Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry

Abstract

Background/Objectives: The present study updates the Spanish registry of patients with urea cycle disorders (UCD), originally established in 2013, to provide comprehensive epidemiological data and evaluate the impact of therapeutic strategies and newborn screening (NBS) on clinical outcomes. Methods: This retrospective, multicenter study focuses on 255 Spanish UCD patients. It includes all living and deceased cases up to February 2024, analyzing demographic, clinical, and biochemical variables. Results: The incidence of UCD in Spain over the past decade was 1:36,063 births. The most common defects were ornithine transcarbamylase deficiency (OTCD) and argininosuccinate synthetase deficiency. Early-onset (EO) cases comprised 32.7%, and 10.6% were diagnosed through NBS. Global mortality was 14.9%, higher in carbamoylphosphate synthetase 1 deficiency (36.8%) and male OTCD patients (32.1%) compared to other defects (p = 0.013). EO cases presented a higher mortality rate (35.8%) than late-onset (LO) cases (7.1%) (p < 0.0001). The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494) (p < 0.0001). Diagnosis through NBS improved survival and reduced neurological impairment compared to symptomatic diagnosis. Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis. Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients. Conclusions: This updated analysis highlights the positive impact of NBS and advanced treatments on mortality and neurologic outcomes. Persistent neurological challenges underscore the need for further therapeutic strategies.