Abstract
Argininosuccinic aciduria (ASA) is an inherited urea cycle disorder and has a highly variable phenotypic spectrum ranging from individuals with lethal hyperammonemic encephalopathy, liver dysfunction, and cognitive deterioration, to individuals with a mild disease course. As it is difficult to predict the phenotypic severity, we aimed at identifying a reliable disease prediction model. We applied a biallelic expression system to assess the functional impact of pathogenic argininosuccinate lyase (ASL) variants and to determine the enzymatic activity of ASL in 58 individuals with ASA. This cohort represented 42 ASL gene variants and 42 combinations in total. Enzymatic ASL activity was compared with biochemical and clinical endpoints from the UCDC and E-IMD databases. Enzymatic ASL activity correlated with peak plasma ammonium concentration at initial presentation and with the number of hyperammonemic events (HAEs) per year of observation. Individuals with ≤9% of enzymatic activity had more severe initial decompensations and a higher annual frequency of HAEs than individuals above this threshold. Enzymatic ASL activity also correlated with the cognitive outcome and the severity of the liver disease, enabling a reliable severity prediction for individuals with ASA. Thus, enzymatic activity measured by this novel expression system can serve as an important marker of phenotypic severity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 946-960 |
| Number of pages | 15 |
| Journal | Human mutation |
| Volume | 41 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2020 |
Bibliographical note
Funding Information:This study was also supported in part by the Clinical Translational Core at Baylor College of Medicine which is supported by the IDDRC grant number 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 K?lker), 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. This study was supported by a Trainee Research Fellowship Award 2018-2019 provided by the UCDC. No external funding was secured for the study. M. Z. (Heidelberg, Germany) was supported by the Physician-Scientist Program at the 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.
Funding 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 UCDC and E‐IMD consortia study group members. Furthermore, we gratefully acknowledge subsequent study coordinators—Jennifer Seminara, Saima Ali, Sondra Bloxam, Kia Bryan, Sara Elsbecker, Joan Hart, Melanie Horn, Elijah Kravets, Audrey Lynn, Mary Mullins, Maya Muldowney, Kendall Parks, Ulrike Mütze, Thu Quan, Kara Simpson, Julia Smith, Suzanne Hollander, and Hayden Vreugdenhil—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, 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, Marshall L. Summar, Peter Burgard, Curtis R. Coughlin II, Gregory Enns, Renata C. Gallagher, Cynthia Le Mons, Shawn E. McCandless, Tamar Stricker, Mendel Tuchman, Susan Waisbren, and James D. Weisfeld‐Adams. 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 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 an NIH grant for Intellectual and Developmental Disability Research Centers (U54HD090257). This study was also supported in part by the Clinical Translational Core at Baylor College of Medicine which is supported by the IDDRC grant number 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. This study was supported by a Trainee Research Fellowship Award 2018‐2019 provided by the UCDC. No external funding was secured for the study. M. Z. (Heidelberg, Germany) was supported by the Physician‐Scientist Program at the 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.
Funding Information:
S. K. 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 (EU PAS Register no. EUPAS17267; http://www.encepp.eu/ ). GFH received lecture fees from Nutricia. A. B. B. has received speaker honoraria and travel support from Sanofi Genzyme, Biomarin, Takeda, PIAM, and Nutricia Danone. The sponsors have in no way influenced the design, conductance, analysis, and report of the present study. All other authors declare that there are no conflicts of interest.
Publisher Copyright:
© 2020 Wiley Periodicals, Inc.
Keywords
- argininosuccinic aciduria
- clinical outcome
- disease course
- enzymatic ASL activity
- predictive biomarker