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Author Notes:

Johan L. K. Van Hove, Department of Pediatrics, Section of Clinic Genetics and Metabolism, University of Colorado, Education 2 South, L28‐4114, 13121 East 17th Ave, Aurora, CO 80045, USA. Email: johan.vanhove@childrenscolorado.org

Study concept and design: Johan L. K. Van Hove. Patient care data: Johan L. K. Van Hove, Lina Ghaloul‐Gonzalez, and Juanita Neira‐Fresneda. Control data: Johan L. K. Van Hove, Lisa Schlichting, Cheryl Peck, Linda Gabel, and Marisa W. Friederich. Laboratory studies: Michael A. Swanson. Statistical analysis: Kristen Miller, Suhong Tong, and Johan L. K. Van Hove. First draft writing: Johan L. K. Van Hove, Michael A. Swanson, and Kristen Miller. Critical rewriting: Johan L. K. Van Hove, Kristen Miller, Michael A. Swanson, Sarah P. Young, and Marisa W. Friederich Lina Ghaloul‐Gonzalez. Leadership and funding: Johan L. K. Van Hove. Final responsibility, guarantor, and communicating author: Johan L. K. Van Hove.

The authors thank the many colleagues who provided clinical information and could not be individually recognized for their contribution. The authors thank Drs S. Wortmann and H. Björneson who provided information on their patients with transient nonketotic hyperglycinemia or ischemic brain damage with increased CSF glycine levels. The authors would like to acknowledge the philanthropic support of the patient organizations that funded this study: NKH Crusaders, Hope for NKH Foundation, Brodyn's Friends, Nora Jane Almany Foundation, the Dickens Family Foundation, Les Petits Bourdons, the Lucas John Foundation, the Jacqueline Kirby Foundation, Exelon Corporation, and the University of Colorado Foundation NKH research fund. Funding sources had no role in the design or execution of the study, the interpretation of data, or the writing of the study.

The authors have no conflicts of interest.



  • Science & Technology
  • Life Sciences & Biomedicine
  • Endocrinology & Metabolism
  • Genetics & Heredity
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • cerebrospinal fluid
  • d-serine
  • l-serine
  • nonketotic hyperglycinemia
  • threonine
  • SLC1A4

Cerebrospinal fluid amino acids glycine, serine, and threonine in nonketotic hyperglycinemia

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Journal Title:



Volume 45, Number 4


, Pages 734-747

Type of Work:

Article | Final Publisher PDF


Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age-related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross-sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d-serine and l-serine levels were stereoselectively determined in seven NKH patients and compared to 29 age-matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age-adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age-adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d-serine was more reduced than l-serine, with a decreased d/l-serine ratio, indicating a specific impact on d-serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l-serine, d-serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one-carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.

Copyright information:

© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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