Peer-reviewed article
Is mild citrullinemia type I truly benign? a study of long-term clinical outcomes.
Elif İşler-Soylu, Tuğçe Aras-Çöl, Hanım Babazade Aghakishili, Kağan Çalışgan, Tanyel Zubarioglu et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a medical case series about citrullinemia type I, a rare genetic metabolic disorder affecting ammonia processing in the body. The study follows six children with mild forms of the condition over an average of 8.5 years to understand long-term outcomes. While biochemical markers remained stable, half the patients developed neurological or psychiatric symptoms. The findings suggest that even mild forms of this disorder may carry unrecognized neurological risks requiring individualized management.
Key points
- Six patients with mild citrullinemia were followed for a median of 8.5 years with no metabolic decompensation
- Half of the patients developed neurocognitive or psychiatric symptoms despite biochemical stability
- Symptoms included learning disabilities, obsessive-compulsive disorder, ADHD, and global developmental delay
- All patients received arginine supplementation; three received ammonia scavengers
- The study suggests mild citrullinemia may carry underrecognized neurological risks
Limitations
This is a small retrospective case series of six patients, which cannot establish causation or generalizable outcomes. The study cannot determine whether observed neurological symptoms are directly caused by the disorder, related to management strategies, or coincidental.
Abstract
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.