Citrullinemia Type I (Argininosuccinate Synthase Deficiency)

ASS1

Overview

Citrullinemia Type I, also known as argininosuccinate synthase deficiency, is a rare inherited disorder of the urea cycle. The urea cycle is the body’s primary pathway for eliminating nitrogen waste, which accumulates as ammonia when proteins are broken down during normal metabolism. In a healthy individual, nitrogen is converted into urea by a series of enzymatic steps and excreted through urine. In Citrullinemia Type I, mutations in the ASS1 gene on chromosome 9 disrupt the production or function of the enzyme argininosuccinate synthase. This enzyme is critical for combining citrulline and aspartate to form argininosuccinate, a key intermediate in the urea cycle. When this step fails, ammonia builds up in the bloodstream — a condition known as hyperammonemia — which is highly toxic to the brain and other organs.

The severity of the disease depends on how much functional enzyme activity remains. Individuals with little or no enzyme activity usually present in the neonatal period with severe symptoms, while those with partial enzyme function may have milder, later-onset presentations. Understanding the specific genetic mutation in each patient provides valuable information about expected disease severity and guides long-term management.

Implicated Genomic Region

The ASS1 gene is located in the 9q34.11 region of chromosome 9. More than 150 pathogenic variants of this gene have been identified. Some mutations result in complete loss of enzyme activity, while others lead to reduced but measurable function, explaining the broad clinical spectrum of the disorder.

Symptoms

Neonatal Onset (Severe Form)

In its most severe form, Citrullinemia Type I presents within the first few days of life as feeding begins. Ammonia rapidly accumulates because the urea cycle cannot process the nitrogen released from dietary protein. This leads to poor feeding, persistent vomiting, and profound lethargy. Hypotonia, or low muscle tone, is often present, and rapid breathing can occur as the body attempts to compensate for metabolic alkalosis. Without immediate intervention, neurological symptoms such as seizures and coma develop, often resulting in death or severe brain injury if not treated aggressively and promptly.

Late-Onset (Milder Form)

Individuals with residual enzyme function may not show symptoms until later in childhood, adolescence, or even adulthood. In these cases, symptoms are often triggered by metabolic stressors such as high protein intake, fasting, intense exercise, or infections. Neurological signs, including headaches, dizziness, confusion, and difficulty concentrating, are common. Children may exhibit delayed speech or slower motor development, reflecting subtle but ongoing neurotoxicity. Periodic episodes of liver dysfunction can also occur, sometimes leading to abnormal liver enzyme levels or mild hepatic enlargement.

Pregnancy-Related Onset

In some women, the metabolic burden of pregnancy or the immediate postpartum period can unmask previously silent disease. These episodes may present with mood changes, confusion, seizures, or acute liver failure. The physiological stress of pregnancy increases nitrogen load, making underlying deficiencies clinically evident even in women who were previously asymptomatic.

Asymptomatic Cases

Not all individuals carrying ASS1 mutations develop symptoms. Some remain entirely asymptomatic throughout their lives and are often identified incidentally through newborn screening programs, cascade genetic testing within affected families, or biochemical testing performed for unrelated reasons. These individuals may have sufficient residual enzyme activity to prevent dangerous ammonia accumulation under normal conditions, though they may still be at risk during periods of metabolic stress.

Diagnosis

Biochemical Testing

The first step in diagnosis typically involves biochemical testing. Elevated plasma ammonia levels, often markedly above the normal range, are a hallmark feature during acute episodes. Elevated plasma citrulline levels are another consistent finding, while levels of argininosuccinate are usually low. Increased orotic acid in urine is frequently detected because the disrupted urea cycle diverts nitrogen into alternative metabolic pathways.

Genetic Testing

Confirmation of the diagnosis requires genetic testing. Sequencing of the ASS1 gene identifies the causative mutations in most patients. When standard sequencing is inconclusive, more comprehensive approaches such as multi-gene panels, whole exome sequencing, or whole genome sequencing can detect rarer or complex variants. Establishing a genetic diagnosis is essential for guiding treatment, providing prognostic information, and facilitating genetic counseling.

Enzyme Activity Testing

Although less commonly used today due to the availability of molecular testing, enzyme activity assays remain useful in select cases. Measuring argininosuccinate synthase activity in cultured fibroblasts or liver biopsy samples can clarify uncertain genetic findings and help estimate residual function, which correlates with clinical severity.

Treatment and Management

Acute Management of Hyperammonemia

Episodes of hyperammonemia constitute a medical emergency due to the risk of irreversible brain injury. Immediate cessation of protein intake is essential to reduce nitrogen load. Intravenous arginine is administered to promote nitrogen excretion via alternative pathways, along with nitrogen-scavenger medications such as sodium benzoate or phenylbutyrate, which bind excess nitrogen and facilitate its elimination. If ammonia levels remain dangerously high, dialysis is initiated to rapidly clear ammonia from the bloodstream. Managing cerebral edema through fluid restriction and intracranial pressure control is also critical when neurological symptoms are present.

Long-Term Management

Once the acute episode is resolved, long-term strategies aim to prevent further hyperammonemic crises. Patients are placed on a protein-restricted diet, carefully calibrated to meet growth and nutritional needs while minimizing nitrogen burden. Nitrogen scavenger medications are often continued chronically, along with oral arginine supplementation to optimize urea cycle efficiency. Some individuals benefit from carnitine supplementation, particularly if secondary carnitine depletion is documented.

Supportive therapies are equally important. Early intervention with physical, occupational, or speech therapy can address developmental delays. Preventing infections and managing them promptly is crucial, as even minor illnesses can precipitate dangerous metabolic decompensation. In severe or unmanageable cases, liver transplantation offers a definitive solution by restoring normal urea cycle function. However, neurological injury sustained before transplant is typically irreversible.

Endocrine and Hormonal Care

Endocrine monitoring is recommended, as individuals with urea cycle disorders, including Citrullinemia Type I, may develop adrenal insufficiency or other hormonal imbalances. In male patients, genital malformations such as hypospadias may also be associated and require evaluation and, if necessary, surgical correction.

Prognosis

The outlook for individuals with Citrullinemia Type I is highly variable. In the absence of treatment, neonatal-onset disease often leads to death within the first days or weeks of life. With prompt recognition and aggressive intervention, survival improves significantly, though neurological complications from early hyperammonemia may persist. Those with milder, late-onset disease can often achieve a near-normal lifespan, provided they adhere to dietary restrictions and medication regimens. Liver transplantation has dramatically improved outcomes for patients with severe forms, stabilizing metabolic control and reducing the frequency of crises, though it does not reverse existing brain injury.

Genetic Counseling

Citrullinemia Type I is inherited in an autosomal recessive pattern. This means that a child must inherit one mutated copy of the ASS1 gene from each parent to develop the condition. Parents who are carriers typically do not show symptoms but have a 25 percent chance of having an affected child with each pregnancy. Genetic counseling provides families with information about recurrence risk, carrier testing for at-risk relatives, and reproductive options, including prenatal or preimplantation genetic diagnosis.

Conclusion

Citrullinemia Type I is a complex metabolic disorder that demands early recognition and careful, lifelong management. Timely diagnosis, evidence-based treatment, and a multidisciplinary care approach are essential for minimizing complications and improving long-term outcomes. Collaboration among metabolic specialists, dietitians, neurologists, and genetic counselors ensures that care is comprehensive, adaptive, and supportive for both patients and their families.

For authoritative clinical information and management guidelines, see Quinonez SC, Lee KN. Citrullinemia Type I. 2004 Jul 7 [Updated 2022 Aug 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. NCBI GeneReviews.