Argininosuccinate Lyase Deficiency Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 13, 2012
 

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.
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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
  • 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.
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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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Contributor Information and Disclosures
Author

Karl S Roth, MD  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 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

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

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, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

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.

Leonard G Feld, MD, PhD, MMM, FAAP  Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center

Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Mitchell S, Ellingson C, Coyne T, et al. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. Jan 2009;30(1):56-60. [Medline].

  2. Nagamani SC, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. Jan 5 2012;[Medline].

  3. Erez A, Nagamani SC, Lee B. Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond. Am J Med Genet C Semin Med Genet. Feb 15 2011;157(1):45-53. [Medline]. [Full Text].

  4. Erez A, Nagamani SC, Shchelochkov OA, Premkumar MH, Campeau PM, Chen Y, et al. Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med. Nov 13 2011;17(12):1619-26. [Medline].

  5. Mercimek-Mahmutoglu S, Moeslinger D, Häberle J, Engel K, Herle M, Strobl MW, et al. Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. Mol Genet Metab. May 2010;100(1):24-8. [Medline].

  6. Falik-Zaccai TC, Kfir N, Frenkel P, et al. Population screening in a Druze community: the challenge and the reward. Genet Med. Dec 2008;10(12):903-9. [Medline].

  7. Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. Oct 2008;97(10):1412-9. [Medline].

  8. Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S56-60; discussion S60-1. [Medline].

  9. Brosnan ME, Brosnan JT. Orotic acid excretion and arginine metabolism. J Nutr. Jun 2007;137(6 Suppl 2):1656S-1661S. [Medline].

  10. Brusilow SW, Batshaw ML. Arginine therapy of argininosuccinase deficiency. Lancet. Jan 20 1979;1(8108):124-7. [Medline].

  11. Collins FS, Summer GK, Schwartz RP. Neonatal argininosuccinic aciduria-survival after early diagnosis and dietary management. J Pediatr. Mar 1980;96(3 Pt 1):429-31. [Medline].

  12. Glick NR, Snodgrass PJ, Schafer IA. Neonatal argininosuccinic aciduria with normal brain and kidney but absent liver argininosuccinate lyase activity. Am J Hum Genet. Jan 1976;28(01):22-30. [Medline].

  13. Kleijer WJ, Garritsen VH, van der Sterre ML, et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenatal Diagnosis. Mar 2006;26(3):242-7. [Medline].

  14. Linnebank M, Tschiedel E, Haberle J, et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. Oct 2002;111(4-5):350-9. [Medline].

  15. Reid Sutton V, Pan Y, Davis EC, Craigen WJ. A mouse model of argininosuccinic aciduria: biochemical characterization. Mol Genet Metab. Jan 2003;78(1):11-6. [Medline].

  16. Saudubray JM, Rabier D. Biomarkers identified in inborn errors for lysine, arginine, and ornithine. J Nutr. Jun 2007;137(6 Suppl 2):1669S-1672S. [Medline].

  17. 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].

  18. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. Jan 2001;138(1 Suppl):S21-9. [Medline].

  19. 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].

  20. 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].

  21. 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].

 
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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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