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Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders

  • Clinical Research Article
  • Published:
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Abstract

Background

Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment.

Methods

Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated.

Results

Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI.

Conclusion

VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management.

Impact

  • The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD).

  • This is the first report of longitudinal biomarkers for treatment outcome in UCD.

  • These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.

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Data availability

As per the policies of the NIH RDCRN, all data from a particular consortium will be deposited into dbGaP. This data deposition will be done after the funding period for the consortium is completed.  At the current time, we are not able to submit participant-level data in a public repository.

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Acknowledgements

We would like to acknowledge the invaluable work of the study coordinators and the psychologists of each of the Urea Cycle Disorders Consortium sites without whom this study would not have been possible. We also thank the participants of the Longitudinal Study for their time and dedication to making this study possible. We would like to dedicate this manuscript to the memory of Cindy Le Mons, Executive Director of the National Urea Cycle Disorders Foundation (NUCDF), who was Co-Principal Investigator of the Urea Cycle Disorders Consortium and a tireless champion and advocate for patients with UCD. She touched and improved the lives of so many patients worldwide. Funding and programmatic support for this project has been provided by the Urea Cycle Disorders Consortium (UCDC; U54HD061221), 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), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). The Urea Cycle Disorders Consortium is also supported by the O’Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund. In addition, support for neuropsychological testing is provided by an NIH grant for Intellectual and Developmental Disability Research Centers (P30HD040677).

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA

    Uta Lichter-Konecki & Jirair K. Bedoyan

  2. UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Uta Lichter-Konecki & Jirair K. Bedoyan

  3. Department of Pediatrics, George Washington University School of Medicine, Washington, DC, USA

    Jacqueline H. Sanz, Nicholas Ah Mew, Andrea Gropman & Robert McCarter

  4. Department of Psychiatry and Behavioral Sciences, George Washington University School of Medicine, Washington, DC, USA

    Jacqueline H. Sanz

  5. Children’s National Hospital, Washington, DC, USA

    Jacqueline H. Sanz, Nicholas Ah Mew, Andrea Gropman, Jennifer Seminara & Robert McCarter

  6. University Children’s Hospital, Zurich, Switzerland

    Matthias R. Baumgartner & Tamar Stricker

  7. Boston Children’s Hospital, Boston, MA, USA

    Gerard Berry & Susan Waisbren

  8. University of Minnesota, Minneapolis, MN, USA

    Susan A. Berry

  9. Heidelberg University, Heidelberg, Germany

    Peter Burgard & Georg F. Hoffmann

  10. Baylor College of Medicine, Houston, TX, USA

    Lindsay Burrage & Sandesh C. S. Nagamani

  11. Children’s Hospital Colorado, Aurora, CO, USA

    Curtis Coughlin & Shawn E. McCandless

  12. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    George A. Diaz

  13. Stanford University Medical Center, Stanford, CA, USA

    Gregory Enns

  14. University of California San Francisco, San Francisco, CA, USA

    Renata C. Gallagher

  15. Oregon Health and Science University, Portland, OR, USA

    Cary O. Harding

  16. National Urea Cycle Disorders Foundation, Pasadena, CA, USA

    Cynthia Le Mons

  17. Seattle Children’s Hospital, Seattle, WA, USA

    J. Lawrence Merritt II

  18. The Hospital for Sick Children, Toronto, ON, Canada

    Andreas Schulze

  19. University of Toronto, Toronto, ON, Canada

    Andreas Schulze

  20. The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

    Derek Wong

  21. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Marc Yudkoff

Authors
  1. Uta Lichter-Konecki
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  2. Jacqueline H. Sanz
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  3. Robert McCarter
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Consortia

Urea Cycle Disorders Consortium

  • Nicholas Ah Mew
  • , Matthias R. Baumgartner
  • , Jirair K. Bedoyan
  • , Gerard Berry
  • , Susan A. Berry
  • , Peter Burgard
  • , Lindsay Burrage
  • , Curtis Coughlin
  • , George A. Diaz
  • , Gregory Enns
  • , Renata C. Gallagher
  • , Andrea Gropman
  • , Cary O. Harding
  • , Georg F. Hoffmann
  • , Cynthia Le Mons
  • , Shawn E. McCandless
  • , J. Lawrence Merritt II
  • , Sandesh C. S. Nagamani
  • , Andreas Schulze
  • , Jennifer Seminara
  • , Tamar Stricker
  • , Susan Waisbren
  • , Derek Wong
  •  & Marc Yudkoff

Contributions

U.L.-K., J.H.S., and R.C. substantially contributed to conception and design, acquisition of data, data analysis and drafting of the article as well as revising it critically for important intellectual content. All three authors provided final approval of the version to be published. The members of the UCDC contributed to acquisition of data and revising the manuscript critically and provided final approval of the version to be published.

Corresponding author

Correspondence to Uta Lichter-Konecki.

Ethics declarations

Competing interests

U.L.-K., J.H.S., and R.C. have no potential conflicts of interest regarding this study. Of the consortium authors: Mathias Baumgartner received a research fund from Nutricia and is a member of the clinical advisory boards of Hemoshear and Moderna neither of these involvements is regarding Urea Cycle disorders. George Diaz is now working for iECure. His involvement in the UCDC occurred, while he was employed by Icahn School of Medicine at Mount Sinai and he declared no competing interests regarding this manuscript. Gregory Enns receives compensation as a consultant for AllStripes, Hemoshear, Horizon Therapeutics, M6P Therapeutics, and Ultragenyx Pharmaceutical and clinical trial support from Aeglea Biotherapeutics. J Lawrence Merritt currently reports employment by, and stock ownership in, Ultragenyx Pharmaceutical Inc. His involvement in the UCDC occurred, while JLM was employed by Seattle Children’s Hospital, prior to this Ultragenyx employment and stock ownership. Andreas Schulze is consulting or on the advisory board of Ultragenyx and Horizon and conducts industry initiated clinical studies for Aeglea. Susan Waisbren consults Ultragenyx Gene Therapy.

Consent statement

The Longitudinal Study of the UCDC was approved by the IRBs at all participating sites and informed consent/assent was obtained from all study participants or legal guardians.

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Lichter-Konecki, U., Sanz, J.H., Urea Cycle Disorders Consortium. et al. Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders. Pediatr Res 94, 2005–2015 (2023). https://doi.org/10.1038/s41390-023-02722-y

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  • DOI: https://doi.org/10.1038/s41390-023-02722-y

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