Citrullinemia is an autosomal recessive inherited disorder caused by arginosuccinate synthetase deficiency, an enzyme involved in the urea cycle.
Prenatal diagnosis is possible but is available only at research centers. DNA testing is possible, using amniotic or chorionic villi sampling. No routine laboratory studies help in the diagnosis. Only when a metabolic disorder is suspected, due to the occurrence of symptoms, may the physician obtain serum ammonia levels that are diagnostic.
Symptoms of hyperammonemia include some or all of the following :
Children with citrullinemia demonstrate delayed development from infancy, including cognitive, gross-motor, and fine-motor impairments . The presence of these delays may be the only reason for the physician to suspect the disorder .
In patients with symptoms of citrullinemia, the measurement of blood ammonia levels is the primary laboratory test in diagnosis. No other routine studies provide useful information for diagnosis.
Magnetic resonance imaging (MRI) of the brain in affected infants, may show abnormalities which are not diagnostic , but may be helpful in predicting the extent of neurological complications .
The treatment of hyperammonemia is the primary intervention in citrullinemia. Intravenous sodium benzoate, sodium phenylacetate, and arginine are used to reduce blood ammonia levels. Intravenous benzoate and phenylacetate are still considered experimental drugs. They provide alternate pathways for nitrogen waste disposal. Benzoate forms hippuric acid, which is rapidly excreted by the kidney. Phenylacetate combines with glutamine to form phenylacetylglutamine, and is also more easily excreted in this form.
In severe cases, hemodialysis may be needed to rapidly reduce the blood ammonia level. Long-term management of citrullinemia requires strict dietary changes, low-protein and pyruvate diets, as well as oral administration of sodium phenylbutyrate and arginine. Referral to a nutritionist for monitoring and education in the low-protein diet is necessary. Frequent monitoring of blood amino acid levels is also important in order to insure that essential amino acid levels remain normal.
Gene-transfer may be a cure in the future. A partial correction of the enzyme defect has been seen in trials .
In the past, most patients were treated with medication and died of severe brain edema within a few years of onset. Currently, with appropriate treatment, survival is possible into adulthood. During the last decade a small number of patients have undergone liver transplantation with good results .
Patients who received living, partial liver transplantation had remission of the neurological symptoms . In patients without liver transplantation, approximately half died of encephalopathy or hepatic cancer . The other half of non-transplant patients had good clinical outcomes with treatment with medication (oral L-arginine) and low- protein diets .
The outcome of neonatal citrullinemia continues to be poor. Ammonia levels at diagnosis is the only indicator of prognosis . The higher the levels the more dire the prognosis.
The degree of cognitive delay in patients with citrullinemia is roughly equal to how severe the initial symptoms and the frequency of episodes of elevated ammonia levels .
Both parents of an affected infant are heterozygotes carriers of the trait because citrullinemia is an autosomal recessive disease. The probability of a subsequent child having the disease born of these parents is 1 in 4, or 25%. Genetic counseling is necessary for any family with a member with the disease.
Citrullinemia is an autosomal recessive genetic mutation of Chromosome 9. The two forms of the disease are actually two separate disorders because the mutations occur in different places on the chromosome .
Occurrence of the neonatal disorder depends on both parents having the defective gene and the probability of it being passed on to their children is 1 in 4.
Untreated neonatal citrullinemia is almost always fatal. However, morbidity from Citrullinemia type II is dictated by other genetic and environmental factors .
The incidence of citrullinemia is not known because it is such a rare disorder and also because screening is not currently routinely done. Mass screening for the adult-onset citrullinemia gene is done only in East Asia .
Morbidity and mortality rates are high, but again are unknown because of the lack of data.
Citrullinemia is inherited as an autosomal recessive trait, thus, both genders are equally affected.
The age of presentation can vary widely, although the most common presentation is in the neonatal period. Older children not treated in the neonatal period may be diagnosed later as part of an evaluation for the etiology of their mental retardation.
The urea cycle is responsible for the disposal of waste nitrogen from the body. Protein and amino acid metabolism result in the production of waste nitrogen. The genetic mutation found in citrullinemia blocks urea production and results in hyperammonemia. N -acetylglutamate, an enzyme activator , incorporates ammonia into the cycle .
This enzyme facilitates the combination of aspartic acid and citrulline to form argininosuccinic acid . The urea-cycle, therefore, promotes ammonia excretion. Disruption of the urea cycle results in the accumulation of ammonia in the body .
Mortality and morbidity from the disease are directly related to the concentration of ammonia in the body. The effect of hyperammonemia on the brain is the primary causes of injury, more so than cerebral edema . Elevated cerebral ammonia level is the cause of the cerebral edema. It also results in the accumulation of lactate, and the alteration in neurotransmission and nitric oxide synthesis .
Glucocorticoids, glucagon and insulin control the functioning of this mutant gene, both during fetal development and in later life . Protein and carbohydrate intake stimulates the activation of this argininosuccinic acid gene .
There are no guidelines for prevention of citrullinemia.
Citirullemia is a condition that results from a dysfunction of the urea cycle. The malfunction is a result of a mutation on chromosome 9 .
There are two forms of the disorder. Type I, neonatal Citirullemia, is an autosomal recessive defect which requires the inheritance of one gene mutation from each parent. Type II is the adult form of the disease and is due to a mutation on a different portion of chromosome 9. Type II Citirullemia occurs almost exclusively in Japan and the Far East .
The urea cycle is involved in the transformation of nitrogen and ammonia, the waste products of metabolism, into forms which can be excreted by the body. An interruption in the urea cycle results in the accumulation of ammonia and citrine in the body, causing cellular damage to multiple organs, but in particular the brain .
What is citrullinemia?
Citrullinemia is an inherited, metabolic disorder. It is caused by a genetic mutation on Chromosome 9 witch results in the malfunction of the urea cycle. The urea cycle is responsible for the conversion of nitrogen, a waste product of metabolism, into forms that can be easily excreted from the body. High levels of ammonia build up in the bloodstream.
The nervous system is particularly susceptible to the toxic effects of ammonia, causing swelling of the brain and interference with the transmission of electrical impulses throughout the nervous system.
There are two forms of citrullinemia. Neonatal citrullinemia, type I, is present at birth. Infants with this disorder are usually diagnosed in the new-born nursery. As ammonia builds up in the body they begin to have symptoms. They tend to be lethargic and feed poorly. Gradually the symptoms become more severe progressing to vomiting, seizures, and coma. If untreated the disorder is life-threatening and death ensues.
How common is citrullinemia?
Type I neonatal citrullinemia is rare, approximately 1 in 57,000 infants worldwide. Type II citrullinemia occurs almost exclusively in the Japan. Its incidence is estimated to be 1 in 230,000 Japanese. Type II also has been reported rarely in the Middle East.
How do people inherit citrullinemia?
Generally neither of the parents has the disease. The probability of two parents with the trait having a child with the disease is 1 in 4 or 25%. The probability of a family with one child with citrullinemia having another child with the disease is also 25%.
Genetic counseling is necessary for all families with a member who has been diagnosed with citrullinemia.
How is citrullinemia treated?
Citrullinemia is treated primarily with medications that reduce the ammonia levels by helping the body form other compounds with the excess nitrogen that are then excreted from the body.