Roland Posset1, Angeles Garcia-Cazorla2, Vassili Valayannopoulos3, Elisa Leão Teles4, Carlo Dionisi-Vici5, Anaïs Brassier3, Alberto B Burlina6, Peter Burgard7, Elisenda Cortès-Saladelafont2, Dries Dobbelaere8, Maria L Couce9, Jolanta Sykut-Cegielska10, Johannes Häberle11, Allan M Lund12, Anupam Chakrapani13,14, Manuel Schiff15, John H Walter16, Jiri Zeman17, Roshni Vara18, Stefan Kölker7. 1. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. roland.posset@med.uni-heidelberg.de. 2. Hospital San Joan de Deu, Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain. 3. Assistance Publique-Hôpitaux de Paris, Service de Maladies Metaboliques, Hôpital Necker-Enfants Malades, Paris, France. 4. Hospital de S. João, EPE, Unidade de Doenças Metabólicas, Serviço de Pediatria, Porto, Portugal. 5. Ospedale Pediatrico Bambino Gésu, U.O.C. Patologia Metabolica, Rome, Italy. 6. Azienda Ospedaliera di Padova, U.O.C. Malattie Metaboliche Ereditarie, Padova, Italy. 7. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. 8. 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. 9. Metabolic Unit, Department of Pediatrics, Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. 10. Screening Department, Institute of Mother and Child, Warsaw, Poland. 11. Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, Steinwiesstraße 75, CH-8032, Zurich, Switzerland. 12. Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 13. Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK. 14. Metabolic Unit Great Ormond Street Hospital and Institute for Child Health, University College London, London, UK. 15. Hôpital Robert Debré, Reference Centre for Inborn Errors of Metabolism, APHP and Université Paris-Diderot, Paris, France. 16. Manchester Academic Health Science Centre, Willink Biochemical Genetics Unit, Genetic Medicine, University of Manchester, Manchester, UK. 17. First Faculty of Medicine, Charles University and General University of Prague, Prague, Czech Republic. 18. Evelina Children's Hospital, St Thomas' Hospital, London, UK.
Abstract
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.
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.
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