Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.
Bibliographical noteFunding Information:
All UCDC and E-IMD sites contributed to the datasets of the longitudinal studies used in this publication. Principal investigators and personnel with key contributions are listed as individual contributors of the UCDC and E-IMD consortia study group. Furthermore, we gratefully acknowledge subsequent study coordinators—Saima Ali, Sondra Bloxam, Kia Bryan, Liora Caspi, Sara Elsbecker, Joan Hart, Melanie Horn, Elijah Kravets, Audrey Lynn, Mary Mullins, Maya Muldowney, Kendall Parks, Thu Quan, Kara Simpson, Julia Smith, Suzanne Hollander, Hayden Vreugdenhil and Ashley Wilson—and study neuropsychologists—Fabienne Dietrich Alber, Talin Babikian, Heidi Bender, Christopher Boys, David Breiger, Mina Nguyen-Driver, Benjamin Goodlett, Elizabeth Kerr, Casey Krueger, Eva Mamak, Jacqueline H. Sanz, David Schwartz, Arianna K. Stefanatos, Rachel Tangen, Magdalena E. Walter, and Greta N. Wilkening. We would also like to acknowledge the contributions of (former) longitudinal study PIs: Mark L. Batshaw, Stephen Cederbaum, Annette Feigenbaum, Douglas S. Kerr, Brendan Lee, Uta Lichter-Konecki, Margretta R. Seashore, and Marshall L. Summar. In particular, we are indebted to all our UCD individuals 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 (NIH) Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research (ORDR), the National Center for Advancing Translational Science (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation, the Rothenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. This work was also supported in part by the Clinical Translational Core at Baylor College of Medicine which is supported by the IDDRC Grant No. U54HD083092 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), the Kettering Fund, and Dietmar Hopp Foundation. MZ was supported by the Physician-Scientist Program at University of Heidelberg and by a Career Development Fellowship provided by the Heidelberg Research Center for Molecular Medicine (HRCMM) in the framework of Excellence Initiative II of the German Research Foundation.
GFH received lecture fees from Nutricia. SK receives funding from Horizon Pharma Ireland Limited for the European Post-Authorization Registry for Ravicti (glycerol phenylbutyrate) oral liquid in partnership with the E-IMD (RRPE) (EU PAS Register No. EUPAS17267; https://www.encepp.eu/). AB has received speaker honoraria and travel support from Sanofi Genzyme, Biomarin, Takeda, PIAM, and Nutricia Danone. CPG has received lecture fees from Nutricia, Mead Johnson and Vitaflo-Nestlé España and travel reimbursement from Biomarin, Nutricia, Vitaflo-Nestlé España, and SOBI. The sponsors have in no way influenced the design, conductance, analysis and report of the present study. All other authors declare that they have no conflict of interest.