Citrullinemia is a rare autosomal recessive hereditary disease characterized by a violation of the urea cycle. Occurs with defects in the ASS1 or SLC25A13 genes. In infants, pathology is manifested by neurological disorders (drowsiness, convulsions, depression of consciousness), delayed psychomotor development, adults are also concerned about headaches, psychoemotional disorders. For diagnosis, biochemical blood tests, genetic tests, and liver imaging are performed. Supportive treatment: diet therapy, drug substitution of intermediates of the ornithine cycle.
E72.2 Disorders of the urea cycle metabolism
The first cases of the disease were described in 1962, 5 years later the enzyme defects responsible for the development of citrullinemia were identified, and in the 1980s the genetic causes of the anomaly were established. Type 1 citrullinemia occurs with a frequency of 1 case per 100 thousand people, type 2 of the disease is diagnosed even less often — about 1 case per 2 million people. In the absence of treatment, the disease leads to severe neurological complications up to a fatal outcome, which causes the great relevance of pathology in modern medicine.
Type 1 citrullinemia is caused by a point mutation in the ASS1 gene, type 2 is associated with damage to SLC25A13. The prerequisites for changes in the genetic code have not yet been established. The mutation inheritance occurs in an autosomal recessive type. For the development of the disease, the child must receive one copy of the mutant gene from each of the parents. The risk of citrullinemia in a family where both parents are carriers of the mutation is 25%.
With type 1 citrullinemia, the structure of the enzyme argininosuccinate synthetase, which controls the reaction between citrullin and aspartate in the urea formation cycle, is disrupted. In the second type of disease, defects are observed in the structure of mitochondrial transport proteins responsible for the movement of glutamate and aspartate molecules. In both cases, the ornithine cycle is disrupted, nitrogenous compounds accumulate in excess in tissues and organs, mainly in the form of ammonia.
Negative manifestations of citrullinemia are caused by the toxic effect of ammonia on the entire body, primarily on the brain. This compound easily penetrates through cell membranes, reduces the formation of alpha-ketoglutarate in tissues, as a result of which the synthesis of neurotransmitters and the production of energy molecules in the Krebs cycle decreases in the central nervous system. Ammonia also causes alkalosis, tissue hypoxia, and disrupts the operation of ion channels.
In the classical form of citrullinemia (type 1), clinical signs occur from the first days of an infant’s life as ammonia accumulates in the body. The child becomes sluggish, sleepy, sucks poorly or refuses to eat. Periodically, vomiting, convulsions, increased muscle tone bother. With a high level of ammonia, depression of consciousness occurs, a coma develops, a lethargic state.
With successful relief of primary manifestations in the future, periodic headache, dark spots in the fields of vision (scotomas) are possible. Some patients complain of the inability to maintain the balance of the body, impaired coordination of movements. A characteristic feature is a preference for foods rich in proteins and fats, an aversion to high-carb foods.
With type 2 citrullinemia, as well as in some patients with type 1 anomaly, symptoms appear in adolescence or adulthood. Provoking factors are alcohol, medications, surgical interventions. The disease manifests itself with neurological disorders: memory loss, disorientation, atypical behavior changes (aggression, nervousness, hyperactivity). Later, convulsive syndrome and disorders of consciousness join.
The main danger of acute hyperammonemia is critical intoxication of the body, which ends in a comatose state and death. With a prolonged increase in the amount of ammonia to a level that does not cause critical neurological consequences, children experience a delay in psychomotor development, mental retardation. Against the background of citrullinemia, non-alcoholic fatty liver disease, intrahepatic cholestasis often occur.
The initial examination of the patient is carried out by a neonatologist, pediatrician or therapist, taking into account the age of symptoms. During the examination, typical clinical signs are taken into account, family history is carefully clarified, the presence of similar manifestations in close relatives. The following methods are used to make a diagnosis:
- Blood test. An increase in ammonia, citrulline and other nitrogenous compounds makes it possible to suspect citrullinemia. In the biochemical analysis, alkalosis is also determined. With concomitant liver dysfunction, an increase in the concentration of enzymes (ALT, AST, alkaline phosphatase), an increase in cholesterol levels is possible.
- Genetic testing. Molecular genetic analysis by fluorescent hybridization, genome sequencing are the main methods of diagnosis verification at the present stage. Detection of mutant genes ASS1 or SLC25A13 allows you to determine citrullinemia and its type with 100% accuracy.
- Ultrasound of the liver. Ultrasound diagnostics is performed when cholestasis, fatty organ dystrophy is suspected, especially in adolescents and adult patients with a long history of the disease. To clarify the diagnosis, noninvasive elastography, CT or MRI of the liver is prescribed.
- Prenatal diagnosis. If both parents have established the carrier of gene mutations, it is advisable to conduct a genetic study while carrying a child. Early detection of citrullinemia is important to plan the tactics of pregnancy management, to prevent possible complications.
Taking into account the genetic nature of the disease, etiotropic therapy methods have not been developed. Treatment of patients suffering from citrullinemia is aimed at reducing the level of nitrogenous compounds in organs, tissues, and blood in order to prevent fatal neurological complications and remove clinical symptoms of the disease. Therapy includes several directions, the main of which are:
- Dietary correction. Together with a nutritionist, a diet with a limited protein content is prescribed to reduce the nitrogen load. At the same time, the menu should be sufficient in calories, with a high level of carbohydrates to cover energy needs.
- Drug therapy. The intake of arginine and citrine, which are intermediates in the ornithine cycle, increases the rate of ammonia neutralization. Phenyl acetate or sodium benzoate is used to remove excess amounts of blood nitrogen.
- Liver transplantation. The help of transplant surgeons is recommended for patients with severe citrullinemia, when conservative measures do not give effect. After organ transplantation, the amount of ammonia decreases, exacerbations of citrullinemia occur less often.
Prognosis and prevention
In most cases, the disease is successfully amenable to therapy, proper treatment contributes to the rapid disappearance of symptoms. The prognosis is favorable, provided that the doctor’s recommendations are followed. Primary prevention consists in medical and genetic counseling before planning conception for people who have citrullinemia or are healthy carriers. Secondary prevention involves early detection of pathology, optimal drug correction.