Citrullinemia type 2




Citrullinemia is one of the urea cycle disorders, caused by argininosuccinic acid synthetase deficiency (ASS), with an estimated incidence of 1/57,000 live births. The diagnosis of citrullinemia is based on biochemical analysis of blood, plasma, and urine, revealing increased levels of ammonia, citrulline, glutamine, and orotic acid. ASS enzyme activity can be assayed in liver samples and cultured fibroblasts. In neonatal-onset disease, neonates exhibit lethargy and vomiting 24–72 hours after birth, rapidly progressing to respiratory insufficiency and coma. Neurodevelopmental outcome of neonatal urea cycle defects is disappointing and is related to the duration of neonatal hyperammonemic coma. There is, however, no consensus regarding other early prognostic indicators. Reports on imaging findings in citrullinemia are sparse. A recent article describes CT findings in two infants in the chronic stage of this disease.

Type 2 citrullinemia is also an adult-onset, autosomal recessive disorder characterized by episodes of hyperammonemic encephalopathy. It is caused by mutations in the SLC25A13 gene, which encodes the liver-specific isoform of the mitochondrial aspartate–glutamate carrier (AGC2).


Physical General Signs of severe hyperammnemia 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. Pulmonary Tachypnea or hyperpnoea may be present. Apnea and respiratory failure may occur in later stages. Abdominal: Hepatmegaly may be present and is usually mild. Neurologic Poor coordination Dysdiadchkinesia Hyptnia or hypertonia Ataxia Tremor Seizures and hypothermia Lethargy progressing t combativeness, btundatin, and coma Decorticate or decerebrate posturing


Many seropositive mothers with anti-SSA and anti-SSB antibodies give birth t infants who don’t show signs and symptoms of NLE. Mothers of children with NLE have been most commonly diagnosed with SLE; however, occasionally another diagnosis, such as mixed connective-tissue disease or leukcytclastic vasculitis, has been rendered. Circulating fetal blood antibodies, which have been passively acquired, can lead to permanent heart disease and transient cutaneous manifestations. Hematologic and hepatic abnormalities may also occur. The cutaneus findings are transient and resemble those of subacute cutaneus lupus erythematsus. They may be urticarialike and desquamative, occasionally with ulceratin. Two thirds of patients with the skin findings have them at birth, with the remainder developing them within the first 2-5 months of life. In some infants, solar exposure seems to precipitate the eruption. The eruptions usually disappear when maternal antibodies are absent in the neonatal circulation at about the sixth month of life. Cardiac rhythm abnormalities and conduction defects may be observed in various forms, but the occurrence of congenital complete heart block is most closely related to NLE, with an incidence of 15-30%. Cardiac blocks usually develop in utero between the 18th and 20th weeks of pregnancy. Hematologic disturbances (eg, hemolytic anemia, profound thrombocytopenia, neutrpenia) may occur in the first 2 weeks of life. Hematologic symptoms may vary from benign to severe and usually appear at around the second week of life and

disappear by the end of the second month. The clinical picture of hepatbiliary diseases may vary from mild elevations of aminotransferase levels to conjugated hyperbilirubinemia with normal or slightly elevated aminotransferase levels. In children selected because of cutaneous involvement, thrombocytopenia and hepatic disease may be as common as cardiac disease, and these diseases occur more often in male babies with crusted plaques than in female babies. Thus, children with cutaneous NLE should be evaluated for hematologic, hepatic, and cardiac involvement. Hydrocephalus and macrocephaly may be new manifestations f NLE.2 Infants born to mothers with anti-R antibodies should probably be monitored for hydrocephalus as part f their routine physical examination. In a neonate with congenital heart block or thrombocytopenia, serum autantibodies should be investigated to rule out NLE, even if a suggestive maternal history is lacking. Physical Cutaneous findings A well-demarcated erythematus, mild, scaling plaque that is often annular and appears predominately on the scalp, neck, or face is present. This plaque is typically periorbital in distribution. Similar plaques may appear on the trunk or extremities. They are sometimes crusted; this finding is observed more often in male babies than in female babies. Follicular plugging is usually not evident. Healing tends to occur within a year, with mild cutaneous atrophy, with or without associated telangiectasia. The atrophic telangiectatic changes are most evident near the temples and scalp. The latter site may be associated with a permanent alopecia. At times, small angiomalike papulndules may be seen. Cardiac findings Mothers with primary SS or UAS have a greater risk of delivering an infant with congenital complete heart block than those with SLE. Other disturbances may also be present. These disturbances lead to blocks in the atriventricular or Purkinje systems, such as sinus bradycardia and prolongation of the QT interval. An irregular heartbeat may also be present. In some cases, myocarditis and periocarditis can develop and lead to bradycardia. Hematlgic findings Autantibdies, mainly anti-R, can bind directly to the neutrphil and cause neutropenia. These findings may improve or disappear as maternal antibodies are metabolized. Hepatomegaly may be present.

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).


At least one half of genetically affected newborns present in the first several days of life. The multiple primary causes of hyperammnemia, 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, hyperammnemia, can manifest clinically as some or all of the following: Anorexia Irritability Heavy or rapid breathing Lethargy Vomiting Disorientation Somnolence Asterixis (rare) Combativeness btundatin 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 f suspicion can prompt the physician to obtain a bold ammonia measurement. The need for a high index of suspicion cannot be sufficiently emphasized. In the face of intercurrent illness, the affected children experience delayed development from infancy with exaggerated lethargy and vomiting. Again, only a high index of suspicion based on a through 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. 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. 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.