Abstract
Background
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.
Methods
Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta-analysis 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-regression.
Results
Twenty-four publications report onset time (n = 1542 patients), survival of EO (n = 665 patients) and outcome at one year of life (n = 172 patients). Proportions for EO manifestation (95 % confidence interval) were: CPS1D = 0.75 (0.61;0.88); OTCDm = 0.52 (0.39;0.65); OTCDf = 0.07 (0.03;0.11); ASSD = 0.65 (0.57;0.73); ASLD = 0.60 (0.44;0.77); for surviving EO patients: CPS1D = 0.64 (0.50;0.79); OTCDm = 0.40 (0.16;0.64); OTCDf = 0.57 (0.29;0.85); ASSD = 0.67 (0.48;0.86); ASLD = 0.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D = 0.20 (0.07;0.38); OTCDm = 0.15 (0.00;0.39); OTCDf no data; ASSD = 0.36 (0.13;0.60); ASLD = 0.36 (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.
Conclusions
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.
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Abbreviations
- ARG1:
-
arginase 1
- ASLD:
-
argininosuccinate lyase deficiency
- ASSD:
-
argininosuccinate synthetase deficiency
- CPS1D:
-
carbamylphosphate synthetase 1 deficiency
- E-IMD:
-
European registry and network for Intoxication type Metabolic Diseases
- HHH syndrome:
-
hyperammonaemia-hyperornithinaemia-homocitrullinuria syndrome
- IMD:
-
inherited metabolic disease
- NAGSD:
-
N-acetylglutamate synthase deficiency
- NBS:
-
newborn screening
- OTCD:
-
ornithine transcarbamylase deficiency
- OTCDf:
-
OTC deficiency, female patients
- OTCDm:
-
OTC deficiency, male patients
- RCT(s):
-
randomized controlled trial(s)
- UCD(s):
-
urea cycle disorder(s)
- UCDC:
-
Urea Cycle Disorders Consortium
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Acknowledgments
This study was conducted as part of the study “Long-term outcome of patients with inborn errors of the urea cycle disorder” funded by the Dietmar Hopp Foundation, St. Leon-Rot, Germany. PB also received a grant by Cytonet GmbH & Co. KG Weinheim, Germany for the literature search. The authors thank Christian Stock, Institute of Medical Biometrics and Informatics, Heidelberg University for helpful discussion of procedures and results.
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Peter Burgard has received a grant from Cytonet GmbH & Co. KG Weinheim, Germany, honoraria for advisory board membership from Merck Serono GmbH, and lecture fees from Swedish Orphan Biovitrum GmbH.
Stefan Kölker and Gisela Haege declare to have no conflict of interest.
Martin Lindner has received consultant fees from Cytonet GmbH & Co. KG Weinheim, Germany, and a writing honorarium from Orphan Europe.
Georg F Hoffmann has received lecture fees from Danone GmbH.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
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Communicated by: Carlo Dionisi-Vici
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Burgard, P., Kölker, S., Haege, G. et al. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders—review and meta-analysis of observational studies published over more than 35 years. J Inherit Metab Dis 39, 219–229 (2016). https://doi.org/10.1007/s10545-015-9901-1
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DOI: https://doi.org/10.1007/s10545-015-9901-1