Argininosuccinate Lyase (ASL) Deficiency

Argininosuccinate (ASA) lyase deficiency results in defective cleavage of ASA. This leads to an accumulation of ASA in cells and an excessive excretion of ASA in urine. In virtually all respects, this disorder shares the characteristics of other urea cycle defects.[1] The most important characteristic of ASA lyase deficiency is its propensity to cause hyperammonemia in affected individuals. See the image below.

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; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl 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.

The hepatic urea cycle is the major route for waste nitrogen disposal; nitrogen generation results 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 may result in hyperammonemia. Overall, the cycle’s activity 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 carbamoyl phosphate synthetase (CPS) disposal of waste nitrogen. However, in patients with a genetic deficiency in an additional enzyme in the cycle (other than CPS), the deficient enzyme becomes rate limiting. This occurs in patients with 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).[2, 3, 4]  

A potential alternative is that the inability to release arginine from ASA leads to arginine deficiency, in turn restricting both protein and nitric oxide synthesis, the latter exposing tissues to damage from oxide radical damage.

Whether ASA itself causes a degree of toxicity due to hepatocellular accumulation is unknown; such an effect could help explain hyperammonemia development in affected individuals. Regardless, the name of the disease is derived from the rapid clearance of ASA in urine, although elevated levels of ASA can be found in plasma. Hyperammonemia in this disease manifests with the typical findings and carries all of the attendant consequences associated with other urea cycle diseases.

Frequency

United States

ASA lyase deficiency is rare,, affecting an estimated 1 in 70,000 live births. It is the second-most common urea cycle disorder.[5] As with other disorders in this category, this deficiency can manifest in neonates or later in life, and true incidence cannot be cited without population screening data.[6]

International

The Druze community in Israel has a carrier frequency of 1:41.[7] According a study of urea cycle diseases in Finland, 20 cases of ASA lyase deficiency had been reported by 2007.[8]

Mortality/Morbidity

ASA lyase deficiency is associated with high mortality and morbidity rates. Failure to suspect hyperammonemia and to obtain blood ammonia levels results in certain morbidity and, likely, death because routine laboratory test findings are unrevealing.

Sex

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

Prognosis is guarded.

Although intellectual impairment is the rule, even among patients who receive excellent and timely treatment, some patients with ASA lyase deficiency reportedly develop normally.

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, although 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 scrupulously follow the dietary and medication instructions and to seek early medical attention for all intercurrent illnesses.

The neonatal presentation of argininosuccinate (ASA) lyase deficiency is consistent with the clinical manifestations of hyperammonemia. The multiple primary causes of hyperammonemia, specifically the urea cycle enzyme deficiencies, vary in manifestation, diagnostic features, and management. For these reasons, the urea cycle defects are considered individually in this article; however, hyperammonemia is the common denominator and can manifest clinically as 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)

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 among the long-term consequences in survivors who do not receive proper treatment.

See the list below:

• 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 occurred.

• Pulmonary

  • Tachypnea or hyperpnea may be present.

  • Apnea and respiratory failure may occur in later stages.

• Abdominal: Hepatomegaly is common.

• Neurologic

  • Poor coordination

  • Dysdiadochokinesia

  • Hypotonia or hypertonia

  • Ataxia

  • Tremor

  • Seizures and hypothermia

  • Lethargy progressing to combativeness, obtundation, and coma

  • Decorticate or decerebrate posturing

• Other: A distinguishing feature in the newborn period, unique to urea cycle defects, is the presence of trichorrhexis nodosa (friable hair). This may be observed clinically and is identifiable with microscopic examination. Trichorrhexis nodosa is likely to be much more apparent in older infants, who may also have a choreoathetotic movement disorder.

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. Approximately 160 mutational variants have been reported, most of which are private and vary widely in nature, from missense to deletions.

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 (see Arginase Deficiency).

In a follow-up study of patients with ASA lyase deficiency, hepatic fibrosis was reported in some cases[9] ; however, other studies have not confirmed this as a regular long-term complication,[10] while EEG changes progress independently of hyperammonemic control.

Untreated patients may develop cerebral edema and die, and some patients die despite treatment.

Mental retardation is a common sequela.

No routine laboratory data assist diagnosis of argininosuccinate (ASA) lyase deficiency.

BUN testing is subject to numerous factors aside from the rate of production via the urea cycle. Among the most obvious is the state of hydration, which frequently causes an artifactual increase to a normal concentration in a very sick infant. A very low BUN level is suggestive but must never be relied on as a diagnostic indicator.

As with all other urea cycle disorders, clinical suspicion is essential and should prompt the clinician to obtain blood ammonia levels, which are significantly elevated in symptomatic patients. This finding should lead to an immediate blood and urine amino acid quantitation, which confirms the presence of argininosuccinic acid in both fluids. In addition, levels of blood citrulline, glutamine, alanine, and lysine may be increased. Argininosuccinic acid lyase may be assayed in cultured fibroblasts, providing the definitive biochemical diagnosis. Urine orotic acid levels are elevated.

All 50 states in the United States include argininosuccinate (ASA) lyase deficiency in their newborn screening programs.

Molecular diagnosis is available for diagnostic confirmation. Prenatal diagnosis is possible, but the nature of the mutation must be known, given the wide variety of private mutations reported.

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

Intravenous benzoate, arginine, and phenylacetate administration may be indicated as initial therapy for hyperammonemia, but such combined therapy is appropriate only prior to specific diagnosis. Hemodialysis, if available, reduces the blood ammonia levels more efficiently and quickly.

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 argininosuccinate (ASA) lyase and, thus, enhances waste nitrogen incorporation. Inclusion of arginine in the regimen helps to offset the inability of deficient tissues to generate free arginine from ASA.

Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate.[11] In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate.[12]

For several years, liver transplantation has been the accepted form of surgical treatment for urea cycle disorders. However, many patients have delayed development, physical debilitation, or both, disqualifying them from the procedure or greatly increasing the associated risks.

Donor cell engraftment has been reported to be an effective technique of reducing the acuity of the disease in patients with neonatal-onset ASA lyase deficiency. This modality may offer a safer approach to surgical treatment of urea cycle disorders in general and may reduce the need for patients to qualify for a place on a transplantation roster.

See the list below:

• Medical geneticist

• Metabolic disease specialist

• Pediatric critical care specialist

• Dietitian

See Medical Care.

Using chorionic villus sampling, prenatal diagnosis is possible as early as 11-12 weeks’ gestation. It is essential to establish the nature of the mutation in the parents first, given the large number of private mutations known to occur. This should be discussed with any family with one or more affected first-degree relatives.

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

Consult with a biochemical geneticist/metabolic disease specialist who is skilled in treating urea cycle diseases when treating patients with argininosuccinate (ASA) lyase deficiency.

Frequent dietary and medication adjustments are essential, especially in growing infants, and should be made only with quantitative monitoring of plasma amino acid levels.

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

Because the enzyme defect interrupts the urea cycle, alternative means of waste nitrogen disposal are required. Some 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.

Class Summary

These are used in management of severe, uncompensated metabolic alkalosis.

Arginine (R-Gene)

Enhances production of ornithine, which facilitates incorporation of waste nitrogen into the formation of citrulline and ASA.

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 (2 mol of nitrogen). Ammonul must be administered with arginine for carbamyl phophate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or ASA lyase 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.

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.