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Argininosuccinate Lyase Deficiency Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
Updated: Sep 10, 2015


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
  • 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.

Contributor Information and Disclosures

Karl S Roth, MD Retired 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 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

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 and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

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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.
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