Information on the following diseases can be found in the Related Disorders section of this report:

• Urea cycle disorders
• Organic Acidemias
• Reye Syndrome

The severity of citrullinemia varies from case to case. A severe form of the disorder, which is characterized by complete lack of the argininosuccinate synthetase enzyme, occurs shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the argininosuccinate synthetase enzyme, affects some infants later during infancy or childhood. A late-onset form, which occurs in adults, has also been identified.

The symptoms of citrullinemia are caused by the accumulation of ammonia in the blood. The severe form of citrullinemia occurs within 24-72 hours after birth, usually following a protein feeding. This form of citrullinemia 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, the accumulation of fluid in the brain (cerebral edema), and an abnormally large liver (hepatomegaly).

In some cases, citrullinemia may progress to coma due to high levels of ammonia in the blood (hyperammonemic coma). In such cases, the disorder may potentially result in neurological abnormalities including developmental delays, mental retardation, and cerebral palsy. The severity of such neurological abnormalities is more severe in infants who are in hyperammonemic coma for more than three days. If left untreated, the disorder will result in life-threatening complications.

In infants 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, vomiting, and/or dry brittle hair. Infants with the mild form of citrullinemia may alternate between periods of wellness and hyperammonemia. Infants and children with this form of citrullinemia may also develop hyperammonemic coma and life-threatening complications.

Another form of citrullinemia that occurs later during life has also been reported in the medical literature. This form of the disorder is often referred to as adult onset citrullinemia. Affected individuals may experience repeated episodes of vomiting, lethargy, seizures, confusion, hallucinations, and potentially coma. As affected individuals age, they often experience such episodes more frequently. Behavioral changes may also occur including manic episodes and psychosis. Affected individuals may also have accumulation of fluid in the brain (cerebral edema).
.

Citrullinemia is inherited an autosomal recessive trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait 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 of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

The classic form of citrullinemia may be caused by disruption or changes (mutations) of the gene regulating the production of the enzyme argininosuccinate synthetase. Investigators have determined that the gene is located on the long arm (q) of chromosome 9 (9q34). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 9q34" refers to band 34 on the long arm of chromosome 9.

Adult onset citrullinemia (citrullinemia type II) may be caused by disruption or changes (mutations) of a gene located on the long arm (q) of chromosome 7 (7q21).

The symptoms of citullinemia develop due to the lack of the enzyme argininosuccinate synthetase, which is needed to break down nitrogen in the body. Failure to properly breakdown nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia).
.

Citrullinemia is a rare disorder affecting fewer than 1,000 people in the United States. The estimated frequency of citrullinemia is one in 250,000 births. Males and females are affected in equal numbers. Onset of the symptoms usually occurs at birth or during the first few years of life. The adult-onset form of citrullinemia occurs most often in Japan with an estimated frequency of one in 100,000.

The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like citrullinemia often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.
.

Symptoms of the following disorders may be similar to those of citrullinemia. Comparisons may be useful for a differential diagnosis:

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, intolerance to protein, and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some cases. In severe cases, life-threatening complications often result. In addition to citrullinemia, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)

Reye syndrome is a rare childhood disorder characterized by liver failure, abnormal brain function (encephalopathy), abnormally low levels of glucose (hypoglycemia), and high levels of ammonia in the blood. This disorder usually follows a viral infection. It may be triggered by the use of aspirin in children recovering from chicken pox or influenza. Deficiencies of the urea cycle enzymes are thought to play a role in the development of Reye syndrome. Symptoms include vomiting, diarrhea, rapid breathing, irritability, fatigue, and behavioral changes. Neurological symptoms may be life-threatening and include seizures, stupor, and coma. (For more information on this disorder, choose "Reye" as your search term in the Rare Disease Database.)

Organic acidemias are a rare group of inherited metabolic disorders characterized by deficiency of certain enzymes that are necessary to break down (metabolize) chemical “building blocks” (amino acids) of certain proteins. Failure to break down amino acids results in the excessive accumulation of acids in the blood. Symptoms may include abnormally diminished muscle tone (hypotonia), poor feeding, vomiting, lethargy, and seizures. If left untreated, organic acidemias may progress to coma and life-threatening complications. These disorders are of a genetic origin and affect the urea cycle as a secondary phenomenon.

Diagnosis
A diagnosis of a urea cycle disorder, such as citrullinemia, should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.

A diagnosis of citrullinemia can be confirmed by a detailed patient/family history, identification of characteristic findings, and a variety of specialized tests. Blood tests may reveal excessive amounts of ammonia in the blood, which is the main criterion for a diagnosis of urea cycles disorders including citrullinemia. However, high levels of ammonia in the blood may characterize other disorders such as the organic acidemias, congenital lactic acidosis, and fatty acid oxidation disorders. Urea cycles disorders can be differentiated from these disorders through the examination of urine for elevated levels of or abnormal organic acids. In urea cycle disorders, urinary organic acids are normal.

Treatment
Treatment of an individual with citrullinemia may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment.

The treatment of citrullinemia is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for citrullinemia combines dietary restrictions and the stimulation of alternative methods of converting and excreting nitrogen from the body (alternative pathways therapy).

Dietary restrictions in individuals with citrullinemia 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 with citrullinemia 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 (e.g., UCD-1 Ross, or Cyclinex, Mead Johnson), and a calorie supplement without protein is often used (e.g., MJ80056, Mead Johnson;x).

In addition to dietary restrictions, individuals with citrullinemia are treated by medications that stimulate the removal of nitrogen from the body. These medications provide an alternative method to the urea cycle in converting and removing nitrogen waste. These medications are unpalatable and often administered via a tube that is placed in the stomach through the abdominal wall (gastrostomy tube) or a narrow tube that reaches the stomach via the nose (nasogastric tube).

The orphan drug sodium phenylbutyrate (Buphenyl) has been approved by the Food and Drug Administration (FDA) for the treatment of urea cycle disorders. This drug does not have an offensive odor that is associated with other similar drugs. Buphenyl is manufactured by Ucyclyd Pharma.

Individuals with citrullinemia benefit from treatment with arginine, which are needed in order to maintain a normal rate of protein breakdown (synthesis). Multiple vitamins and calcium supplements may also be used in the treatment of citrullinemia.

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.

Aggressive treatment including hospitalization and complete 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 wastes 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 citrullinemia during hyperammonemic coma.

Preventive Care
After diagnosis of citrullinemia, steps can be taken to anticipate the onset of a hyperammonemic episode. Affected individuals should receive periodic blood tests to determine the levels of ammonia in the blood. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear.
.

In some individuals with citrullinemia who do not respond to drug therapy, liver transplantation may be considered. Initial studies have shown that liver transplants have resulted in the correction of metabolic abnormalities allowing for normal urea formation and protein intake. More research is needed to determine the long-term safety and effectiveness of this procedure for the most severe cases of citrullinemia.

Enzyme replacement therapy shows potential promise for treatment of urea cycle disorders including citrullinemia. Research on this type of therapy is in a preliminary stage. More research is necessary to determine the long-term safety and effectiveness of this treatment for CPS deficiency.

For information regarding clinical studies under way at Vanderbilt University Medical Center, please contact:

Dr. Marshall L. Summar
Department of Medical Genetics
Vanderbilt University Medical School
Nashville, TN 37232
Tel: (615) 322-7601

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).
.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:215700, Last Update:5/26/99; Entry No:603471, Last Update:1/18/01.

TEXTBOOKS
Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:935-37.

Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:350-55.

Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:12-14.

Menkes JH, au., Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995:46-52.

Urea Cycle Disorders. In: Gellis and Kagan (Eds.), Current Pediatric Therapy, 17th Ed., WB Saunders and Co.

JOURNAL ARTICLES
Lee B, et al. Long-term outcome of urea cycle disorders. J Pediatr. 2000;138:S-62-S71.

Yasuda L, et al. Identification of two novel mutations in the SLC25A13 gene and detection of seven mutations in 102 patients with adult-onset type II citrullinemia. Hum Genet. 2000;107:537-45.

Tsuboi Y, et al. Liver transplantation in type II citrullinemia. Rinsho Sinkeigaku. 1999;39:1049-53.

Kobayashi K, et al. Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia. Hum Genet. 1995;96:454-63.

Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. 1994;35:133-41.

Inui Y, et al. Impaired ketogenesis in patients with adult-type citrullinemia. Gastroenterology. 1994;107:1154-61.

Brusilow SW. Disorders of the urea cycle. Hosp Prac. 1985;305:65-72.