Abstract
Purpose: Liver transplantation (LTx) is performed in individuals with urea cycle disorders when medical management (MM) insufficiently prevents the occurrence of hyperammonemic events. However, there is a paucity of systematic analyses on the effects of LTx on health-related outcome parameters compared to individuals with comparable severity who are medically managed. Methods: We investigated the effects of LTx and MM on validated health-related outcome parameters, including the metabolic disease course, linear growth, and neurocognitive outcomes. Individuals were stratified into “severe” and “attenuated” categories based on the genotype-specific and validated in vitro enzyme activity. Results: LTx enabled metabolic stability by prevention of further hyperammonemic events after transplantation and was associated with a more favorable growth outcome compared with individuals remaining under MM. However, neurocognitive outcome in individuals with LTx did not differ from the medically managed counterparts as reflected by the frequency of motor abnormality and cognitive standard deviation score at last observation. Conclusion: Whereas LTx enabled metabolic stability without further need of protein restriction or nitrogen-scavenging therapy and was associated with a more favorable growth outcome, LTx—as currently performed—was not associated with improved neurocognitive outcomes compared with long-term MM in the investigated urea cycle disorders.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 101039 |
| Tidsskrift | Genetics in Medicine |
| Vol/bind | 26 |
| Udgave nummer | 4 |
| ISSN | 1098-3600 |
| DOI | |
| Status | Udgivet - apr. 2024 |
Bibliografisk note
Funding Information:The authors thank the following study coordinators: Saima Ali, Kia Bryan, Liora Caspi, Kiaira Coles, Sara Elsbecker, Debbie Fu, Florian Gleich, Seishu Horikoshi, Elijah Kravets, Genya Kisin, Rhonda Jones, Levonne Phillip, Thu Quan, Kara Simpson, Julia Sloan, Tamar Stricker, Hayden Vreugdenhil, Ashley Wilson, and Melissa Zerofsky—and study neuropsychologists—Fabienne Dietrich Alber, Elizabeth Kerr, Casey Krueger, Eva Mamak, Ami Norris-Brilliant, David Schwartz, Arianna K. Stefanatos, Rachel Tangen, and Magdalena E. Walter. The authors would also like to acknowledge the contributions of (former) longitudinal study PIs: Mark L. Batshaw, Stephen Cederbaum, Annette Feigenbaum, Brendan Lee, Uta Lichter-Konecki, Margretta R. Seashore, and Marshall L. Summar. Moreover, the authors thank Dr Carmen Capito, and Dr Florence Lacaille for their contribution. The authors are grateful for the contributions and leadership of the late Cynthia LeMons. Ms LeMons served as a Co-PI for the UCDC and the Executive Director for the National Urea Cycle Disorders Foundation. In particular, we are indebted to all our individuals with UCDs and their families for their trust, patience, and participation in both longitudinal registry studies for many years. The Urea Cycle Disorders Consortium (UCDC; U54HD061221) is part of the National Institutes of Health Rare Disease Clinical Research Network, supported through collaboration between the Office of Rare Diseases Research, the National Center for Advancing Translational Science and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The UCDC is also supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. In addition, support for neuropsychological testing is provided by a National Institutes of Health grant for Intellectual and Developmental Disability Research Centers (U54HD090257). This work was also supported in part by the Clinical Translational Core at Baylor College of Medicine, which is supported by the IDDRC grant number P50 HD103555 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The E-IMD patient registry has received funding by the European Union (E-IMD; EAHC no 2010 12 01; coordinator: Stefan Kölker), in the framework of the Health Programme. After the end of the EU funding period the E-IMD patient registry has been sustained by funding from the Kindness-for-Kids Foundation (Munich, Germany) and the Kettering Fund. This work was supported by a Trainee Research Fellowship Award 2022-2023 provided by the UCDC. S.K. and G.F.H. received funding from the Dietmar Hopp Foundation for coordinating the study “Newborn Screening and Metabolic Medicine 2020 (NBS2020)”, which included individuals with UCDs. Supplemental Table 3 Conceptualization: R.P. M.Z.; Data Curation: S.F.G. F.G. UCDC, E-IMD; Formal Analysis: R.P. S.F.G. F.G. S.S. J.G.O. A.L.G. S.C.S.N. A.-C.D. F.E. G.F.H. S.K. M.Z. UCDC, E-IMD; Methodology: R.P. S.F.G. F.G. S.S. J.G.O. A.L.G. S.C.S.N. A.-C.D. F.E. M.Z.; Investigation: R.P. S.F.G. F.G. F.G. S.S. J.G.O. A.L.G. S.C.S.N. A.-C.D. F.E. G.F.H. S.K. M.Z. UCDC, E-IMD; Resources: J.G.O. A.L.G. S.C.S.N. G.F.H. S.K.; Validation: R.P. S.F.G. F.G. M.Z.; Visualization: S.F.G. F.G.; Writing-original draft: R.P. M.Z.; Writing-review and editing: R.P. S.F.G. F.G. F.G. S.S. J.G.O. A.L.G. S.C.S.N. A.-C.D. F.E. G.F.H. S.K. M.Z. UCDC, E-IMD; Supervision: S.C.S.N. S.K. All procedures complied with the ethical standards of the Helsinki Declaration of 1975, as revised in 2013. Before enrollment to this study, written informed consent was given by the probands or their legal representatives. The respective UCDC and E-IMD study sites received written approval from an Institutional Review Board or Research Ethics Committee. Roland Posset receives consultancy fees from Immedica Pharma AB. Stefan Kölker receives funding from Immedica Pharma AB for the European Post-Authorization Registry for Ravicti (glycerol phenylbutyrate) oral liquid in partnership with the European registry and network for Intoxication type Metabolic Diseases (E-IMD) (EU PAS Register number EUPAS17267; http://www.encepp.eu/). Georg F. Hoffmann received lecture fees from Swedish Orphan Biovitrum GmbH. The sponsors have in no way influenced the design, conductance, analysis, and report of this study. All other authors declare no conflicts of interest.
Funding Information:
The Urea Cycle Disorders Consortium (UCDC; U54HD061221) is part of the National Institutes of Health Rare Disease Clinical Research Network, supported through collaboration between the Office of Rare Diseases Research, the National Center for Advancing Translational Science and the Eunice Kennedy Shriver National Institute of Child Health and Human Development . The UCDC is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation , the Kettering Fund , and the National Urea Cycle Disorders Foundation . In addition, support for neuropsychological testing is provided by a National Institutes of Health grant for Intellectual and Developmental Disability Research Centers (U54HD090257). This work was also supported in part by the Clinical Translational Core at Baylor College of Medicine , which is supported by the IDDRC grant number P50 HD103555 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development . The E-IMD patient registry has received funding by the European Union (E-IMD; EAHC no 2010 12 01; coordinator: Stefan Kölker), in the framework of the Health Programme. After the end of the EU funding period the E-IMD patient registry has been sustained by funding from the Kindness-for-Kids Foundation (Munich, Germany) and the Kettering Fund. This work was supported by a Trainee Research Fellowship Award 2022-2023 provided by the UCDC . S.K. and G.F.H. received funding from the Dietmar Hopp Foundation for coordinating the study “Newborn Screening and Metabolic Medicine 2020 (NBS2020)”, which included individuals with UCDs.
Funding Information:
Roland Posset receives consultancy fees from Immedica Pharma AB. Stefan Kölker receives funding from Immedica Pharma AB for the European Post-Authorization Registry for Ravicti (glycerol phenylbutyrate) oral liquid in partnership with the European registry and network for Intoxication type Metabolic Diseases (E-IMD) (EU PAS Register number EUPAS17267; http://www.encepp.eu/ ). Georg F. Hoffmann received lecture fees from Swedish Orphan Biovitrum GmbH. The sponsors have in no way influenced the design, conductance, analysis, and report of this study. All other authors declare no conflicts of interest.
Publisher Copyright:
© 2023 The Authors
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