argininosuccinic aciduria

Argininosuccinic aciduria is a metabolic disorder affecting the urea cycle that disrupts the body’s ability to remove ammonia, a toxic byproduct of protein metabolism. It is caused by variants in the ASL gene, which encodes the enzyme argininosuccinate lyase, essential for converting argininosuccinic acid into arginine and fumarate. The condition can present in early life, often in the neonatal period with severe hyperammonemia, or later in life with stress-triggered episodes, and it is inherited in an autosomal recessive pattern. In general, it is considered uncommon, affecting roughly 1 to 9 individuals per 100,000 people.

Individuals with argininosuccinic aciduria may present with a range of clinical features that affect both the neurological and systemic domains. Early presentations in neonates include symptoms such as vomiting, hypothermia, lethargy, and poor feeding associated with hyperammonemia. As the condition progresses, some children develop neurological and behavioral challenges including specific learning disabilities, intellectual disability, seizures, and neurodevelopmental delay, along with systemic signs such as liver dysfunction, elevated hepatic transaminase levels, and hepatomegaly. Not all individuals experience all features, and severity varies considerably.

Argininosuccinic aciduria is caused by pathogenic variants in the ASL gene. The ASL gene provides instructions for making argininosuccinate lyase, an enzyme that plays a crucial role in the urea cycle by enabling the conversion of argininosuccinic acid into arginine and fumarate. When this enzyme is deficient, toxic levels of ammonia and argininosuccinic acid accumulate in the body. The condition follows an autosomal recessive inheritance pattern, which means that an individual must inherit two defective copies of the ASL gene, one from each parent, for the disorder to manifest. Families may benefit from genetic counseling to understand the implications for future pregnancies.

Currently, management of argininosuccinic aciduria focuses on supportive care and symptom management, as there are no treatments specifically approved for this condition. Treatment strategies are tailored individually and typically involve a multidisciplinary team to manage metabolic imbalances and prevent complications, with careful surveillance to monitor for liver dysfunction and neurological issues. Given the potential for episodic hyperammonemia, ongoing monitoring is an essential component of long-term care. Patients and families are encouraged to discuss all treatment options, including dietary management and specialized supportive therapies, with their healthcare providers, and genetic counseling is recommended.

The clinical course of argininosuccinic aciduria is highly variable, with outcomes that depend on the severity of metabolic disruptions, age at diagnosis, and access to specialized care. With current standards of care, many individuals can manage the condition into later childhood and adulthood, although challenges such as neurodevelopmental difficulties and liver dysfunction may persist. Outcomes described in medical literature continue to evolve as standards of care improve, and families often find it helpful to connect with specialists familiar with metabolic disorders. Genetic counseling and support groups serve as important resources for families to navigate long-term management and care planning.

Several clinical trials are currently underway exploring new treatment approaches for argininosuccinic aciduria. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team to learn about eligibility opportunities.