Argininosuccinic aciduria is a rare inherited disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL). Argininosuccinate lyase is one of six enzymes that play a role in the breakdown and 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. Affected infants may experience vomiting, refusal to eat, progressive lethargy, and coma. Argininosuccinic aciduria is inherited as an autosomal recessive trait.
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. Failure to break down nitrogen results in the abnormal accumulation of nitrogen, in the form of ammonia, in the blood.
The severity of argininosuccinic aciduria varies from case to case. A severe form of the disorder, which is characterized by complete lack of the ASL enzyme, occurs shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASL enzyme, affects some infants later during infancy or childhood. A late-onset form, which occurs in adults, has also been identified.
The symptoms of argininosuccinic aciduria are caused by the accumulation of ammonia in the blood. The severe form of argininosuccinic aciduria occurs within 24-72 hours after birth, usually following a protein feeding. This form of argininosuccinic aciduria is initially characterized by refusal to eat, lethargy, lack of appetite, vomiting, and irritability. Affected infants may also experience seizures, respiratory abnormalities, the accumulation of fluid in the brain (cerebral edema), and an abnormally large liver (hepatomegaly).
In some cases, argininosuccinic aciduria 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 and mental retardation. 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 protein from the diet, inability to coordinate voluntary movements (ataxia), lethargy, and vomiting. Affected infants and children may also have dry, brittle hair that may result in scattered patches of hair loss (alopecia).
Infants with the mild form of argininosuccinic aciduria may alternate between periods of wellness and hyperammonemia. Infants and children with this form of the disorder may also develop hyperammonemic coma and life-threatening complications.
Argininosuccinic aciduria is inherited as 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 gene that is responsible for regulating the production of the enzyme involved in argininosuccinic aciduria is thought to be located on the long arm (q) of chromosome 7 (7cen-7q11.2). 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.”
The symptoms of argininosuccinic aciduria develop due to the lack of the enzyme argininosuccinate lyase, which is needed to break down nitrogen in the body. Failure to properly break down nitrogen leads to the abnormal accumulation of nitrogen, in the form of ammonia, in the blood (hyperammonemia).
Argininosuccinic aciduria is a rare disorder that occurs in approximately one in 70,000 live births and affects fewer than a thousand people in the United States. Males and females are affected in equal numbers. Onset of symptoms usually occurs at birth, but may not be noticeable for days or weeks. In some cases, onset of symptoms may not occur until later during infancy or childhood.
The estimated frequency of urea cycle disorders collectively is one in 30,000. However, because urea cycle disorders like argininosuccinic aciduria often go unrecognized, these disorders are under-diagnosed, making it difficult to determine their true frequency in the general population.
A diagnosis of a urea cycle disorder, such as argininosuccinic aciduria, should be considered in any newborn that has an undiagnosed illness characterized by vomiting, progressive lethargy, and irritability.
A diagnosis of argininosuccinic aciduria 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 argininosuccinic aciduria. 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 of an individual with argininosuccinic aciduria may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, geneticists, dieticians, and physicians who are familiar with metabolic disorders may need to work together to ensure a comprehensive approach to treatment. Occupational, speech language, and physical therapists may be needed to treat children with developmental disabilities.
The treatment of argininosuccinic aciduria is aimed at preventing excessive ammonia from being formed or from removing excessive ammonia during a hyperammonemic episode. Long-term therapy for argininosuccinic aciduria 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 argininosuccinic aciduria 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 argininosuccinic aciduria 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).
In addition to dietary restrictions, individuals with argininosuccinic aciduria 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 argininosuccinic aciduria 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 Argininosuccinic aciduria.
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 FDA has approved the marketing and use of the orphan drug(s) benzoate and phenylacetate for adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy due to, among others, argininosuccinic aciduria (Argininosuccinate synthetase deficiency).
This combination of drugs is manufactured by:
B. Braun Medical Inc.
2525 McGaw Avenue
P.O. Box 19791
Irvine, C. 92623
Aggressive treatment is needed in hyperammonemic episodes that have progressed to vomiting and increased lethargy. Affected individuals may be hospitalized and protein may be completely eliminated from the diet for 24 hours. 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 argininosuccinic aciduria during hyperammonemic coma.
After diagnosis of argininosuccinic aciduria, 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.
Enzyme replacement therapy shows potential promise for treatment of urea cycle disorders including argininosuccinic aciduria. 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 argininosuccinic aciduria.
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
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
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
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; 1996:350-35.
Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:12-4.
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.
Lee B, et al. Long-term outcome of urea cycle disorders. J Pediatr. 2000;138:S-62-S71.
Kamoun P, et al. Prenatal diagnosis of urea cycle diseases: a survey of European cases. Am J Med Genet. 1995;55:247-50.
Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. 1994;35:133-41.
Widhalm K, et al. Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lysase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics. 1992;89:1182-84.
Walker DC, et al. Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc Natl Acad Sci USA. 1990;87:9625-29.
Brusilow SW, Disorders of the urea cycle. Hosp Prac. 1985;305:65-72.
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McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:207900; Last Update:9/2/99.