Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders

• DOI: 10.1007/s10545-016-9938-9
• Publication Date: 2016-04-22T09:42:15Z
• Authors: Roland Posset; Angeles Garcia‐Ca...; Vassili Valayanno...; Elisa Leão Teles; Carlo Dionisi‐Vici; Anaïs Brassier; Alberto B. Burlina; Peter Burgard; Elisenda Cortès‐S...; Dries Dobbelaere; Maria L. Couce; Jolanta Sykut‐Ceg...; Johannes Häberle; Allan M. Lund; Anupam Chakrapani; Manuel Schiff; John H. Walter; Jiri Zeman; Roshni Vara; Stefan Kölker
• Keywords: Male; 2716 Genetics (clinical); Adolescent; 610 Medicine & health; Argininosuccinate Synthase; Late Onset Disorders; 03 medical and health sciences; Neonatal Screening; 0302 clinical medicine; 1311 Genetics; Ammonium Compounds; Humans; Hyperammonemia; Urea; Prospective Studies; Child; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders, Inborn; Citrullinemia; Infant, Newborn; 3. Good health; 10036 Medical Clinic; Female; Human medicine; Nervous System Diseases

AbstractBackgroundPatients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation.AimsDetermining the effect of diagnostic and therapeutic interventions on the neurological outcome.MethodsEvaluation of baseline, regular follow‐up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E‐IMD patient registry.ResultsAbout 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.ConclusionsPromising 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.