of plasma citrulline helps to differentiate proximal from distal defects. Citrulline level is normal in arginine deficiency and is markedly elevated in argininosuccinic lyase deficiency, usually 100 times the upper limit of the normal range. Argininosuccinic acid in plasma and urine permits the specific diagnosis of Argininosuccinic lyase deficiency. The diagnostic algorithm for urea cycle disorders must consider the total metabolic pathway and the specific enzyme deficiencies leading to characteristic substrate elevation.

Diagnosis confirmation

Specific metabolic testing and ultimately enzymatic and molecular confirmation are necessary to establish a diagnosis. Assay of argininosuccinate lyase may be determined in cultured fibroblasts (skin) or tissue (liver) biopsies and erythrocytes. Mutation analysis of the ASL gene is performed on genomic DNA extracted from blood, buccal brushes and amniotic fluid fibroblast cultures.

Newborn screening in all 50 states applies tandem mass spectrometry to detect argininosuccinate lyase deficiency allowing for presymptomatic detection. The biochemical marker is elevated plasma citrulline level. Elevated plasma citrulline levels are typical of citrullinemia , but the levels in citrullinemia are three- to fourfold greater than in argininosuccinic lyase deficiency . The incidence of “false negative” screens is unknown.

Who is at Risk for Developing Argininosuccinic Aciduria?

Argininosuccinic aciduria is a rare disorder and may be one of many metabolic abnormalities considered in any child with significant metabolic derangements specifically associated with hyperammonemia.

Argininosuccinic aciduria is an autosomal recessive trait. An affected child therefore must receive one mutant allele from each parent. Following the birth of an affected child, the parents will have a 1 in 4 or 25% risk of recurrence in another child.

What is the Cause of Argininosuccinic Aciduria?

Argininosuccinic aciduria is caused by mutations in the argininosuccinate lyase gene (ASL) which catalyzes the cleavage of the argininosuccinate to fumarate and arginine. This is the fourth step in the urea acid cycle in the liver. Argininosuccinic lyase is involved in the conversion of the citrulline to arginine in other tissues.

The ASL gene is located on chromosome 7 in the region 7cen-q11.2. Over 16 mutations have been described in the ASL gene. Clinical variation is considerable and there is no current genotype-phenotype correlation.

This is an uncommon metabolic disorder and is estimated to occur in 1 in 70,000-1 and 250,000 live births.

Urea acid cycle disorders are characterized by the triad of hyperammonemia, encephalopathy and respiratory alkalosis. Argininosuccinic aciduria is one of six disorders effecting the biosynthesis of enzymes of the urea cycle. These include ornithine transcarbamylase deficiency, carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency and arginase deficiency.

Systemic Implications and Complications

The symptoms that occur in the first few days or weeks of life include convulsions, episodic unconsciousness, liver enlargement, and abnormal brittle hair in more than half of patients as a consequence of arginine deficiency in this condition.

Trichorrhexis nodosa is characterized by dry, coarse, brittle hair with thickened or weak nodes along the hair shaft which leads to easy breakage. Later onset may be associated with mental and physical retardation. Neurologic abnormalities are more pronounced than in other urea cycle defects. Seizures are common.

Liver disease occurs with elevated hepatic enzymes. Hepatomegaly and liver fibrosis are apparently independent of the primary metabolic defect and likely related to additional toxic products.

Treatment Options

Therapy requires institution of a low-protein diet modified to provide appropriate caloric intake for growth but sufficiently limited to avoid hyperammonemia, and the use of ammonia scavenger drugs to enhance excretion of ammonia. Arginine is deficient in all cells and oral or intravenous supplementation with arginine is initiated as early as the diagnosis is achieved.

In the acute stage, discontinuingoral protein intake is essential. Calories are provided by intravenous glucose and lipids . Reducing the ammonia level is critical and may require hemodialysis if oral and intravenous therapies are ineffective .

Optimal Therapeutic Approach for Argininosuccinic Aciduria

Therapy is directed towards lowering the ammonia level to normal levels to avoid central nervous system injury. If excluding protein intake does not result in normalization of ammonia level, then oral and intravenous therapy can assist in the process.

Sodium benzoate conjugates with glycine to form hippurate, which is readily excreted in the urine. One mole of nitrogen is removed for every mole of benzoate administered.

Sodium phenylbutyrate is converted to phenylacetate, which conjugates with glutamine, resulting in a compound that is readily excreted in the urine. Two moles of nitrogen are eliminated for every mole of phenylbutyrate administered. Supplemental arginine enhances the formation of citrulline, which is readily excreted in the urine reducing the nitrogen load.

Patient Management

Treatment of urea cycle disorders is geared to reduce plasma ammonia concentration by a use of dialysis, intravenous administration of arginine chloride, and nitrogen scavenger drugs to allow alternative pathway excretion of excess nitrogen.

The diet consists of protein restriction and providing calories as carbohydrates and fat (Intralipid) to reduce catabolism. Adequate intravenous fluids are essential to maintain adequate tissue perfusion and to avoid overhydration, which may result in cerebral edema.

Long-term therapy requires a continuous and carefully monitored low-protein diet with arginine supplementation. Ammonia levels are obtained once stabilization has occurred every 1-3 months.

Protein intake is restricted, with calories provided by carbohydrates and fat. Fat is provided by intralipid or protein free formula to reduce catabolism. In the early stages of treatment, intravenous fluids are needed to maintain blood pressure and tissue perfusion, with careful monitoring to avoid overhydration and potential cerebral edema.

Unusual Clinical Scenarios to Consider in Patient Management

Liver transplantation is required for those patients who do not respond to dietary control or have unremitting progressive hepatic failure. Although aggressive therapy in the newborn period may lead to stabilization and normalization of ammonia levels, those who survive usually have neurologic impairment .

What is the Evidence?

Summar, ML, Pagon, RA, Bird, TC, Dolan, CR, Stephens, K. “Urea cycle disorders overview”. . 1993-2011. (A comprehensive overview of urea cycle abnormalities provides a systematic pathway for establishing the diagnosis and differentiating among the 6 urea cycle enzyme deficiencies.)

Nagamani, SCS, Erez, A, Lee, B, Pagon, RA, Bird, TC, Dolan, CR, Stephens, K. “Argininosuccinate lyase deficiency”. . 1993-2011. (This is a current comprehensive summary of the disease characteristics, clinical testing to establish the diagnosis and the treatment of acute manifestations and ongoing healthcare surveillance.)

Deignan, JL, Cederbaum, SD, Grody, WW. “Contrasting features of urea cycle disorders in human patients and knockedout mouse models”. Mol Genet Metab. vol. 93. 2007. pp. 7-14. (An outstanding review of the features of the urea cycle disorders in human patients with a discussion of the potential therapeutic approaches provided by mouse models of these enzyme deficiencies.)

Berry, GT, Steiner, RD. “Long-term management of patients with urea cycle disorders”. J Pediatr. vol. 138. 2001. pp. S56-S61. (An excellent summary by experienced clinicians on the long-term treatment of patients with urea cycle disorders emphasizing the importance of tailoring therapy to each individuals specific enzyme dysfunction.)

Leonard, JV, Morris, AAM. ” Urea cycle disorders”. Semin Neonatol. vol. 7. 2002. pp. 27-36. (This paper presents the challenges in the recognition and timely diagnosis of patients with urea cycle disorders, pointing out that the presenting signs are nonspecific and the clinician must have a high level of awareness for an underlying metabolic disorder.)

Summar, ML. “Current strategies for the management of neonatal urea cycle disorders”. J Pediatr. vol. 138. 2001. pp. S30-S39. (A thoughtful and challenging summary outlining strategies for the management of neonatal urea cycle disorders, emphasizing the importance of aggressive metabolic testing, coordination of interventions and the importance of early management and stabilization.)

Summar, ML, Dobbelaere, D, Brusilow, S, Lee, D. “Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21 year, multicentre study of acute hyperammonemic episodes”. Acta Paediatr. vol. 97. 2008. pp. 1420-25. (This represents a longitudinal survey of patients with urea cycle disorders, documenting presenting symptoms, complications and long-term survival).

Smith, W, Kishnani, PS, Lee, B, Singh, RH, Rhead, WJ, King, LS. “Urea cycle disorders: Clinical presentation outside the newborn period”. Crit Care Clin. vol. 21. 2005. pp. S9-17. (This article alerts the physician to the fact that urea cycle disorders more often present outside of the newborn period as recurrent symptoms of neurologic decompensation.)

Enns, GM, Berry, SA, Berry, GT, Rhead, WJ, Brusilow, SW, Hamosh, A. “Survival after treatment with phenylacetate and benzoate for urea cycle disorders”. N Engl J Med. vol. 56. 2007. pp. 2282-92. (This report summarizes a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy in urea cycle disorders, indicating the effectiveness of the treatment and the point at which further therapy with hemodialysis may be indicated .)

Stephenne, X, Sibille, NM, Nassongne, MC, Smet, F, Sokal, EM. “Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency”. Gastroenterol. vol. 130. 2006. pp. 1317-23. (This is a comprehensive case report demonstrating the success of liver transplantation in reversing the adverse effects of argininosuccinate lyase deficiency, leading to sustained metabolic and clinical control and psychomotor improvement.)

Lee, B, Singh, RH, Rhead, WJ, Sniderman, L, Smith, W, Summar, ML. “Considerations in the difficult-to-manage urea cycle disorder patient”. Crit Care Clin. vol. 21. 2005. pp. S19-S25. (With aggressive therapy, patients with urea cycle disorders may survive beyond infancy and require ongoing healthcare surveillance to prevent metabolic decompensation.)