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Multicenter Study
. 2025 Mar 28;17(7):1173.
doi: 10.3390/nu17071173.

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

Elena Martín-Hernández  1 , Marcello Bellusci  1 , Patricia Pérez-Mohand  1 , Patricia Correcher Medina  2 , Javier Blasco-Alonso  3 , Ana Morais-López  4 , Javier de Las Heras  5 , Silvia María Meavilla Olivas  6 , Lucy Dougherty-de Miguel  7 , Maria Luz Couce  8 , Elvira Cañedo Villarroya  9 , María Concepción García Jiménez  10 , Pedro Juan Moreno-Lozano  11 , Inmaculada Vives  12 , Mercedes Gil-Campos  13 , Sinziana Stanescu  14 , Leticia Ceberio-Hualde  5 , María Camprodón  7 , Elisenda Cortès-Saladelafont  15 , Rafael López-Urdiales  16 , Mercedes Murray Hurtado  17 , Ana María Márquez Armenteros  18 , Concha Sierra Córcoles  19 , Luis Peña-Quintana  20 , Mónica Ruiz-Pons  21 , Carlos Alcalde  22 , Fernando Castellanos-Pinedo  23 , Elena Dios  24 , Delia Barrio-Carreras  1 , María Martín-Cazaña  1 , Mónica García-Peris  2 , José David Andrade  4 , Camila García-Volpe  6 , Mariela de Los Santos  6 , Angels García-Cazorla  6 , Mireia Del Toro  7 , Ana Felipe-Rucián  7 , María José Comino Monroy  13 , Paula Sánchez-Pintos  8 , Ana Matas  11 , David Gil Ortega  12 , Álvaro Martín-Rivada  17 , Ana Bergua  4 , Amaya Belanger-Quintana  14 , Isidro Vitoria  2 , Raquel Yahyaoui  3 , Belén Pérez  25 , Montserrat Morales-Conejo  1 , Pilar Quijada-Fraile  1
Affiliations
Multicenter Study

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

Elena Martín-Hernández et al. Nutrients. .

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.

Keywords: N-acetylglutamate synthase (NAGS); arginase 1 (ARG1); argininosuccinate lyase (ASL); argininosuccinate synthetase (ASS1); carbamoylphosphate synthetase (CPS1); carbonic anhydrase VA (CA-VA); citrin; hyperornithinemia-hyperammonemia-homocitrullinuria (HHH); ornithine transcarbamylase (OTC); ornithine/citrulline antiporter (ORNT); urea cycle disorders (UCDs).

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Conflict of interest statement

E.M.-H. has received financial support for attending conferences from Sanofi Spain, Lucane, and Nutricia Danone and has received writing support from Immedica Pharma Spain. None of them have influenced the content of this manuscript, and therefore, no conflicts of interest are declared. E.C.-S. received honoraria from Takeda as a speaker, received reimbursements from Lucane Pharma, Biomarin Pharmaceutical, Eisai and Takeda for attending scientific meetings and medical congresses, but E.C. confirms independence from the sponsors and that the content of the article has not been influenced by them. A.B.-Q. has received speaker fees, meeting funding, advisory work, or investigation grants from various companies (Danone, Nestle, Recordati Rare Diseases, Grand Fontaine, Rendon, Sobi, Sanofi, Shire, Takeda, Biomarin, PTC, Jnana) over the last 5 years. None of these have influenced the content of this manuscript, and therefore, no conflicts of interest are declared. S.S. has received speaker and travel fees from Sanofi Spain, Nutricia Danone and Nestlé Vitaflo. A.G.-C. has received honoraria for research support and lectures from PTC Therapeutics and Immedica, honoraria for lectures from Biomarin, Immedica, Eisai, Orchard Therapeutics, and Recordati Rare Diseases Foundation, and is a co-founder of the Hospital Sant Joan de Déu start-up ‘Neuroprotect Life Sciences’. M.B. has received financial support for attending conferences and/or giving lectures from Lucane Pharma, Nutricia Metabolics, and Orphan Europe. Á.M.-R. and M.M.H. have received writing support from Immedica Pharma Spain. B.P. has received financial support for attending conferences or honoraria from PTC Therapeutics, Chiesi, and Immedica Pharma Spain. None of these entities have influenced the content of this manuscript, and therefore, no conflicts of interest are declared. The rest of the authors declare no conflict of interest with this study. The sponsors had no role in the design, execution, interpretation, or writing of the study.

Figures

Figure 1
Figure 1
Number of cases according to date of diagnosis.
Figure 2
Figure 2
Mortality. (A) Overall survival estimate (Kaplan–Meier). (B) Survival by type of disorder (Kaplan–Meier). (C) Ammonia levels at onset. (D) Survival by clinical presentation time (Kaplan–Meier).
Figure 3
Figure 3
Age distribution of patients at follow-up. (A) Number of patients by age group. (B) Percentage of patients categorized as children. 109 females (53.4%) and 95 males (46.6%).
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