Argininosuccinic aciduria (ASA) is a rare inherited disorder that impacts the body’s ability to process and remove nitrogenous waste. It falls under a group of conditions known as urea cycle disorders. This metabolic condition leads to the accumulation of a toxic substance called ammonia in the bloodstream.
The Genetic Cause and Urea Cycle Disruption
The body constantly processes proteins, which are broken down into amino acids, producing ammonia as a byproduct. The urea cycle is a series of biochemical reactions primarily occurring in the liver that converts this toxic ammonia into urea, a non-toxic substance that can be safely excreted through urine.
Argininosuccinic aciduria specifically arises from a deficiency of the enzyme argininosuccinate lyase (ASL). This enzyme is one of six involved in the urea cycle, and its absence or malfunction disrupts the cycle’s ability to convert argininosuccinic acid into arginine and fumarate.
The deficiency of the ASL enzyme is caused by specific changes, or mutations, within the ASL gene. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit a non-working ASL gene copy from each parent. Parents who carry one copy typically show no symptoms but can pass the gene to their children.
Signs and Symptoms
The presentation of argininosuccinic aciduria can vary, with symptoms generally categorized into two main forms based on their onset. The severe, neonatal-onset form typically manifests within the first few days of life. Infants may show signs such as poor feeding, frequent vomiting, excessive sleepiness (lethargy), and rapid breathing.
If left unaddressed, these initial symptoms can progress to more severe neurological issues. This includes seizures and, in advanced cases, a coma, due to the toxic effects of high ammonia levels on the brain.
A later-onset form of argininosuccinic aciduria also exists, which can present with a broader range of less severe, chronic symptoms. Children with this form may experience developmental delays, learning disabilities, and behavioral abnormalities. Physical signs can include brittle hair, medically known as trichorrhexis nodosa, and potential liver dysfunction or enlargement. The severity of symptoms in all forms of ASA is directly influenced by the extent of ammonia elevation in the blood, known as hyperammonemia.
Diagnosis and Newborn Screening
Identifying argininosuccinic aciduria often begins with newborn screening programs, which are implemented in many regions. These programs involve testing a dried blood spot collected from the infant, typically within a few days of birth. The screening aims to detect elevated levels of specific amino acids, such as citrulline and argininosuccinic acid, which can indicate a urea cycle disorder like ASA.
An abnormal newborn screening result prompts immediate further diagnostic testing to confirm the presence of the disorder. One of the first steps involves a plasma ammonia test to measure the concentration of ammonia in the blood, checking for hyperammonemia. A plasma amino acid analysis is also performed, which will reveal distinctly elevated levels of citrulline and, most tellingly, argininosuccinic acid.
To definitively confirm the diagnosis, genetic testing is conducted to identify specific mutations in the ASL gene. This genetic analysis provides conclusive evidence of argininosuccinic aciduria, distinguishing it from other metabolic conditions. The comprehensive diagnostic approach ensures an accurate identification of the disorder, allowing for timely management.
Management and Treatment Strategies
Managing argininosuccinic aciduria is a lifelong process focused on preventing ammonia buildup and mitigating its effects. A primary aspect of treatment involves strict dietary management, which includes a controlled low-protein diet. This dietary restriction minimizes the production of ammonia from protein breakdown, and special medical formulas may be used to provide necessary nutrients without excessive protein.
Another important component of treatment involves medication, specifically nitrogen-scavenging drugs. These medications, such as sodium phenylbutyrate or glycerol phenylbutyrate, help the body remove excess nitrogen and ammonia through alternative metabolic pathways. This pharmacological intervention works to reduce circulating ammonia levels and prevent neurological damage.
Arginine supplementation is also a routine part of managing ASA. For individuals with this disorder, arginine, an amino acid, becomes an essential nutrient because the impaired urea cycle cannot produce it sufficiently. Arginine supplementation helps to maintain some function of the urea cycle and supports growth.
Acute episodes of hyperammonemia, which can be life-threatening, require immediate hospitalization for intensive treatment. These episodes may involve intravenous medications to rapidly lower ammonia levels, and sometimes, more aggressive interventions like hemodialysis are necessary to filter ammonia directly from the blood. In some cases, particularly for individuals who do not respond well to other treatments or develop liver complications, a liver transplant can be considered a curative option, as it provides a new liver with a functioning ASL enzyme.