Abstract

Urea cycle disorders (UCDs) are rare inherited metabolic diseases caused by defects in urea cycle enzymes or transporters. The main objective of dietary management in patients with UCDs is to ensure stable metabolic control and prevent long-term complications, while supporting normal growth and development. Dietary protein restriction remains the cornerstone of long-term management, in combination with nitrogen-scavenging drugs, supplementation of arginine/citrulline, vitamins, minerals and essential amino acids if needed. However, lifelong low-protein diets raise concerns regarding growth, bone health, body composition, immune function and quality of life in patients with UCDs. Evidence on optimal protein intake in UCDs is scarce and heterogeneous, largely based on retrospective data and inconsistent nutritional methodologies. In this expert opinion, a multidisciplinary panel comprising eight inherited metabolic disease specialists from five Italian reference centers reviewed current challenges. It proposed recommendations for optimizing protein intake in UCD patients. The panel highlighted that dietary management involves not only metabolic aspects but also psycho-relational factors, both of which must be addressed to achieve optimal health outcomes in patients with UCDs. Clinical, biochemical, nutritional, instrumental, and psychological tools should be integrated to monitor outcomes, and optimization strategies should be tailored individually across all ages. The panel emphasized that all patients are potentially eligible for protein optimization, provided that individual tolerance, nutritional status, metabolic control, and psychosocial context are carefully assessed. Nitrogen-scavenging therapy may support higher protein intake, with close clinical and biochemical monitoring required during titration. This consensus represents the first expert opinion specifically addressing protein optimization in UCDs, providing a practical framework for dietary management.