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Abstract
Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.
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1 University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908)
2 Children’s National Health System, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
3 Université Paris-Descartes, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Service de Maladies Metaboliques (MaMEA), filière G2M, Paris, France (GRID:grid.10992.33) (ISNI:0000 0001 2188 0914)
4 Hospital San Joan de Deu, Institut Pediàtric de Recerca. Servicio de Neurologia and CIBERER, ISCIII, Barcelona, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427)
5 Baylor College of Medicine and Texas Children’s Hospital, Department of Molecular and Human Genetics, Houston, USA (GRID:grid.416975.8) (ISNI:0000 0001 2200 2638)
6 University Children’s Hospital Zurich and Children’s Research Center, Zurich, Switzerland (GRID:grid.412341.1) (ISNI:0000 0001 0726 4330)
7 University of Toronto and the Hospital for Sick Children, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646)
8 University Lille 2, Centre de Référence Maladies Héréditaires du Métabolisme de L’Enfant Et de L’Adulte, Jeanne de Flandre Hospital, CHRU Lille, and Faculty of Medicine, Lille, France (GRID:grid.503422.2) (ISNI:0000 0001 2242 6780)
9 University of Pennsylvania, School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
10 University Hospital Heidelberg, Center for Pediatric and Adolescent Medicine, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908); Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany (GRID:grid.5253.1)
11 University of Minnesota, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000000419368657)
12 Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X)
13 Stanford Children’s Health, Palo Alto, USA (GRID:grid.430503.1)
14 University of California, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
15 Oregon Health and Science University, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690)
16 National Urea Cycle Disorders Foundation (NUCDF), Pasadena, USA (GRID:grid.491045.d)
17 University of Washington and Seattle Children’s Hospital, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657)
18 University Hospitals Cleveland Medical Center and Case Western Reserve University, Center for Human Genetics and Department of Genetics and Genome Sciences, Cleveland, USA (GRID:grid.443867.a) (ISNI:0000 0000 9149 4843)
19 Harvard Medical School and Boston Children’s Hospital, Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438)
20 Mount Sinai School of Medicine, Department of Genetics and Genomics Sciences, New York City, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351)
21 David Geffen School of Medicine at UCLA, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)
22 University Hospital Padova, Division of Inherited Metabolic Diseases, Reference Centre Expanded Newborn Screening, Department of Woman’s and Child’s Health, Padua, Italy (GRID:grid.411474.3) (ISNI:0000 0004 1760 2630)
23 Unidade de Doenças Metabólicas, Serviço de Pediatria, Porto, Portugal (GRID:grid.411474.3)
24 Hospital Infantil Universitario Niño Jesús, Division of Gastroenterology and Nutrition, Madrid, Spain (GRID:grid.411107.2) (ISNI:0000 0004 1767 5442)
25 Copenhagen University Hospital, Centre for Inherited Metabolic Diseases, Departments of Paediatrics and Clinical Genetics, Copenhagen, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373)
26 Ospedale Pediatrico Bambino Gesù, U.O.C. Patologia Metabolica, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809)
27 Erasmus Universiteit Rotterdam, Erasmus MC-Sophia Kinderziekenhuis, Rotterdam, The Netherlands (GRID:grid.6906.9) (ISNI:0000000092621349)
28 Medical University of Innsbruck, Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Innsbruck, Austria (GRID:grid.5361.1) (ISNI:0000 0000 8853 2677)
29 Hospital Materno-Infantil, Málaga, Spain (GRID:grid.414833.9) (ISNI:0000 0004 1772 5876)
30 Hospital Clinico Universitario de Santiago de Compostela, Metabolic Unit, Department of Pediatrics, Santiago de Compostela, Spain (GRID:grid.411048.8) (ISNI:0000 0000 8816 6945)
31 Institute of Mother and Child, Department of Inborn Errors of Metabolism and Paediatrics, Warsaw, Poland (GRID:grid.418838.e) (ISNI:0000 0004 0621 4763)
32 Aristotle University of Thessaloniki, 1st Pediatric Department, Thessaloniki, Greece (GRID:grid.4793.9) (ISNI:0000000109457005)
33 Hospital Universitario Son Dureta, Metabolic Diseases Unit, Pediatric Neurology Department, Palma de Mallorca, Spain (GRID:grid.411161.2) (ISNI:0000 0001 0057 8847)
34 University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia (GRID:grid.412688.1) (ISNI:0000 0004 0397 9648)
35 Robert-Debré University Hospital, Reference Center for Inborn Errors of Metabolism, Paris, France (GRID:grid.413235.2) (ISNI:0000 0004 1937 0589)
36 National Taiwan University College of Medicine, Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241)
37 University Children’s Hospital Frankfurt, Frankfurt, Germany (GRID:grid.411088.4) (ISNI:0000 0004 0578 8220)
38 Hôpital d’Enfants, CHU Timone, Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Marseille, France (GRID:grid.411266.6) (ISNI:0000 0001 0404 1115)
39 Institute of Child Health, Athens, Greece (GRID:grid.414709.f) (ISNI:0000 0004 0383 4326)
40 First Faculty of Medicine and General Faculty Hospital, Department of Paediatrics, Prague, Czech Republic (GRID:grid.411798.2) (ISNI:0000 0000 9100 9940)
41 Cliniques Universitaires St Luc, Université Catholique de Louvain, Service Gastroentérologie and Hépatologie Pédiatrique, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320)
42 University Medical Center Eppendorf, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
43 Universitair Ziekenhuis Antwerpen, Antwerp, Belgium (GRID:grid.411414.5) (ISNI:0000 0004 0626 3418)
44 Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany (GRID:grid.440206.4) (ISNI:0000 0004 1765 7498)
45 Las Palmas de Gran Canaria University, Gastroenterology and Nutrition Unit Complejo Hospitalario Universitario Insular-Materno Infantil, CIBEROBN, Las Palmas, Spain (GRID:grid.4521.2) (ISNI:0000 0004 1769 9380)
46 Institut de Pathologie et de Génétique ASBL, Centre Agréé des Maladies Héréditaires du Métabolisme, Centre de Génétique Humaine, Gosselies, Belgium (GRID:grid.452439.d) (ISNI:0000 0004 0578 0894)
47 Universitat Autònoma de Barcelona, Department of Paediatrics, Badalona, Spain (GRID:grid.7080.f)
48 Institut za zdravstvenu zastitu majke i deteta Srbije “Dr Vukan Cupic”, Radoja Dakica Street 6-8, and University of Belgrade, School of Medicine, Novi Beograd, Republic of Serbia (GRID:grid.7149.b) (ISNI:0000 0001 2166 9385)