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KG, Weinheim, Germany"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>For urea cycle disorders (UCD), proportions and mortality of early onset (EO) patients, as well as outcome at one year of life show large variability. We aimed to integrate available evidence to create benchmarks for new diagnostic and therapeutic strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta\u2010analysis was done for four UCDs, deficiency of carbamylphosphate synthetase 1 (CPS1D), male\/female ornithine transcarbamylase (OTCDm\/f), argininosuccinate synthetase (ASSD) and lyase (ASLD). Effects of publication year and geographic area were analysed by meta\u2010regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty\u2010four publications report onset time (n\u2009=\u20091542 patients), survival of EO (n\u2009=\u2009665 patients) and outcome at one year of life (n\u2009=\u2009172 patients). Proportions for EO manifestation (95 % confidence interval) were: CPS1D\u2009=\u20090.75 (0.61;0.88); OTCDm\u2009=\u20090.52 (0.39;0.65); OTCDf\u2009=\u20090.07 (0.03;0.11); ASSD\u2009=\u20090.65 (0.57;0.73); ASLD\u2009=\u20090.60 (0.44;0.77); for surviving EO patients: CPS1D\u2009=\u20090.64 (0.50;0.79); OTCDm\u2009=\u20090.40 (0.16;0.64); OTCDf\u2009=\u20090.57 (0.29;0.85); ASSD\u2009=\u20090.67 (0.48;0.86); ASLD\u2009=\u20090.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D\u2009=\u20090.20 (0.07;0.38); OTCDm\u2009=\u20090.15 (0.00;0.39); OTCDf no data; ASSD\u2009=\u20090.36 (0.13;0.60); ASLD\u2009=\u20090.36 (0.17;0.58). Between study variation was large. Year of publication had no effect. Studies from Europe showed lower survival rates than those from Japan or USA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>UCDs, except for OTCDf, have high risks of EO disease manifestation and, except for ASLD, of neonatal death. No improvement of survival was observed over more than three decades. Geographic variation remains to be explained. This comprehensive description of the natural history of EO UCDs should be considered by scientists, clinicians, health policy makers and guideline developers.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-015-9901-1","type":"journal-article","created":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T12:30:53Z","timestamp":1449145853000},"page":"219-229","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders\u2014review and meta\u2010analysis of observational studies published over more than 35 years"],"prefix":"10.1002","volume":"39","author":[{"given":"Peter","family":"Burgard","sequence":"first","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, Division for Neuropaediatrics and Metabolic Medicine Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg D\u201069120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"K\u00f6lker","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, Division for Neuropaediatrics and Metabolic Medicine Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg D\u201069120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela","family":"Haege","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, Division for Neuropaediatrics and Metabolic Medicine Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg D\u201069120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lindner","sequence":"additional","affiliation":[{"name":"University Hospital Frankfurt, Children's Hospital Theodor\u2010Stern\u2010Kai 7 Frankfurt am Main D\u201060590 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg F.","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Centre for Paediatric and Adolescent Medicine, Division for Neuropaediatrics and Metabolic Medicine Heidelberg University Hospital Im Neuenheimer Feld 430 Heidelberg D\u201069120 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,12,3]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"GeneReviews(R)","author":"Ah Mew N","year":"2014"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2005-2633I"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-003-1347-z"},{"key":"e_1_2_10_5_1","volume-title":"EpiGear International Pty Ltd","author":"Barendregt JJ","year":"2011"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jech-2013-203104"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.08.001"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.8167"},{"key":"e_1_2_10_9_1","unstructured":"BrusilowS HorwichAL(2011)Urea cycle enzymes.In:ValleD(ed)The Online Metabolic and Molecular Bases of Inherited Disease.http:\/\/ommbid.mhmedical.com\/content.aspx?bookid=971&sectionid=62674945."},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2010.44"},{"key":"e_1_2_10_11_1","unstructured":"E\u2010IMDEuropean registry and network for Intoxication type Metabolic Diseaseshttps:\/\/www.eimd\u2010registry.org\/17.02.2015."},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2008.05.007"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066596"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-7-32"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1037\/0021-9010.74.3.469"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1186"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1186"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.5453"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2008.00923.x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9427-0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.1482"},{"key":"e_1_2_10_22_1","unstructured":"K\u00f6lkerS CazorlaAG ValayannopoulosVet al (2015a)The phenotypic spectrum of organic acidurias and urea cycle disorders. 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