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Citrullinemia Clinical Presentation

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
Updated: Sep 08, 2015


At least one half of newborns with citrullinemia present in the first several days of life.

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in presentation, diagnostic features, and treatment. For these reasons, urea cycle defects are considered individually; however, the common denominator, hyperammonemia, can manifest clinically as some or all of the following:

  • 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 relate to this constellation of symptoms and rough temporal sequence of events.

No routine laboratory studies provide a diagnostic clue, and only a high index of suspicion can prompt the physician to obtain a blood ammonia measurement. The need for a high index of suspicion cannot be sufficiently emphasized.

In the face of intercurrent illness, other affected children experience delayed development from infancy with exaggerated lethargy and vomiting. Again, only a high index of suspicion based on a thorough history can lead to proper diagnosis.

The adult form of citrullinemia has been reported almost exclusively in Japan, and these cases are associated with unusual self-selection of diet.[5, 6] These individuals have been shown by DNA studies to be affected by a mutation that impairs function of the mitochondrial malate-aspartate shuttle. The abnormal protein that affects this impairment is called citrin and is encoded by the SLC25A13 gene at locus 7q21.3. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is also due to a mutation in the same gene. Whether such infants will be affected by the adult form of citrullinemia later in life is unclear.




Signs of severe hyperammonemia may be present.

Poor growth may be evident.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.


Tachypnea or hyperpnea may be present.

Apnea and respiratory failure may occur in later stages.


Hepatomegaly may be present and is usually mild.


See the list below:

  • Poor coordination
  • Dysdiadochokinesia
  • Hypotonia or hypertonia
  • Ataxia
  • Tremor
  • Seizures and hypothermia
  • Lethargy progressing to combativeness, obtundation, and coma
  • Decorticate or decerebrate posturing


Citrullinemia is an autosomal recessive genetic condition. The gene has been mapped to chromosome 9 and has a locus at band 9q34.[7, 8] The adult-onset type is caused by mutation at locus 7q21.3 and, therefore, must be considered a separate disorder; the same mutation also causes NICCD. The etiologic connection between the 2 clinical entities remains problematic.

At least 20 distinct mutations have been reported. Most of them are single-base substitutions that cause missense mutations that result in an enzyme protein with abnormal kinetic properties.

Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The 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).

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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Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also 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 (4); the reaction is mediated by argininosuccinate (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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