The human body functions through a complex network of chemical reactions, many of which depend on proteins called enzymes. One of these is argininosuccinate lyase (ASL), an enzyme that plays a part in processing waste products from protein metabolism. Without the proper function of enzymes like ASL, the body’s internal systems cannot operate correctly, leading to a range of health issues.
Function of Argininosuccinate Lyase in the Urea Cycle
When the body breaks down proteins, it generates nitrogen, which forms a compound called ammonia that is toxic in high concentrations. To prevent this, the body uses a detoxification pathway in the liver called the urea cycle. This series of enzymatic reactions converts the harmful ammonia into a safer, water-soluble compound called urea, which is then expelled from the body in urine.
Within this pathway, argininosuccinate lyase performs a specific task as the fourth enzyme in the cycle. It is responsible for cleaving a molecule named argininosuccinate into two smaller components: arginine and fumarate. The arginine produced is the direct precursor to urea, while the fumarate can be recycled. If ASL is not working correctly, the entire process halts, preventing the cycle from completing and leading to a buildup of precursor materials.
Argininosuccinate Lyase Deficiency
Argininosuccinate lyase deficiency, also known as Argininosuccinic Aciduria (ASA), is a rare genetic disorder that disrupts the urea cycle. The condition arises from mutations in the ASL gene, which holds the instructions for making the enzyme. The prevalence is estimated to be between 1 in 70,000 and 1 in 218,000 newborns worldwide.
This disorder is inherited in an autosomal recessive pattern, meaning a child must inherit one non-working copy of the ASL gene from each parent. The parents, who each carry one mutated copy, are typically carriers and do not show symptoms. The result of the faulty gene is an inability to properly break down argininosuccinate, causing it and ammonia to accumulate in the blood.
Signs and Symptoms of Deficiency
The clinical presentation of argininosuccinate lyase deficiency varies and is categorized into two main forms: a severe neonatal-onset form and a later-onset form. In the severe neonatal-onset form, symptoms appear within the first few days of life. Affected infants may quickly develop lethargy, poor appetite, vomiting, and rapid breathing. Without immediate treatment, the high ammonia levels can lead to seizures, coma, and can be fatal.
The later-onset form can manifest from infancy to adulthood with varied symptoms. Because these individuals have partial enzyme activity, symptoms may be milder or appear episodically, often triggered by illness or a high-protein meal. Common signs include developmental delay, learning disabilities, and behavioral abnormalities. About half of patients develop brittle, coarse hair (trichorrhexis nodosa), and some may also develop liver problems like cirrhosis.
Diagnosis and Medical Management
The diagnosis of ASL deficiency is often made through newborn screening programs, which test for high levels of argininosuccinic acid or citrulline in the blood. If screening results are abnormal, confirmatory tests are performed, including measuring plasma ammonia levels and quantitative amino acid analysis. A definitive diagnosis can be made through molecular genetic testing to identify mutations in the ASL gene.
Management of ASL deficiency is a lifelong process focused on preventing hyperammonemia and its toxic effects. The primary strategy is a strict low-protein diet to limit nitrogen intake, combined with arginine supplementation. Supplying arginine helps the urea cycle proceed to some extent and promotes the excretion of waste nitrogen in the form of argininosuccinate.
Physicians often prescribe nitrogen-scavenging medications, such as sodium benzoate or glycerol phenylbutyrate. These drugs provide an alternative pathway for nitrogen to be removed from the body, bypassing the block in the urea cycle. During acute episodes of high ammonia, hospitalization is required for intravenous administration of these medications and glucose. In severe cases, hemodialysis may be necessary, and for some patients, a liver transplant may be considered to correct the enzyme deficiency.