Citrullinemia Clinical Presentation

Updated: Aug 06, 2019
  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
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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. [8] {ref628-INVALID REFERENCE} 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 in citrullinemia (see History).

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. [9, 10, 6] 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 137 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. [11]

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).



Complications of citrullinemia are chiefly neurological, including mental retardation, acute hyperammonemic coma, and death.