NORD gratefully acknowledges Jess G. Thoene, MD, Director, Biochemical Genetics Laboratory, Active Professor Emeritus of Pediatrics, University of Michigan, for assistance in the preparation of this report.
Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy, and an asymptomatic form.
CTLN1 is caused by deficiency or absence of the enzyme argininosuccinate synthetase (ASS). ASS is one of six enzymes that play a role in the removal of nitrogen from the body, a process known as the urea cycle. The lack of this enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood and all body fluids.
Infants with the classic form may experience vomiting, refusal to eat, progressive lethargy, and show signs of increased intracranial pressure. Prompt treatment can prolong survival, but neurologic deficits are usually present. The course of the late-onset form is sometimes milder but episodes of hyperammonemia are similar to the classic form.
The severity of CTLN1 varies from patient to patient. The classic form, characterized by profound lack of ASS enzyme activity, displays symptoms shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASS enzyme, affects some infants later during infancy or childhood.
The symptoms of CTLN1 are caused by the accumulation of ammonia in the blood and cerebrospinal fluid (CSF). The classic form occurs within 24-72 hours after birth, usually following a protein feeding and is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Affected infants may also experience seizures, diminished muscle tone (hypotonia), respiratory distress, accumulation of fluid in the brain (cerebral edema), and an abnormally large liver (hepatomegaly).
If untreated, CTLN1 may progress to coma due to high levels of ammonia in the CSF (hyperammonemic coma). Neurological abnormalities including developmental delays, intellectual disability, and cerebral palsy may occur and are more severe in infants who are in hyperammonemic coma for more than three days. Increased intracranial pressure can result in increased muscle tone, spasticity, abnormal reflex movements of the foot (ankle clonus), and seizures. If left untreated, the disorder will result in life-threatening complications.
In some patients, including those with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood. Symptoms may include failure to grow and gain weight at the expected rate (failure to thrive), avoidance of high-protein foods from the diet, inability to coordinate voluntary movements (ataxia), progressive lethargy, and vomiting. Infants with the mild form may alternate between periods of wellness and hyperammonemia. Infants and children with this form of CTLN1 may also develop hyperammonemic coma and life-threatening complications.
Another form of CTLN1 occurs during and after pregnancy. Affected women may experience repeated episodes of vomiting, lethargy, seizures, confusion, hallucinations, and potentially coma. Behavioral changes may also occur including manic episodes and psychosis. Affected women may also have accumulation of fluid in the brain (cerebral edema).
Some individuals with CTLN1 do not experience symptoms or hyperammonemia. The basis for these milder variants is not established.
CTLN1 is caused by mutations in the ASS1 gene that is responsible for production of the argininosuccinate synthetase (ASS) enzyme. The symptoms of CTLN1 develop due to deficiency of this enzyme, which is needed to detoxify ammonia in the body. Failure to properly remove ammonia via synthesis of urea leads to the abnormal accumulation of ammonia in the blood (hyperammonemia).
CTLN1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
A diagnosis of citrullinemia can be confirmed by a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Excessive amounts of ammonia and citrulline in the blood strongly suggests the diagnosis of CTLN1. Molecular genetic testing for ASS1 gene mutations is available to confirm the diagnosis.
CTLN1 may also be diagnosed through newborn screening programs. Citrulline can be measured on the newborn blood spot by tandem mass spectroscopy. Every state in the U.S. screens every newborn for CTLN1. Early detection is important because prompt identification and treatment may prevent the hyperamonnemia that causes brain damage.
Carrier testing and prenatal diagnosis are available if the specific gene-causing mutation has been identified in the family.
Siblings of an affected child should be tested immediately after birth and those with elevated ammonia or citrulline should receive a low protein diet.
Treatment of an individual with CTLN1 requires the coordinated efforts of a team of specialists. Biochemical geneticists, pediatricians, neurologists, and dieticians, are needed to work together to ensure a comprehensive approach to treatment. Management involves prompt diagnosis, control of hyperammonemia and control of intracranial pressure.
Prompt treatment is necessary when individuals have extremely high ammonia levels (severe hyperammonemic episode). Prompt treatment can avoid hyperammonemic coma and associated neurological symptoms. However, in some cases, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.
The treatment of CTLN1 is aimed at preventing excessive ammonia from being formed or for removing excessive ammonia during a hyperammonemic episode. Medications that assist in the removal of nitrogen from the body by providing an alternative means of waste nitrogen removal are employed. Available medications are Buphenyl, Ammonul, and Raviciti, as well as arginine.
Dietary restrictions are aimed at limiting the amount of protein intake to avoid the development of excess ammonia. However, enough protein must be taken in by an affected infant to ensure proper growth. Infants are placed a low protein, high calorie diet supplemented by essential amino acids. A combination of a high biological value natural protein such as breast milk or cow’s milk formulate, an essential amino acid formula, and a calorie supplement without protein is often used.
Multiple vitamins and calcium supplements may also be used.
Aggressive treatment including hospitalization and protein restriction is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may also receive treatment with intravenous administration of arginine and a combination of sodium benzoate and sodium phenylacetate. Non-protein calories may be also provided as glucose.
In cases where there is no improvement or in cases where hyperammonemic coma develops, the removal of ammonia by filtering an affected individual’s blood through a machine (hemodialysis) may be necessary. Hemodialysis is also used to treat infants, children, and adults who are first diagnosed with CTLN1 during hyperammonemic coma.
Affected children should be monitored to prevent increased intracranial pressure and to anticipate the onset of a hyperammonemic episode. Warning signs include mood changes, headaches, lethargy, nausea, vomiting, refusal to eat, and ankle clonus. Affected individuals should receive periodic blood tests to determine the level of ammonia in the blood and to determine the concentration of plasma amino acids to assist in the management of the protein restricted diet. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear.
Liver transplantation has been reported to improve quality of life and prolong survival in some patients.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
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Contact for additional information about this condition:
Jess G. Thoene, MD
Active Professor Emeritus of Pediatrics
3732 Medical Sciences Building II Box 5629
1150 West Medical Center Drive
University of Michigan
Ann Arbor, MI
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