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Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria

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Book cover JIMD Reports, Volume 24

Part of the book series: JIMD Reports ((JIMD,volume 24))

Abstract

Alkaptonuria is an autosomal recessive disease involving a deficiency of the enzyme homogentisate dioxygenase, which is involved in the tyrosine degradation pathway. The enzymatic deficiency results in high concentrations of homogentisic acid (HGA), which results in orthopedic and cardiac complications, among other symptoms. Nitisinone (NTBC) has been shown to effectively treat alkaptonuria by blocking the conversion of 4-hydroxyphenylpyruvate to HGA, but there have been concerns that using doses higher than about 2 mg/day could cause excessively high levels of tyrosine, resulting in crystal deposition and corneal pathology. We have enrolled seven patients in a study to determine whether higher doses of NTBC were effective at further reducing HGA levels while maintaining tyrosine at acceptable levels. Patients were given varying doses of NTBC (ranging from 2 to 8 mg/day) over the course of between 0.5 and 3.5 years. Urine HGA, plasma tyrosine levels, and plasma NTBC were then measured longitudinally at various doses. We found that tyrosine concentrations plateaued and did not reach significantly higher levels as NTBC doses were increased above 2 mg/day, while a significant drop in HGA continued from 2 to 4 mg/day, with no significant changes at higher doses. We also demonstrated using untargeted metabolomics that elevations in tyrosine from treatment resulted in proportional elevations in alternative tyrosine metabolic products, that of N-acetyltyrosine and γ-glutamyltyrosine.

Competing interests: None declared

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Abbreviations

3,4-DPA:

3,4-Dihydroxyphenylacetate

4-HPPD:

4-Hydroxyphenylpyruvate dioxygenase

ACN:

Acetonitrile

FA:

Formic acid

HGA:

Homogentisic acid

LC-MS-Q-TOF:

Liquid chromatography-quadrupole-time of flight mass spectrometry

mg/d:

Milligrams per day

NTBC:

Nitisinone

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Acknowledgments

We would like to thank Gabrielle Golden for helping with the organization of the study and sample acquisition. We would like to thank Kasie Auler for the tyrosine analysis by the amino acid analyzer. We would like to thank Swedish Orphan Biovitrum for the supply of NTBC used in the study and Abbott Laboratories for the supply of Tyrex-2.

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Authors and Affiliations

  1. Biochemical Genetics and Metabolomics Laboratory, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Ilya Gertsman, Bruce A. Barshop, Jan Panyard-Davis, Jon A. Gangoiti & William L. Nyhan

Authors
  1. Ilya Gertsman
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  2. Bruce A. Barshop
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  3. Jan Panyard-Davis
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  4. Jon A. Gangoiti
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  5. William L. Nyhan
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Corresponding author

Correspondence to Bruce A. Barshop .

Editor information

Editors and Affiliations

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

    Johannes Zschocke

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

    Matthias Baumgartner

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

    Eva Morava

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

    Marc Patterson

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

    Shamima Rahman

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

    Verena Peters

Additional information

Communicated by: Feillet, MD, PhD

Synopsis

Treatment of alkaptonuria with nitisinone doses greater than 2 mg/day significantly lowers homogentisic acid levels while tyrosine levels remain unchanged.

Compliance with Ethics Guidelines

Conflicts of Interest

Ilya Gertsman has no conflict of interest to declare.

Bruce Barshop has no conflict of interest to declare.

Jan Panyard-Davis has no conflict of interest to declare.

Jon Gangoiti has no conflict of interest to declare.

William Nyhan has no conflict of interest to declare.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Author Contributions

IG: Developed methods for analysis, analyzed the data collected, principal author of the manuscript

BAB: Assisted in the design of chemometric analyses and identification of target compounds, contributed substantially to writing the manuscript

JP-D: Planned and coordinated patient treatment regimens, reviewed the manuscript

JAG: Developed chemometric methodology, reviewed the manuscript

WLN: Conceived of patient treatment regimens, contributed to writing of the manuscript

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Gertsman, I., Barshop, B.A., Panyard-Davis, J., Gangoiti, J.A., Nyhan, W.L. (2015). Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_403

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  • DOI: https://doi.org/10.1007/8904_2014_403

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  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-48226-1

  • Online ISBN: 978-3-662-48227-8

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