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Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria

  • Research Report
  • Chapter
  • First Online:
JIMD Reports, Volume 34

Part of the book series: JIMD Reports ((JIMD,volume 34))

Abstract

Introduction: Researchers hypothesized that in phenylketonuria (PKU) high brain phenylalanine (Phe) levels and low brain tyrosine (Tyr) levels affect neuropsychological functioning. However, traditional magnetic resonance spectroscopy (MRS) yielded uncertain results of brain Phe and could not adequately measure brain Tyr. This pilot study examined the potential of correlated spectroscopy (COSY) to quantify these biomarkers and explain variability in neuropsychological functioning.

Methods: Nine adults with early treated classic PKU received magnetic resonance imaging (MRI) with COSY and a battery of neuropsychological tests. Brain Phe and Tyr in parietal white matter (PWM) were compared to results in gray matter of the posterior cingulate gyrus (PCG).

Results: Brain Phe ranged from 101 to 182 (mean = 136.76 ± 23.77) μmol/L in PCG and 76 to 185 (mean = 130.11 ± 37.88) μmol/L in PWM. Brain Tyr ranged from 4.0 to 7.4 (mean = 5.44 ± 1.01) μmol/L in PCG and 4.1 to 8.4 (mean = 5.90 ± 1.48) μmol/L in PWM. Correlation coefficients were largest for brain Phe PWM and measures of auditory memory (rho = −0.79), anxiety (rho = 0.79), and executive functioning (rho = 0.69). Associations were in the expected direction, with higher brain Phe and lower brain Tyr related to poorer functioning. The two participants with severe structural MRI abnormalities had low brain Tyr levels in PCG and 3/5 of the participants with moderate to severe MRI abnormalities had higher than average brain Phe levels.

Conclusion: COSY has the potential to quantify brain Phe and Tyr at low concentrations and in specific brain regions. In this pilot study, these biomarkers were associated with indices of neuropsychological functioning. Additional studies are needed to validate the COSY results.

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Authors and Affiliations

  1. Boston Children’s Hospital, 1 Autumn Street, #525, Boston, MA, 02115, USA

    Susan E. Waisbren, Sanjay P. Prabhu, Carter Petty, Vera Anastasoaie & Kalin Charette

  2. Harvard Medical School, Boston, MA, USA

    Susan E. Waisbren, Patricia Greenstein, Donald Schomer & Alexander P. Lin

  3. Beth Israel Deaconess Medical Center, Boston, MA, USA

    Patricia Greenstein & Donald Schomer

  4. Brigham and Women’s Hospital, Boston, MA, USA

    Daniel Rodriguez, Sai Merugumala & Alexander P. Lin

Authors
  1. Susan E. Waisbren
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  2. Sanjay P. Prabhu
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  3. Patricia Greenstein
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  4. Carter Petty
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  5. Donald Schomer
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  6. Vera Anastasoaie
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  7. Kalin Charette
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  8. Daniel Rodriguez
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  9. Sai Merugumala
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  10. Alexander P. Lin
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Corresponding author

Correspondence to Susan E. Waisbren .

Editor information

Editors and Affiliations

  1. Tulane University Medical School, New Orleans, Louisiana, USA

    Eva Morava

  2. Division of Metabolism and Children’s Research Centre, University Children’s Hospital Zurich, Zurich, Switzerland

    Matthias Baumgartner

  3. Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minnesota, USA

    Marc Patterson

  4. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  5. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  6. Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Nenad Blau, PhD

Appendices

Synopsis

Correlated Spectroscopy (COSY) measures brain phenylalanine (Phe) and tyrosine (Tyr) in distinct brain regions and may provide a means for understanding the variability in neuropsychological outcomes found in phenylketonuria (PKU).

Details of the Contributions of Individual Authors

Susan E. Waisbren, PhD, led the research team in planning the study, recruiting participants, conducting neuropsychological evaluations, analyzing and interpreting the data, and drafting the manuscript for publication.

Sanjay P. Prabhu, MD, participated in planning the study, obtaining and interpreting MRI findings, analyzing the data, and drafting the manuscript.

Patricia Greenstein, MD, conducted neurological examinations and participated in planning the study, analyzing the data, and drafting the manuscript.

Carter Petty, MA, conducted statistical analyses and participated in interpreting the results and drafting the manuscript.

Donald Schomer, MD, conducted neurological examinations and participated in planning the study, analyzing the data, and drafting the manuscript.

Vera Anastasoaie participated in planning the study, collecting data, and critically reviewing the manuscript.

Kalin Charette participated in planning the study, collecting data, and critically reviewing the manuscript.

Daniel Rodriguez conducted the post-processing of the COSY data in controls, assisted in conducting the phantom studies, and contributed to the manuscript.

Sai Merugumala developed the software to reconstruct and quantify the COSY spectra, participated in the analyzing and interpreting of the data, and contributed to the manuscript.

Alexander P. Lin, PhD, participated in planning the study, obtaining MRI and COSY, conducting post-scanning analyses, analyzing and interpreting the data, and drafting the manuscript.

Dr. Waisbren serves as guarantor for the article.

This investigator-initiated study was funded by a grant from BioMarin Pharmaceuticals, Inc. The authors confirm independence from the company and the content of the article has not been influenced by BioMarin Pharmaceuticals, Inc.

Competing Interest Statements

Dr. Waisbren consults to BioMarin Pharmaceuticals, Inc.

Vera Anastasoaie serves as research coordinator for studies supported by BioMarin Pharmaceuticals, Inc.

Kalin Charette serves as research coordinator for studies supported by BioMarin Pharmaceuticals, Inc.

Drs. Greenstein, Prabhu, Schomer, and Lin and Mr. Carter, Mr. Rodriguez, and Mr. Merugumala have no competing interests and nothing to declare.

This study was approved by the Committee on Clinical Investigations (Institutional Review Board) at Boston Children’s Hospital (IRB-P00003864) and all participants provided written informed consent.

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© 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM)

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Waisbren, S.E. et al. (2016). Improved Measurement of Brain Phenylalanine and Tyrosine Related to Neuropsychological Functioning in Phenylketonuria. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 34. JIMD Reports, vol 34. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2016_11

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  • DOI: https://doi.org/10.1007/8904_2016_11

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  • Print ISBN: 978-3-662-55585-9

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