BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

1st Faculty of Medicine Charles University and General University of Prague Prague Czech Republic

1st Pediatric Department Metabolic Laboratory General Hospital of Thessaloniki 'Hippocration' Thessaloniki Greece

Azienda Ospedaliera di Padova U O C Malattie Metaboliche Ereditarie Padova Italy

Birmingham Children's Hospital NHS Foundation Trust Steelhouse Lane Birmingham B4 6NH UK

Centre de Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte Hôpital Jeanne de Flandre Lille France

Centre de Référence des Maladies Héréditaires du Métabolisme Service de Neurologie Hôpital d'Enfants CHU Timone Marseilles France

Centre for Inherited Metabolic Diseases Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Children's National Medical Center 111 Michigan Avenue N W Washington DC 20010 USA

Cliniques Universitaires St Luc Université Catholique de Louvain Service Gastroentérologie and Hépatologie Pédiatrique Bruxelles Belgium

Department of General Pediatrics Division of Inherited Metabolic Diseases University Children's Hospital Heidelberg Im Neuenheimer Feld 430 69120 Heidelberg Germany

Department of Laboratory Diagnostics The Children's Memorial Health Institute Warsaw Poland

Department of Pediatrics Academisch Medisch Centrum Amsterdam Netherlands

Department of Pediatrics Hospital Universitari Germans Trias 1 Pujol Badalona Spain

Department of Pediatrics Kumamoto University Hospital Kumamoto City Japan

Department of Pediatrics Metabolic Diseases Unit Hospital Infantil Universitario Niño Jesús Madrid Spain

Division of Metabolism and Children's Research Centre University Children's Hospital Zurich Steinwiesstraße 75 8032 Zurich Switzerland

Erasmus MC Sophia Kinderziekenhuis Erasmus Universiteit Rotterdam Rotterdam Netherlands

Evelina Children's Hospital St Thomas' Hospital London United Kingdom

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

Hôpital Robert Debré Université de Paris Paris France

Hospital Materno Infantil Málaga Spain

Hospital San Joan de Deu Servicio de Neurologia and CIBERER ISCIII Barcelona Spain

Hospital Virgen de la Arrixaca de Murcia Inborn Metabolic Disease Unit El Palmar Spain

Institute of Mother and Child Care Alfred Rusescu Bucharest Romania

Manchester Academic Health Science Centre University of Manchester Willink Biochemical Genetics Unit Genetic Medicine Manchester UK

Medical University of Innsbruck Clinic for Pediatrics 1 Inherited Metabolic Disorders Innsbruck Austria

Metabolic Unit Department of Pediatrics Hospital Clinico Universitario de Santiago de Compostela Santiago de Compostela Spain

Metabolic Unit Great Ormond Street Hospital and Institute for Child Health University College London London UK

N 1 R M A N Om Rachna Society Vashi Navi Mumbai Mumbai India

National Hospital for Neurology and Neurosurgery Charles Dent Metabolic Unit London UK

Ospedale Pediatrico Bambino Gésu U O C Patologia Metabolica Rome Italy

School of Medicine University Hospital Center Zagreb and University of Zagreb Zagreb Croatia

Screening Department Institute of Mother and Child Warsaw Poland

Unidade de Doenças Metabólicas Serviço de Pediatria Hospital de S João EPE Porto Portugal

Universitätsklinikum Hamburg Eppendorf Klinik für Kinder und Jugendmedizin Hamburg Germany

University Hospital Center Zagreb Zagreb Croatia

University Hospital Vrije Universiteit Brussel Bruxelles Belgium

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J Inherit Metab Dis. 2015 Nov;38(6):1157-8. doi: 10.1007/s10545-015-9868-y. PubMed   Garcia Cazorla, Angeles [corrected to Garcia-Cazorla, Angeles]

Zobrazit více v PubMed

Brain. 2009 Jul;132(Pt 7):1764-82 PubMed

Pediatr Res. 2007 Sep;62(3):357-63 PubMed

J Inherit Metab Dis. 2015 Nov;38(6):1155-6 PubMed

J Inherit Metab Dis. 2008 Feb;31(1):44-54 PubMed

Biochim Biophys Acta. 2010 Jun;1802(6):552-60 PubMed

Pediatr Transplant. 2011 Sep;15(6):E110-5 PubMed

J Pediatr. 2010 Jan;156(1):128-34 PubMed

N Engl J Med. 2007 May 31;356(22):2282-92 PubMed

Pediatr Dev Pathol. 2002 Nov-Dec;5(6):597-601 PubMed

J Neurochem. 2007 May;101(3):806-14 PubMed

J Mol Med (Berl). 2007 Jul;85(7):763-70 PubMed

J Biol Chem. 2005 Jun 10;280(23):21830-6 PubMed

J Inherit Metab Dis. 2013 Jul;36(4):635-44 PubMed

Mol Genet Metab. 2008 Aug;94(4):397-402 PubMed

Pediatr Res. 2006 Jun;59(6):840-7 PubMed

J Child Neurol. 2010 Mar;25(3):352-8 PubMed

Mol Genet Metab. 2010 May;100(1):24-8 PubMed

Brain. 2010 Jan;133(Pt 1):76-92 PubMed

Orphanet J Rare Dis. 2013 Jan 10;8:6 PubMed

Eur J Clin Nutr. 1990 Jan;44(1):45-60 PubMed

J Inherit Metab Dis. 2014 Jan;37(1):21-30 PubMed

Ann Neurol. 2010 Nov;68(5):743-52 PubMed

Mov Disord. 2008 Dec 15;23(16):2392-7 PubMed

Neurology. 2012 Aug 14;79(7):e63-8 PubMed

Mol Genet Metab. 2009 Jul;97(3):172-8 PubMed

J Clin Invest. 2007 Nov;117(11):3258-70 PubMed

Mol Genet Metab. 2012 Jan;105(1):5-9 PubMed

J Inherit Metab Dis. 2011 Jun;34(3):677-94 PubMed

J Inherit Metab Dis. 2006 Aug;29(4):586 PubMed

Brain. 2007 Jul;130(Pt 7):1905-20 PubMed

FASEB J. 2009 Apr;23(4):1252-61 PubMed

J Inherit Metab Dis. 2013 Jul;36(4):595-612 PubMed

AJNR Am J Neuroradiol. 2003 Jun-Jul;24(6):1184-7 PubMed

Stat Med. 1998 Feb 28;17 (4):407-29 PubMed

J Inherit Metab Dis. 2013 May;36(3):525-33 PubMed

J Inherit Metab Dis. 2009 Oct;32(5):630-9 PubMed

Mol Genet Metab. 2014 Sep-Oct;113(1-2):113-7 PubMed

Mol Genet Metab. 2012 Nov;107(3):315-21 PubMed

J Nutr. 2006 Jan;136(1 Suppl):218S-26S PubMed

Mitochondrion. 2014 Jul;17:150-6 PubMed

Am J Ophthalmol. 2009 May;147(5):929-33 PubMed

Biochem J. 2006 Aug 15;398(1):107-12 PubMed

Mol Genet Metab. 2013 Mar;108(3):161-5 PubMed

Acta Paediatr. 1997 Oct;86(10):1144-7 PubMed

Eur J Pediatr. 2011 Feb;170(2):241-5 PubMed

Biochim Biophys Acta. 2013 Oct;1832(10):1463-72 PubMed

J Neuroophthalmol. 2011 Dec;31(4):344-6 PubMed

JIMD Rep. 2015;22:29-38 PubMed

J Cereb Blood Flow Metab. 2003 Mar;23(3):263-74 PubMed

Pediatr Res. 2009 Jul;66(1):91-5 PubMed

J Pediatr. 2011 Nov;159(5):862-4 PubMed

J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):327-31 PubMed

Orphanet J Rare Dis. 2014 Jul 16;9:105 PubMed

J Inherit Metab Dis. 2014 Sep;37(5):763-73 PubMed

J Inherit Metab Dis. 2008 Feb;31(1):35-43 PubMed

Mol Genet Metab. 2010;100 Suppl 1:S20-30 PubMed

J Inherit Metab Dis. 2006 Dec;29(6):701-4; discussion 705-6 PubMed

Mol Genet Metab. 2008 May;94(1):4-15 PubMed

J Inherit Metab Dis. 1999 Dec;22(8):867-81 PubMed

Biochem Med. 1975 Jan;12(1):12-21 PubMed

Pflugers Arch. 2008 Oct;457(1):223-31 PubMed

J Clin Invest. 1979 Dec;64(6):1544-51 PubMed

Orphanet J Rare Dis. 2013 Sep 23;8:148 PubMed

Pediatr Res. 2007 Aug;62(2):225-30 PubMed

Am J Hum Genet. 2004 Dec;75(6):1136-42 PubMed

J Pediatr. 2001 Jan;138(1 Suppl):S46-54; discussion S54-5 PubMed

Acta Paediatr. 2008 Oct;97(10):1420-5 PubMed

J Inherit Metab Dis. 2005;28(3):407-14 PubMed

J Pediatr. 2013 Feb;162(2):324-9.e1 PubMed

Mol Genet Metab. 2010;100 Suppl 1:S97-105 PubMed

Mol Genet Metab. 2012 Jan;105(1):16-25 PubMed

Ann Hum Biol. 2011 Jan;38(1):7-11 PubMed

J Neurochem. 2002 Jul;82(2):410-9 PubMed

Mol Genet Metab. 2012 Aug;106(4):488-90 PubMed

J Biol Chem. 2011 May 20;286(20):17777-84 PubMed

Nat Med. 2011 Nov 13;17(12):1619-26 PubMed

Tohoku J Exp Med. 1982 Jul;137(3):329-34 PubMed

Orphanet J Rare Dis. 2012 Jan 25;7:9 PubMed

Neurology. 2013 Aug 27;81(9):849-50 PubMed

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