eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Argininosuccinate Lyase Deficiency
Updated: Mar 24, 2009
Introduction
Background
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.
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.
Pathophysiology
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).
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. 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.
International
The Druze community in Israel has a carrier frequency of 1:41.2 According a study of urea cycle diseases in Finland, 20 cases of ASA lyase deficiency had been reported by 2007.3
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.
Clinical
History
- 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.
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 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.
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. Few mutational variants have been reported compared with other urea cycle defects.
- 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).
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References
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Stadler S, Gempel K, Bieger I, et al. Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry. J Inherit Metab Dis. Jun 2001;24(3):370-8. [Medline].
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Stephenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology. Apr 2006;130(4):1317-23. [Medline].
Trevisson E, Salviati L, Baldoin MC, et al. Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. Hum Mutat. Feb 26 2007;28(7):694-702. [Medline].
Widhalm K, Koch S, Scheibenreiter S, et al. 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. Jun 1992;89(6 Pt 2):1182-4. [Medline].
Further Reading
Keywords
argininosuccinase, ASA, argininosuccinase lyase deficiency, ASA lyase deficiency, argininosuccinic aciduria, argininosuccinase deficiency, hyperammonemia, hepatic urea cycle, -acetylglutamate, carbamyl phosphate synthetase, CPS, trichorrhexis nodosa, friable hair, choreoathetotic movement disorder, ASL deficiency, diagnosis, treatment, mental retardation, respiratory failure
