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Citrullinemia
Updated: Mar 26, 2009
Introduction
Background
Citrulline is the resultant product of the condensation reaction that occurs during normal function of the ornithine transcarbamylase reaction. Under normal circumstances, citrulline is condensed with aspartic acid to form argininosuccinic acid (ASA), which is a reaction mediated by the argininosuccinic acid synthase enzyme. Participation of aspartate in the reaction fixes a second waste nitrogen atom into the reaction product, ASA; the first waste nitrogen molecule derives from free ammonia in the carbamyl phosphate synthetase (CPS) reaction. ASA synthase deficiency leads to accumulation of citrulline, a condition known as citrullinemia.
Pathophysiology
The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in hyperammonemia (see Hyperammonemia). Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle.
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.
Citrulline can be metabolized outside the liver, and ASA synthase is normally expressed in the brain, kidney, and skin fibroblasts. In citrullinemia, the genetic defect is expressed in all of these tissues. The body is unable to circumvent the defect by conversion of citrulline to arginine, as it can under normal circumstances. As mentioned above, a second waste nitrogen molecule is incorporated into the urea cycle by a reaction of citrulline to aspartic acid; however, this reaction is impaired and results in a 50% reduction of the overall capacity of the urea cycle to dispose of ammonia. Accordingly, affected individuals have a propensity for developing hyperammonemia.
In vitro evidence in rat brains suggests that accumulated citrulline and ammonia impair the organ's antioxidant capacity. L-citrulline added to the cerebral cortex reduced the 30-day-old rat brains’ total radical-trapping antioxidant potential, the total antioxidant reactivity, and specific activities of catalase, superoxide dismutase, and glutathione peroxidase.1 Therefore, oxidative stress may contribute to the neuropathologic events observed in citrullinemia.
The relationship of the disorder to a condition known as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) remains unclear because the same gene is implicated in both conditions and the mutations do not seem unique to each. The citrin gene (SLC25A13) codes for a mitochondrial aspartate-glutamate carrier. NICCD is usually a transient condition, whereas adult-onset citrullinemia is not benign. The pathophysiologic relationship between the mutation and the form of clinical disease has yet to be elucidated.2
Frequency
United States
Incidence cannot be cited because of the lack of population-screening data. Recent developments in expanded metabolic screening may soon lead to a better understanding of the incidence of neonatal citrullinemia.
International
Cases have been reported in Japan that show a particular form of citrullinemia in adults that had been previously undiscovered and untreated; one case was discovered as late as age 48 years.3 Some patients were developmentally delayed from childhood, whereas others were asymptomatic until onset. Thus, age of onset is as unpredictable in citrullinemia as in ornithine transcarbamylase (OTC) deficiency. Mass screening for the citrin mutation that causes both NICCD and adult-onset citrullinemia has occurred in East Asia.
Mortality/Morbidity
Morbidity and mortality rates are high.
Sex
Citrullinemia is inherited as an autosomal recessive trait; thus, both genders are equally affected.
Age
As with other urea cycle defects, the age of presentation can widely vary, although the most common presentation is in the neonatal period. Older children who were not treated in the neonatal period and were diagnosed later as part of an evaluation for the etiology of their mental retardation have been reported.
Clinical
History
- 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. 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.
Physical
- General
- 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.
- Pulmonary
- Tachypnea or hyperpnea may be present.
- Apnea and respiratory failure may occur in later stages.
- Abdominal: Hepatomegaly may be present and is usually mild.
- Neurologic
- Poor coordination
- Dysdiadochokinesia
- Hypotonia or hypertonia
- Ataxia
- Tremor
- Seizures and hypothermia
- Lethargy progressing to combativeness, obtundation, and coma
- Decorticate or decerebrate posturing
Causes
- Citrullinemia is an autosomal recessive genetic condition. The gene has been mapped to chromosome 9 and has a locus at band 9q34.4 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).
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| References |
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References
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Further Reading
Keywords
citrullinemia, citrulline, argininosuccinic acid synthase deficiency, citrullinuria, aminoaciduria, ornithine transcarbamylase reaction, argininosuccinic acid, ASA, ASA synthase, carbamyl phosphate synthetase reaction, CPS reaction, waste nitrogen disposal, hyperammonemia, mental retardation, urea cycle defect, neonatal intrahepatic cholestasis, NICCD, hepatomegaly, treatment, diagnosis
