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Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods

Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results

Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion

Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.

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Acknowledgments

We gratefully acknowledge the contribution of Veronique Rüfenacht and Martin Volleberg, University Children’s Hospital Zürich, Switzerland; Andreas Kurringer, Christian Kerle, Fulya Zimmerer, Martin Fleger, Maximilian Obwegeser, Evelyn Gamper and Klaus Ludescher, LKH Bregenz, Austria and Luca Fierro and George A. Diaz, Icahn School of Medicine at Mount Sinai, New York, USA. The Government of Vorarlberg, Austria and Nutricia Metabolics, Friedrichsdorf, Germany have financially supported the study.

Author information

Authors and Affiliations

  1. Division of Metabolic Diseases and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

    Martina Huemer & Johannes Häberle

  2. Radiz – Rare Disease Initiative Zurich, University Zurich, Zurich, Switzerland

    Martina Huemer & Johannes Häberle

  3. Department of Paediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria

    Martina Huemer & Brunhilde Riesner

  4. Genetic Unit, SARAH Network of Rehabilitation Hospital, Brasilia, Brazil

    Daniel R. Carvalho

  5. Molecular Pathology Department, Rede Sarah de Hospitais de Reabilitação, Brasilia, Brazil

    Jaime M. Brum

  6. Department of Paediatrics, Division of Paediatric Nutrition and Metabolism, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Özlem Ünal & Turgay Coskun

  7. Ankara Children’s Hospital, Haematology-Oncology Research and Education Hospital, Ankara, Turkey

    Özlem Ünal

  8. Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    James D. Weisfeld-Adams & Nina L. Schrager

  9. Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA

    James D. Weisfeld-Adams

  10. Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria

    Sabine Scholl-Bürgi & Daniela Karall

  11. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich Heine University, Düsseldorf, Germany

    Andrea Schlune

  12. Department of Gastroenterology, Hepatology and Infectious diseases, Heinrich Heine University, Düsseldorf, Germany

    Markus G. Donner

  13. Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Zurich, Switzerland

    Martin Hersberger & Claudio Gemperle

  14. Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria

    Hanno Ulmer

Authors
  1. Martina Huemer
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  2. Daniel R. Carvalho
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  3. Jaime M. Brum
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  4. Özlem Ünal
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  5. Turgay Coskun
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  6. James D. Weisfeld-Adams
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  7. Nina L. Schrager
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  8. Sabine Scholl-Bürgi
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  9. Andrea Schlune
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  10. Markus G. Donner
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  11. Martin Hersberger
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  12. Claudio Gemperle
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  13. Brunhilde Riesner
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  14. Hanno Ulmer
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  15. Johannes Häberle
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  16. Daniela Karall
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Corresponding author

Correspondence to Martina Huemer.

Ethics declarations

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

Conflict of interest

None.

Additional information

Communicated by: Johan Lodewijk Karel Van Hove

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Huemer, M., Carvalho, D.R., Brum, J.M. et al. Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency. J Inherit Metab Dis 39, 331–340 (2016). https://doi.org/10.1007/s10545-016-9928-y

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  • DOI: https://doi.org/10.1007/s10545-016-9928-y

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