Stefan Kölker1, Angeles Garcia-Cazorla2, Angeles Garcia Cazorla, Vassili Valayannopoulos3, Allan M Lund4, Alberto B Burlina5, Jolanta Sykut-Cegielska6, Frits A Wijburg7, Elisa Leão Teles8, Jiri Zeman9, Carlo Dionisi-Vici10, Ivo Barić11, Daniela Karall12, Persephone Augoustides-Savvopoulou13, Lise Aksglaede4, Jean-Baptiste Arnoux3, Paula Avram14, Matthias R Baumgartner15, Javier Blasco-Alonso16, Brigitte Chabrol17, Anupam Chakrapani18, Kimberly Chapman19, Elisenda Cortès I Saladelafont2, Maria L Couce20, Linda de Meirleir21, Dries Dobbelaere22, Veronika Dvorakova9, Francesca Furlan5, Florian Gleich23, Wanda Gradowska24, Stephanie Grünewald25, Anil Jalan26, Johannes Häberle15, Gisela Haege23, Robin Lachmann27, Alexander Laemmle15, Eveline Langereis7, Pascale de Lonlay3, Diego Martinelli10, Shirou Matsumoto28, Chris Mühlhausen29, Hélène Ogier de Baulny30, Carlos Ortez2, Luis Peña-Quintana31, Danijela Petković Ramadža32, Esmeralda Rodrigues8, Sabine Scholl-Bürgi12, Etienne Sokal33, Christian Staufner23, Marshall L Summar19, Nicholas Thompson25, Roshni Vara34, Inmaculada Vives Pinera35, John H Walter36, Monique Williams37, Peter Burgard23. 1. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. Stefan.Koelker@med.uni-heidelberg.de. 2. Servicio de Neurologia and CIBERER, ISCIII, Hospital San Joan de Deu, Barcelona, Spain. 3. Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Reference Center for Inherited Metabolic Disease, Necker-Enfants Malades University Hospital and IMAGINE Institute, Paris, France. 4. Centre for Inherited Metabolic Diseases, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 5. U.O.C. Malattie Metaboliche Ereditarie, Azienda Ospedaliera di Padova, Padova, Italy. 6. Screening Department, Institute of Mother and Child, Warsaw, Poland. 7. Department of Pediatrics, Academisch Medisch Centrum, Amsterdam, Netherlands. 8. Unidade de Doenças Metabólicas, Serviço de Pediatria, Hospital de S. João, EPE, Porto, Portugal. 9. First Faculty of Medicine, Charles University and General University of Prague, Prague, Czech Republic. 10. U.O.C. Patologia Metabolica, Ospedale Pediatrico Bambino Gésu, Rome, Italy. 11. School of Medicine, University Hospital Center Zagreb and University of Zagreb, Zagreb, Croatia. 12. Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria. 13. 1st Pediatric Department, Metabolic Laboratory, General Hospital of Thessaloniki 'Hippocration', Thessaloniki, Greece. 14. Institute of Mother and Child Care "Alfred Rusescu", Bucharest, Romania. 15. Division of Metabolism and Children's Research Centre, University Children's Hospital Zurich, Steinwiesstraße 75, CH-8032, Zurich, Switzerland. 16. Hospital Materno-Infantil (HRU Carlos Haya), Málaga, Spain. 17. Centre de Référence des Maladies Héréditaires du Métabolisme, Service de Neurologie, Hôpital d'Enfants, CHU Timone, Marseilles, France. 18. Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK. 19. Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC, 20010, USA. 20. Metabolic Unit, Department of Pediatrics, Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. 21. University Hospital Vrije Universiteit Brussel, Bruxelles, Belgium. 22. Centre de Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Hôpital Jeanne de Flandre, Lille, France. 23. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120, Heidelberg, Germany. 24. Department of Laboratory Diagnostics, The Children's Memorial Health Institute, Warsaw, Poland. 25. Metabolic Unit Great Ormond Street Hospital and Institute for Child Health, University College London, London, UK. 26. N.I.R.M.A.N., Om Rachna Society, Vashi, Navi Mumbai, Mumbai, India. 27. Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK. 28. Department of Pediatrics, Kumamoto University Hospital, Kumamoto City, Japan. 29. Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. 30. Hôpital Robert Debré, Université de Paris, Paris, France. 31. Hospital Universitario Materno-Infantil de Canarias, Unit of Pediatric Gastroenterology, Hepatology and Nutrition, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 32. University Hospital Center Zagreb, Zagreb, Croatia. 33. Service Gastroentérologie and Hépatologie Pédiatrique, Cliniques Universitaires St Luc, Université Catholique de Louvain, Bruxelles, Belgium. 34. Evelina Children's Hospital, St Thomas' Hospital, London, UK. 35. Inborn Metabolic Disease Unit, Hospital Virgen de la Arrixaca de Murcia, El Palmar, Spain. 36. Manchester Academic Health Science Centre, Willink Biochemical Genetics Unit, Genetic Medicine, University of Manchester, Manchester, UK. 37. Erasmus MC-Sophia Kinderziekenhuis, Erasmus Universiteit Rotterdam, Rotterdam, Netherlands.
Abstract
BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/ METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.
BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/ METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PApatients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.
Authors: Ulrike Teufel; Jürgen Weitz; Christa Flechtenmacher; Viola Prietsch; Jan Schmidt; Georg F Hoffmann; Stefan Kölker; Guido Engelmann Journal: Pediatr Transplant Date: 2009-04-26
Authors: Sven W Sauer; Jürgen G Okun; Marina A Schwab; Linda R Crnic; Georg F Hoffmann; Stephen I Goodman; David M Koeller; Stefan Kölker Journal: J Biol Chem Date: 2005-04-19 Impact factor: 5.157
Authors: Sven W Sauer; Silvana Opp; Anne Mahringer; Marcin M Kamiński; Christian Thiel; Jürgen G Okun; Gert Fricker; Marina A Morath; Stefan Kölker Journal: Biochim Biophys Acta Date: 2010-03-17
Authors: S B van der Meer; F Poggi; M Spada; J P Bonnefont; H Ogier; P Hubert; E Depondt; D Rapoport; D Rabier; C Charpentier Journal: J Pediatr Date: 1994-12 Impact factor: 4.406
Authors: Inga Harting; Eva Neumaier-Probst; Angelika Seitz; Esther M Maier; Birgit Assmann; Ivo Baric; Monica Troncoso; Chris Mühlhausen; Johannes Zschocke; Nikolas P S Boy; Georg F Hoffmann; Sven F Garbade; Stefan Kölker Journal: Brain Date: 2009-05-11 Impact factor: 13.501
Authors: Gregory M Enns; Susan A Berry; Gerard T Berry; William J Rhead; Saul W Brusilow; Ada Hamosh Journal: N Engl J Med Date: 2007-05-31 Impact factor: 91.245
Authors: Stefan Kölker; Sven F Garbade; Nikolas Boy; Esther M Maier; Thomas Meissner; Chris Mühlhausen; Julia B Hennermann; Thomas Lücke; Johannes Häberle; Jochen Baumkötter; Wolfram Haller; Edith Muller; Johannes Zschocke; Peter Burgard; Georg F Hoffmann Journal: Pediatr Res Date: 2007-09 Impact factor: 3.756
Authors: Peter Burgard; Stefan Kölker; Gisela Haege; Martin Lindner; Georg F Hoffmann Journal: J Inherit Metab Dis Date: 2015-12-03 Impact factor: 4.982
Authors: Jana Heringer; Vassili Valayannopoulos; Allan M Lund; Frits A Wijburg; Peter Freisinger; Ivo Barić; Matthias R Baumgartner; Peter Burgard; Alberto B Burlina; Kimberly A Chapman; Elisenda Cortès I Saladelafont; Daniela Karall; Chris Mühlhausen; Victoria Riches; Manuel Schiff; Jolanta Sykut-Cegielska; John H Walter; Jiri Zeman; Brigitte Chabrol; Stefan Kölker Journal: J Inherit Metab Dis Date: 2015-12-21 Impact factor: 4.982
Authors: Kathryn Clarkston; Joy Lee; Sarah Donoghue; Heidi Peters; Hernan Eiroa; Amit A Shah; Kathleen Loomes; Jessica Wen; Mark Oliver; Winita Hardikar; Carlos E Prada; Akihiro Asai Journal: Am J Med Genet A Date: 2020-12-24 Impact factor: 2.802
Authors: Roland Posset; Angeles Garcia-Cazorla; Vassili Valayannopoulos; Elisa Leão Teles; Carlo Dionisi-Vici; Anaïs Brassier; Alberto B Burlina; Peter Burgard; Elisenda Cortès-Saladelafont; Dries Dobbelaere; Maria L Couce; Jolanta Sykut-Cegielska; Johannes Häberle; Allan M Lund; Anupam Chakrapani; Manuel Schiff; John H Walter; Jiri Zeman; Roshni Vara; Stefan Kölker Journal: J Inherit Metab Dis Date: 2016-04-22 Impact factor: 4.982
Authors: Roland Posset; Sven F Garbade; Nikolas Boy; Alberto B Burlina; Carlo Dionisi-Vici; Dries Dobbelaere; Angeles Garcia-Cazorla; Pascale de Lonlay; Elisa Leão Teles; Roshni Vara; Nicholas Ah Mew; Mark L Batshaw; Matthias R Baumgartner; Shawn E McCandless; Jennifer Seminara; Marshall Summar; Georg F Hoffmann; Stefan Kölker; Peter Burgard Journal: J Inherit Metab Dis Date: 2019-01 Impact factor: 4.982