The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation
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The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.
To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry.
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).
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.
KeywordsNewborn Screening Newborn Period Urea Cycle Disorder Metabolic Crisis Propionic Aciduria
Carbamylphosphate synthetase 1
European network and registry for homocystinurias and methylation defects
European registry and network for intoxication type metabolic diseases
Glutaric aciduria type 1
Quality of life
Urea cycle disorder
We are indebted to all patients and their families who have been willing to contribute to this study, to share their experience on living with a rare disease, and for their trust, and we thank all colleagues very much for their contribution to the project. We are grateful for fruitful collaboration with the following clinical partners, patient support groups and industrial partners (in alphabetical order of countries): Lut de Baere, Nathalie Stroobant (Belgische Organisatie voor Kinderen en Volwassenen met een Stofwisselingsziekte VZW [BOKS], Belgium), Nela Carić (Hrvatska udruga za rijetke bolesti, Croatia), Tomas Honzik (Charles University and General University of Prague, First Faculty of Medicine, Prague, Czech Republic), Annika and Kennet Rovsing (PND - Protein Nedbrydnings Defekt Foreningen, Denmark), Samantha Parker (Orphan Europe SARL, France), EURORDIS, European Organisation for Rare Disease (France), Eric Bauchart (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), Markus Ott, Beate Szczerbak (Nutricia Metabolics GmbH, Germany), Hubertus von Voss, Raimund Schmid (Kindernetzwerk e.V., Germany), Mandy Kretschmer (Glutarazidurie e.V., Germany), Reinhild Link (Wiesbaden, representing the SSIEM Dieticians Group), Harikleia Ioannou (University A’Pediatric Department, Metabolic Laboratory, ‘Hippocration’ General Hospital of Thessaloniki), Zarifis Dimitroulis (KRIKOS ZOIS – Society for patients and friends of patients with inherited metabolic diseases), Evridiki Drogari (University of Athens, Aghia Sophia Children's Hospital, Unit of Metabolic Diseases, Athens), Renza Barbon Galluppi (UNIAMO FIMR, Italy), Susan Udina (COMETA ASMME – Associazione Studio Malattie Metaboliche Ereditarie – ONLUS, Italy), Hanka Meutgeert (Volwassenen en Kinderen met Stoffwisselingsziekten [VKS], Netherlands), Vanessa Ferreira (Associação Portuguesa CDG, Portugal), Miguel Macedo (Apofen, Portugal), Sérgio Braz Antão (Rarrisimas, Portugal), Sergi Faber (Catalana de Trastorns Metabòlics Hereditaris, Spain), Sofia Nordin (Svedish Orphan Biovitrium AB [SOBI], Sweden), and Steven Hannigan (CLIMB, Children Living with Inherited Metabolic Diseases, National Information Centre for Metabolic Diseases, and EMDA, the European Metabolic Disorders Alliance).
This publication arises from the project “European registry and network for intoxication type metabolic diseases” (E-IMD; EAHC no 2010 12 01) which has received funding from the European Union, in the framework of the Health Programme. After the end of the EU funding period the E-IMD patient registry will be sustained by funding from the Kindness-for-Kids Foundation (Munich, Germany).
M. Baumgartner, J. Häberle and A. Laemmle (Zurich, Switzerland) are supported by radiz – Rare Disease Initiative Zurich, a clinical research priority programme of the University of Zurich.
Drs Murphy and Lachmann were supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.
Compliance with ethics guidelines
Conflict of interest
Human and animal rights and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human studies (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients or their legal guardians prior to being included in the study in countries where this was needed by law.
This article does not contain animal subjects.
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