Exploring the Spectrum of Urea Cycle Disorders (UCD): An Investigation into the Varied Etiological Classifications

Introduction:

Urea cycle disorders (UCDs) result from defects in enzymes or transporters responsible for converting ammonia to urea. This study aims to determine the frequency, biochemical distribution, and clinical characteristics of various UCD subtypes in a large cohort.

Methods:

A cross-sectional study was conducted at the Biochemical Genetic Laboratory, Aga Khan University, analyzing patients tested for urine organic acids (UOA) or plasma amino acids (PAA) from January 2013 to December 2025.

Results:

Out of 26,405 PAA and 28,146 UOA tests, 216 (0.4%) patients were diagnosed with a UCD over a 12-year period. The mean age of the study cohort was 2.8 years, with a male-to-female ratio of 1.2. An orotic acid peak on UOA chromatograms was noted in 35.6% (n=77) of cases. Median laboratory values at presentation were pH 7.39, lactic acid 41.5 mmol/L, ammonia 732.5 mg/dL, citrulline 740 mmol/L, glutamine 1101 mmol/L, ornithine 156.0 mmol/L, and arginine 145.2 mmol/L. Frequent clinical presentations included poor sucking (31%, n=67), fever (14.8%, n=32), and developmental delay (9.3%, n=20).

Distal UCDs were more prevalent than proximal UCDs (25%, n=54, including NAGS, CPS, and OTC). Distal subtypes included citrullinemia type I/II (17.6%, n=38), hyperornithinemia (10.6%, n=23), argininosuccinic acid (ASA) lyase deficiency (9.7%, n=21), and arginase deficiency (5.6%, n=12).

Acute neurological symptoms are more pronounced in distal UCDs, where lethargy (66% vs. 43%) and seizures (43% vs. 26%) present with higher frequencies compared to proximal UCDs. While fever (40% vs 13%) and failure to thrive (38% vs. 20%) were more common in proximal UCDs than in distal UCDs.

Conclusions:

Distal disorders, predominantly citrullinemia type I/II, were more frequent than proximal UCDs in this large cohort, and neurological deficit was more common in this group. Standard metabolic screening using PAA and UOA effectively differentiates these specific etiological subtypes, providing a critical foundation for prompt, targeted patient management.