Is mild citrullinemia type I truly benign? a study of long-term clinical outcomes

Objectives Citrullinemia type I (CTLN1), caused by variants in the ASS1 gene, is characterized by life-threatening neonatal hyperammonemia. The severity of CTLN1 correlates with residual enzyme function: nearly absent activity leads to severe neonatal presentations, while partial function results in milder forms. The increasing identification of patients with mild citrullinemia highlights the need for a deeper understanding of its natural history, genotype–phenotype correlations, and long-term management strategies. This study aims to characterize the clinical and molecular features of mild citrullinemia and explore its implications for long-term management. Methods We conducted a retrospective analysis of six pediatric patients diagnosed with mild CTLN1, examining their clinical presentations, biochemical parameters, and long-term outcomes. Results We present a case series of six patients (three males, three females; median age at presentation 0.5 years, median follow-up 8.5 years) identified through newborn screening (66.7 %), cascade testing (16.7 %), or symptomatic presentation (16.7 %). Consanguinity was present in half of the patients, including one sibling pair. None experienced metabolic decompensation. Baseline citrulline levels were mildly elevated (median 294 μmol/L) and ammonia levels ranged from mild to moderate (median 101 μmol/L; range 51–154 μmol/L). Arginine supplementation was administered to all patients at various stages without dietary protein restriction. Ammonia scavengers were used in three cases – two during the neonatal period and one at age 14 following neurological symptoms. Despite biochemical stability, half of patients had neurocognitive or psychiatric symptoms, including learning disabilities, obsessive compulsive disorder, attention deficit and hyperactivity disorder, and global developmental delay. Conclusions Our findings indicate that, despite its classification as “mild”, citrullinemia may involve underrecognized neurological risks, reflecting an incompletely understood pathophysiology. This underscores the importance of individualized treatment and long-term care.