BACKGROUND: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. AIMS: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. METHODS: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. RESULTS: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome. CONCLUSIONS: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.

1st Faculty of Medicine Charles University and General University of Prague Prague Czech Republic

Assistance Publique Hôpitaux de Paris Service de Maladies Metaboliques Hôpital Necker Enfants Malades Paris France

Azienda Ospedaliera di Padova U O C Malattie Metaboliche Ereditarie Padova Italy

Birmingham Children's Hospital NHS Foundation Trust Steelhouse Lane Birmingham B4 6NH UK

Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte Jeanne de Flandre Hospital CHRU Lille and RADEME EA 7364 Faculty of Medicine University Lille 2 Lille 59037 France

Centre for Inherited Metabolic Diseases Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of General Pediatrics Division of Inherited Metabolic Diseases University Children's Hospital Heidelberg Im Neuenheimer Feld 430 D 69120 Heidelberg Germany

Division of Metabolism and Children's Research Centre University Children's Hospital Zurich Steinwiesstraße 75 CH 8032 Zurich Switzerland

Evelina Children's Hospital St Thomas' Hospital London UK

Hôpital Robert Debré Reference Centre for Inborn Errors of Metabolism APHP and Université Paris Diderot Paris France

Hospital de S João EPE Unidade de Doenças Metabólicas Serviço de Pediatria Porto Portugal

Hospital San Joan de Deu Servicio de Neurologia and CIBERER ISCIII Barcelona Spain

Manchester Academic Health Science Centre Willink Biochemical Genetics Unit Genetic Medicine University of Manchester Manchester UK

Metabolic Unit Department of Pediatrics Hospital Clinico Universitario de Santiago de Compostela Santiago de Compostela Spain

Metabolic Unit Great Ormond Street Hospital and Institute for Child Health University College London London UK

Ospedale Pediatrico Bambino Gésu U O C Patologia Metabolica Rome Italy

Screening Department Institute of Mother and Child Warsaw Poland

J Inherit Metab Dis. 2018 Jul;41(4):743-744. doi: 10.1007/s10545-017-0117-4. PubMed

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