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.
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 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 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, the 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 instances, due to high levels of ammonia in the blood (hyperammonemic coma), the disorder may progress to coma. In such instances, 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 non-compliance with the recommended dietary restrictions (e.g. high 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 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 alterations (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 particular 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.
The alteration in the ASL gene 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 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 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 the 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 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 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).
Individuals with argininosuccinic aciduria benefit from treatment with arginine, which helps to promote the excretion of nitrogen. 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. Multiple vitamins and calcium supplements may also be used in the treatment of argininosuccinic aciduria. Finally, because of decreased production of nitric oxide in patients with argininosuccinic aciduria, the addition of low protein foods rich in nitrite may be helpful.
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 instances, 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 age 2 years and older. Ravicti is a liquid therapy that helps to remove ammonia from the body. Ravicti is used in individuals who cannot management the disorder 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.
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.
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 individuals where there is no improvement or 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.
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.
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. 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 the urea cycle disorders. Similarly, liver-directed gene therapy and mRNA replacement therapy are also being studied. Research on these types of therapy are being explored for urea cycle disorders including argininosuccinic aciduria. More research is necessary to determine the long-term safety and effectiveness of these treatments.
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