citrullinemia type I

Citrullinemia type I is a metabolic disorder affecting the urea cycle caused by a deficiency in the enzyme argininosuccinate synthase, which is encoded by the ASS1 gene. This deficiency leads to an accumulation of ammonia and citrulline in the blood. The condition may present in the neonatal period with symptoms such as poor feeding, progressive lethargy, and vomiting, or later in life with variable hyperammonemia. It is inherited in an autosomal recessive fashion and is considered uncommon, affecting approximately 1 to 9 per 100,000 people.

The clinical presentation of citrullinemia type I is primarily driven by disrupted ammonia metabolism. In the neonatal form, infants often show signs of poor feeding, vomiting, and progressive lethargy that prompt further evaluation. Laboratory findings indicative of the condition include reduced tissue argininosuccinate synthetase activity, elevated plasma citrulline, hyperglutaminemia, and oroticaciduria. In a smaller subset of individuals, stroke has also been reported. Not all individuals experience all features, and severity varies considerably.

Citrullinemia type I is caused by pathogenic variants in the ASS1 gene. This gene encodes argininosuccinate synthase, an enzyme that plays a critical role in the urea cycle by helping to convert ammonia to urea for excretion. A deficiency in this enzyme leads to the accumulation of toxic levels of ammonia and related metabolites in the bloodstream. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual has inherited two copies of the altered gene, one from each parent. Genetic counseling is recommended for families to understand recurrence risks and implications for future pregnancies.

Currently, management focuses on supportive care and symptom management, as there are no treatments specifically approved for citrullinemia type I. Treatment is tailored to each individual and typically involves a multidisciplinary team aimed at reducing ammonia levels and managing metabolic imbalances. Dietary management and other interventions to lower blood ammonia may be recommended. In addition, genetic counseling is advised to help families navigate the implications of an autosomal recessive inheritance pattern and to discuss potential treatment strategies with their healthcare team.

The outlook for individuals with citrullinemia type I varies considerably depending on the severity of enzyme deficiency, the timeliness of intervention, and access to specialized care. In the neonatal form, rapid recognition and treatment of hyperammonemia are critical and can improve long-term outcomes. Over time, patients may experience stabilization of symptoms, although the course of the condition differs from one individual to another. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with a genetic counselor for guidance on managing the condition and planning for the future.

Clinical trials are underway exploring new treatment approaches for citrullinemia type I. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility as research in this area continues to evolve.