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Last updated: 05/11/2023
Years published: 1986, 1987, 1990, 1993, 1996, 1997, 2001, 2002, 2016, 2019, 2023
NORD gratefully acknowledges Brendan Lee, M.D., Ph.D., Robert and Janice McNair Endowed Chair in Molecular and Human Genetics, Professor and Chairman, Department of Molecular and Human Genetics, Baylor College of Medicine for assistance in the preparation of this report.
Summary
Argininosuccinic aciduria is a rare genetic disorder characterized by deficiency or lack of the enzyme argininosuccinate lyase (ASL). This enzyme 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 argininosuccinate lyase results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Ammonia is a neurotoxin, which means that it damages or inhibits the function of neurons, the cells of the central nervous system. Excess ammonia travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with the disorder. Affected infants may experience vomiting, refusal to eat, progressive lethargy and coma. Argininosuccinic aciduria is inherited in an autosomal recessive pattern. Symptoms unrelated to high ammonia may occur in some patients because of additional roles of this enzyme in the body.
Introduction
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 and specific symptoms of argininosuccinic aciduria varies from one person to another. A severe form of the disorder, which is characterized by a complete or near 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 individuals later during infancy or childhood or even adulthood (late-onset form).
Symptoms are caused by the accumulation of ammonia in the blood. The severe form occurs within 24-72 hours after birth, usually following a protein feeding. This form is initially characterized by a refusal to eat, lethargy, lack of appetite, vomiting and irritability. Affected infants may also experience seizures, breathing (respiratory) abnormalities, accumulation of fluid in the brain (cerebral edema) and an abnormally large liver (hepatomegaly). Less commonly, some individuals develop progressive liver disease and dysfunction such as the buildup of scar tissue (fibrosis) and cirrhosis. In rare instances, chronic kidney (renal) disease has been reported. Abnormally rapid breathing (tachypnea) may be detected and sometimes is the first sign recognized of elevated ammonia in the blood. As affected individuals grow older, they may have coarse and brittle (friable) hair that breaks off easily and can leave patches of hair loss, a condition known as trichorrhexis nodosa.
In some patients, due to high levels of ammonia in the blood (hyperammonemic coma), the disorder may progress to coma. In these patients, argininosuccinic aciduria may potentially result in neurological abnormalities including delays in reaching developmental milestones (developmental delays) and intellectual disability. 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. However, even individuals without significant hyperammonemia may develop neurological abnormalities suggesting alternative causes of injury.
In infants with partial enzyme deficiency, onset of the disorder may not occur until later during infancy or childhood (late onset form). 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. Some individuals with the late onset form may not develop any symptoms (asymptomatic).
Infants with the mild form may alternate between periods of wellness and hyperammonemia. Episodes of hyperammonemia are usually triggered by acute infection, stress, certain medications or not following the recommended dietary restrictions (e.g., high protein intake or also insufficient, too low protein intake). Other individuals with the mild form may not have any documented episodes of hyperammonemia but can still develop behavioral abnormalities such as attention deficit/hyperactivity disorder, cognitive impairment and learning disabilities.
Both the severe and late-onset forms of argininosuccinic aciduria can be associated with long-term complications including liver dysfunction, neurocognitive deficits such as cognitive impairment, seizures, brittle hair and high blood pressure (hypertension). These long-term complications appear to be unrelated to the frequency, length or severity of episodes of hyperammonemia. Increasingly, high blood pressure has been diagnosed in some but not all children and adults with this condition. This may be due to an inability of the body to generate a chemical called nitric oxide.
Argininosuccinic aciduria is caused by changes (pathogenic variants or mutations) in the ASL gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.
Symptoms of argininosuccinic aciduria develop due to the near complete or partial lack of the enzyme argininosuccinate lyase. The ASL gene is responsible for regulating the production of this enzyme. Alterations in the ASL gene lead to low levels of functional 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).
Researchers have determined that argininosuccinic aciduria is a more complex metabolic disorder than originally suspected. Affected individuals have developed some of the long-term complications described above (e.g., liver disease, hypertension, neurocognitive issues) despite not having any episodes of hyperammonemia and having an overall good metabolic profile. Researchers theorize that the deficient enzyme, argininosuccinate lyase, may have more roles in the body other than breaking down nitrogen (i.e., its role in the urea cycle) including the production of nitric oxide. More research is necessary to fully understand the complex, underlying mechanisms of argininosuccinic aciduria.
Argininosuccinic aciduria is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits 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 altered gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
Argininosuccinic aciduria is a rare disorder that affects fewer than a thousand people in the United States. It is estimated to affect anywhere between approximately one in 70,000 to 1 in 218,000 live births. 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 children, onset of symptoms may not occur until later during infancy or childhood.
The estimated frequency of urea cycle disorders collectively is approximately 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. All 50 states in the U.S. include argininosuccinic aciduria in newborn screening programs.
A diagnosis of argininosuccinic aciduria can be made through 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. Blood tests may also reveal high levels of an amino acid called citrulline. However, high levels of ammonia or citrulline in the blood may characterize other disorders such as organic acidemias, congenital lactic acidosis and fatty acid oxidation disorders and are also present in other urea cycle disorders.
A diagnosis can be confirmed by identifying elevated levels of argininosuccinic acid in blood or urine samples. A diagnosis can also be confirmed by molecular genetic testing, which detects the gene alteration that causes the disorder.
Treatment
Treatment 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.
Genetic counseling is recommended for affected individuals and their families.
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 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 on 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 cowโs 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).
Individuals with argininosuccinic aciduria benefit from treatment with arginine, which helps to promote the excretion of nitrogen (in the form of increased argininosuccinic acid production). Arginine supplementation has shown benefits in improving or reversing changes to the hair, but its impact on the long-term, chronic complications of the disorder are not fully understood. The dose of arginine is often higher than is used in other forms of urea cycle disorder and it is effective in decreasing ammonia in emergent situations of elevated ammonia. However, chronic treatment with high doses of arginine may contribute to liver disease as it produces higher levels of argininosuccinic acid. Therefore, in individuals with liver disease, lower doses should be considered for long term treatment. In this situation, other medications like alternative pathway therapies may be needed. The dose of arginine can be increased during illnesses to clear excess nitrogen and thereby reduce risk of high ammonia. Multiple vitamins, vitamin D, and calcium supplements may also be used in the treatment of argininosuccinic aciduria as some patients may suffer from osteoporosis or low bone mass. This and other systemic complications like high blood pressure may be caused by decreased production of nitric oxide in patients with argininosuccinic aciduria, the addition of low protein foods rich in nitrite and/or supplementation of nutraceuticals that provide nitrite as an independent source may be helpful, although there are no definitive clinical trials that prove this.
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 individuals, especially those with complete enzyme deficiency, prompt treatment will not prevent recurrent episodes of hyperammonemia and the potential development of serious complications.
In some patients, despite early treatment and good metabolic control, affected individuals may develop certain symptoms such as neurocognitive deficiencies, behavior issues such as ADHD, developmental disability and seizures.
In addition to dietary restrictions and supplements, 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. This is known as alternative pathway therapy or nitrogen scavenging therapy. This includes sodium benzoate, sodium phenylbutyrate, and glycerol triphenylbutyrate.
In 2013, the U.S. Food and Drug Administration (FDA) approved Ravicti (glycerol phenylbutyrate) for the chronic management of urea cycle disorders including argininosuccinic aciduria in affected individuals aged 2 years and older. Ravicti is a liquid therapy that helps to remove ammonia from the body. Ravicti is used in individuals whose disease cannot be managed through a low-protein diet and dietary supplements alone.
In 1996, the FDA approved Buphenyl (sodium phenylbutyrate) for chronic management of urea cycle disorders including argininosuccinic aciduria. Buphenyl is a powder therapy that helps to remove ammonia from the body. A generic form of Buphenyl is also now available.
Sodium benzoate is a powder that is not FDA approved for treatment urea cycle disorders, but it has been used in chronic treatment of urea cycle disorders. It is not believed to be as effective as Buphenyl or Ravicti based on theoretical considerations, though this has never been tested in patients. A combination of sodium benzoate and phenylbutyrate has been used in some patients who may have problems tolerating the latter but the clinical effectiveness of this combined approach vs. phenylbutyrate alone is unknown.
In 2005, the FDA approved the use Ammonul (sodium benzoate and sodium phenylacetate) as an intravenous, rescue therapy for the prevention and treatment of hyperammonemia and associated disease of the brain (encephalopathy) in individuals with urea cycle disorders. This is only used in a hospitalized setting.
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. As mentioned above, a patient who has been treated on a chronic lower dose of arginine can be given a higher dose during illness either orally (with arginine base) or intravenously (with arginine hydrochloride).
In individuals where there is no improvement or where hyperammonemic coma develops, the removal of wastes by filtering an affected individualโs 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.
In some individuals, a liver transplant may be recommended. This is an option of last resort for specific individuals who have progressive liver disease, experience recurrent medical crises and hospitalizations despite therapy, or who have a poor quality of life.
Preventive Care
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 and amino acids in the blood. Detection of elevated levels of ammonia may allow treatment before clinical symptoms appear. Monitoring for complications such as high blood pressure, liver inflammation and fibrosis and developmental delay should be closely monitored from the time of diagnosis.
Researchers have studied nitric oxide supplementation for the treatment of certain long-term complications associated with argininosuccinic aciduria. Affected individuals have a deficiency of nitric oxide, a naturally occurring compound in humans. Nitric oxide has several roles in the body. Initial reports of nitric oxide supplementation for individuals with argininosuccinic aciduria has led to a resolution in hypertension and improvement in other neurocognitive issues. So far, only a small number of individuals have been treated with nitric oxide supplementation. More research is necessary including appropriate clinical trials to determine the long-term safety and effectiveness of this potential therapy for individuals with argininosuccinic aciduria.
Enzyme replacement therapy and gene therapy have shown potential promise for treatment of metabolic disorders such as urea cycle disorders. Similarly, liver-directed gene therapy and mRNA replacement therapy are also being studied. Research on these types of therapy is being explored for urea cycle disorders including argininosuccinic aciduria. More research is necessary to determine the long-term safety and effectiveness of these treatments.
Cell therapy with infusion of hepatocytes and/or hepatocyte stem cells have been tried primarily in a safety setting.
Information on current clinical trials is posted on the Internet at https://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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Menkes JH, Sarnat HB, Maria BL. Eds. Textbook of Child Neurology. 7th ed. Williams & Wilkins. Baltimore, MD; 1995:47-48.
Mian AI, Lee B. Urea Cycle Disorders. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:505.
JOURNAL ARTICLES
Kho J, Tian X, Wong WT, et al. Argininosuccinate lyase deficiency causes an endothelial-dependent form of hypertension. Am J Hum Genet. 2018 Aug 2;103(2):276-287. https://www.ncbi.nlm.nih.gov/pubmed/30075114
Kolker S, Cazorla AG, Valayannopoulos V, et al. The phenotypic spectrum of organic acidemias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. 2015;38:1041-1057. https://www.ncbi.nlm.nih.gov/pubmed/25875215
Kolker S, Valayannopoulos V, Burlina AB, et al. The phenotypic spectrum of organic acidemias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. 2015;38:1059-1074. https://www.ncbi.nlm.nih.gov/pubmed/25875216
Erez A. Argininosuccinic aciduria: from a monogenic to a complex disorder. Genet Med. 2013;15:251-57. https://www.ncbi.nlm.nih.gov/pubmed/23306800
Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013;110:179-80. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364413/
Nagamani SCS, Campeau PM, Shchelochkov OA, et al. Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet. 2012;90:836-846. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376491/
Haberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488504/
Nagamani CS, Lee B, Erez A. Optimizing therapy for argininosuccinic aciduria. Mol Genet Metab. 2012;107:10-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444682/
Nagamani SCS, Erez A, Lee B. Argininosuccinate lyase deficiency. Genet Med. 2012;14:501-507. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709024/
Erez A, Nagamani SCS, Lee B. Argininosuccinate lyase deficiency. Am J Med Genet C Semin Med Genet. 2011;157:45-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073162/
Erez A, Nagamani SCS, Shchelochkov OA, et al. Requirement of argininosuccinic lyase for systemic nitric oxide production. Nat Med. 2011;17:1619-1626. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348956/
Newnham T, Hardikar W, Allen K, et al. Liver transplantation for argininosuccinic aciduria: clinical, biochemical and metabolic outcome. Liver Transpl. 2008;14:41-45. https://www.ncbi.nlm.nih.gov/pubmed/18161830
Smith W, Kishnani PS, Lee B, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005;21:S9-17. https://www.ncbi.nlm.nih.gov/pubmed/16227115
Lee B, Goss J. Long-term outcome of urea cycle disorders. J Pediatr. 2001;138:S-62-S71. https://www.ncbi.nlm.nih.gov/pubmed/11148551
Kamoun P, Fensom AH, Shin YS, et al. Prenatal diagnosis of urea cycle diseases: a survey of European cases. Am J Med Genet. 1995;55:247-50. https://www.ncbi.nlm.nih.gov/pubmed/7717428
Batshaw ML. Inborn errors of urea synthesis. Ann Neurol. 1994;35:133-41. https://www.ncbi.nlm.nih.gov/pubmed/7906500
Widhalm K, Koch S, Scheibenreiter S, et al. Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics. 1992;89:1182-84. https://www.ncbi.nlm.nih.gov/pubmed/1594374
Walker DC, McCloskey DA, Simard LR, McInnes RR. Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. Proc Natl Acad Sci USA. 1990;87:9625-29. https://www.ncbi.nlm.nih.gov/pubmed/2263616
Brusilow SW. Disorders of the urea cycle. Hosp Prac. 1985;305:65-72. https://www.ncbi.nlm.nih.gov/pubmed/3930543
INTERNET
Nagamani SCS, Erez A, Lee B. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [Updated 2019 Mar 28]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK51784/ Accessed April 17, 2023.
Haberle J. Argininosuccinic Aciduria. Orphanet Encyclopedia, November 2019. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=23 Accessed April 17, 2023.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:207900; Last Update: 11/22/2021. Available at: https://omim.org/entry/207900 Accessed April 17, 2023.
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