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Journal of Inherited Metabolic Disease

, Volume 39, Issue 3, pp 331–340 | Cite as

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

  • Martina HuemerEmail author
  • Daniel R. Carvalho
  • Jaime M. Brum
  • Özlem Ünal
  • Turgay Coskun
  • James D. Weisfeld-Adams
  • Nina L. Schrager
  • Sabine Scholl-Bürgi
  • Andrea Schlune
  • Markus G. Donner
  • Martin Hersberger
  • Claudio Gemperle
  • Brunhilde Riesner
  • Hanno Ulmer
  • Johannes Häberle
  • Daniela Karall
Original Article

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.

Notes

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.

Compliance with ethical standards

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.

References

  1. Adam S, Champion H, Daly A et al (2012) Dietary management of urea cycle disorders: UK practice. J Hum Nutr Diet 25:398–404CrossRefPubMedGoogle Scholar
  2. Amayreh W, Meyer U, Das AM (2014) Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev Med Child Neurol 56:1021–1024CrossRefPubMedGoogle Scholar
  3. Anderssohn M, Schwedhelm E, Lüneburg N, Vasan RS, Böger RH (2010) Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. Diab Vasc Dis Res 7:105–118CrossRefPubMedGoogle Scholar
  4. Andrade F, Llarena M, Lage S, Aldámiz-Echevarría L (2015) Quantification of arginine and its methylated derivatives in healthy children by liquid chromatography-tandem mass spectrometry. J Chromatogr Sci 53:787–792CrossRefPubMedGoogle Scholar
  5. Arias A, Ormazabal A, Moreno J et al (2006) Methods for the diagnosis of creatine deficiency syndromes: a comparative study. J Neurosci Methods 156:305–309CrossRefPubMedGoogle Scholar
  6. Carvalho DR, Brum JM, Speck-Martins CE et al (2012) Clinical features and neurologic progression of hyperargininemia. Pediatr Neurol 46:369–374CrossRefPubMedGoogle Scholar
  7. Crombez EA, Cederbaum SD (2005) Hyperargininemia due to liver arginase deficiency. Mol Gen Metab 84:243–251CrossRefGoogle Scholar
  8. Deignan JL, Marescau B, Livesay JC et al (2008) Increased plasma and tissue guanidino compounds in a mouse model of hyperargininemia. Mol Gen Metab 93:172–178CrossRefGoogle Scholar
  9. Deignan JL, DeDeyn PP, Cederbaum SD et al (2010) Guanidino compound levels in blood, cerebrospinal fluid, and post-mortem brain material of patients with argininemia. Mol Gen Metab 100:S31–S36CrossRefGoogle Scholar
  10. Delwing de Lima D, Delwing F, da Cruz JG, Wyse AT, Delwing-Dal Magro D (2012) Protective effect of antioxidants on blood oxidative stress caused by arginine. Fundam Clin Pharmacol 26:250–258CrossRefGoogle Scholar
  11. Delwing D, Delwing D, Bavaresco CS, Wyse AT (2008) Protective effect of nitric oxide synthase inhibition or antioxidants on brain oxidative damage caused by intracerebroventricular arginine administration. Brain Res 1193:120–127CrossRefPubMedGoogle Scholar
  12. Grioni D, Furlan F, Canonico F, Parini R (2014) Epilepsia partialis continua and generalized nonconvulsive status epilepticus during the course of argininemia: a report on two cases. Neuropediatr 45:123–128Google Scholar
  13. Joncquel-Chevalier Curt M, Cheillan D, Briand G et al (2013) Creatine and guanidinoacetate reference values in a French population. Mol Genet Metab 110:263–267CrossRefPubMedGoogle Scholar
  14. Kayacelebi AA, Langen J, Weigt-Usinger K et al (2015) Biosynthesis of homoarginine (hArg) and asymmetric dimethylarginine (ADMA) from acutely and chronically administered free L-arginine in humans. Amino Acids 47(9):1893–1908CrossRefPubMedGoogle Scholar
  15. Kolling J, Wyse AT (2010) Creatine prevents the inhibition of energy metabolism and lipid peroxidation in rats subjected to GAA administration. Metab Brain Dis 25:331–338CrossRefPubMedGoogle Scholar
  16. Loscalzo J (2003) Adverse effects of supplemental L-arginine in atherosclerosis. Consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol 23:3–5CrossRefPubMedGoogle Scholar
  17. Lüneburg N, Xanthakis V, Schwedhelm E (2011) Reference intervals for plasma L-arginine and the L-arginine:asymmetric dimethylarginine ratio in the Framingham Offspring Cohort. J Nutr 141:2186–2190CrossRefPubMedPubMedCentralGoogle Scholar
  18. Mc Guire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98:173–180CrossRefPubMedPubMedCentralGoogle Scholar
  19. Nagasaka H, Tsukahara H, Yorifuji T et al (2009) Evaluation of endogenous nitric oxide synthesis in congenital urea cycle enzyme defects. Metabolism 58:278–282CrossRefPubMedGoogle Scholar
  20. Olsen RK, Cornelius N, Gregersen N (2015) Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. J Inherit Metab Dis doi: 10.1007/s10545-015-9861-5Google Scholar
  21. Pastore A, Martinelli D, Piemonte F et al (2014) Glutathione metabolism in cobalamin deficiency type C (cblC). J Inherit Metab Dis 37:125–129CrossRefPubMedGoogle Scholar
  22. Ribas GS, Vargas CR, Wajner M (2014) L-carnitine supplementation as a potential antioxidant therapy for inherited neurometabolic disorders. Gene 533:469–476CrossRefPubMedGoogle Scholar
  23. Rüegger CM, Lindner M, Ballhausen D et al (2014) Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis 37:21–30CrossRefPubMedGoogle Scholar
  24. Schlune A, Ensenauer R, Häussinger D, vom Dahl S, Mayatepek E (2015) Hyperarginiemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. doi: 10.1007/s00726-015-2032-z PubMedGoogle Scholar
  25. Scholl-Bürgi S, Sigl SB, Häberle J et al (2008) Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency. J Inherit Metab Dis 31:S323–S328CrossRefPubMedGoogle Scholar
  26. Schulze A, Battini R (2008) Pre-symptomatic treatment of creatine biosynthesis defects. In: Salomons GS, Wyss M (eds) Creatine and creatine kinase in health and disease, Subcellular Biochemistry 46:167–181Google Scholar
  27. Schulze F, Wesemann R, Schwedhelm E et al (2004) Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay. Clin Chem Lab Med 42:1377–1383CrossRefPubMedGoogle Scholar
  28. Schulze F, Lenzen H, Hanefeld C et al (2006) Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter coronary artery risk determination investigating the influence of ADMA concentration (CARDIAC) study. Am Heart J 152:e1–e8Google Scholar
  29. Snyderman SE, Sansaricq C, Norton PM, Goldstein F (1979) Argininemia treated from birth. J Pediatr 95:61–63CrossRefPubMedGoogle Scholar
  30. Tsikas D (2005) Methods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids. Free Rad Res 39:797–815CrossRefGoogle Scholar
  31. Vockley JG, Tabor DE, Kern RM et al (1994) Identification of mutations (D128G, H141L) in the liver arginase gene of patients with hyperargininemia. Hum Mutat 4:150–154CrossRefPubMedGoogle Scholar
  32. Wijnands KA, Hoeksema MA, Meesters DM et al (2014) Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia. PLoS One 9:e86135Google Scholar
  33. Zugno AI, Stefanello FM, Scherer EB et al (2008) Guanidinoacetate decreases antioxidant defenses and total protein sulfhydryl content in striatum of rats. Neurochem Res 33:1804–1810CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2016

Authors and Affiliations

  • Martina Huemer
    • 1
    • 2
    • 3
    Email author
  • Daniel R. Carvalho
    • 4
  • Jaime M. Brum
    • 5
  • Özlem Ünal
    • 6
    • 7
  • Turgay Coskun
    • 6
  • James D. Weisfeld-Adams
    • 8
    • 9
  • Nina L. Schrager
    • 8
  • Sabine Scholl-Bürgi
    • 10
  • Andrea Schlune
    • 11
  • Markus G. Donner
    • 12
  • Martin Hersberger
    • 13
  • Claudio Gemperle
    • 13
  • Brunhilde Riesner
    • 3
  • Hanno Ulmer
    • 14
  • Johannes Häberle
    • 1
    • 2
  • Daniela Karall
    • 10
  1. 1.Division of Metabolic Diseases and Children’s Research CenterUniversity Children’s Hospital ZurichZurichSwitzerland
  2. 2.Radiz – Rare Disease Initiative ZurichUniversity ZurichZurichSwitzerland
  3. 3.Department of PaediatricsLandeskrankenhaus BregenzBregenzAustria
  4. 4.Genetic Unit, SARAH Network of Rehabilitation HospitalBrasiliaBrazil
  5. 5.Molecular Pathology DepartmentRede Sarah de Hospitais de ReabilitaçãoBrasiliaBrazil
  6. 6.Department of Paediatrics, Division of Paediatric Nutrition and MetabolismHacettepe University Faculty of MedicineAnkaraTurkey
  7. 7.Ankara Children’s Hospital, Haematology-Oncology Research and Education HospitalAnkaraTurkey
  8. 8.Program for Inherited Metabolic Diseases, Icahn School of Medicine at Mount SinaiNew YorkUSA
  9. 9.Section of Clinical Genetics and Metabolism, Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  10. 10.Clinic for Pediatrics I, Inherited Metabolic DisordersMedical University of InnsbruckInnsbruckAustria
  11. 11.Department of General Pediatrics, Neonatology and Pediatric CardiologyUniversity Children’s Hospital, Heinrich Heine UniversityDüsseldorfGermany
  12. 12.Department of Gastroenterology, Hepatology and Infectious diseasesHeinrich Heine UniversityDüsseldorfGermany
  13. 13.Division of Clinical Chemistry and BiochemistryUniversity Children’s Hospital ZurichZurichSwitzerland
  14. 14.Department of Medical Statistics, Informatics and Health EconomicsMedical University of InnsbruckInnsbruckAustria

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