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The Paradox of Hyperdopaminuria in Aromatic l-Amino Acid Deficiency Explained

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JIMD Reports - Case and Research Reports, 2012/1

Part of the book series: JIMD Reports ((JIMD,volume 4))

Abstract

Aromatic l-amino acid decarboxylase (AADC) decarboxylates 3,4-l-dihydroxylphenylalanine (l-dopa) to dopamine, and 5-hydroxytryptophan to serotonin. In AADC deficiency, dopamine and serotonin deficiency leads to a severe clinical picture with mental retardation, oculogyric crises, hypotonia, dystonia, and autonomic dysregulation. However, despite dopamine deficiency in the central nervous system, urinary dopamine excretion in AADC-deficient patients is normal to high.

In human, renal AADC-activity is very high compared to other tissues including brain tissue. Plasma l-dopa levels are increased in AADC deficiency. In this study, the hypothesis that in AADC deficiency relatively high-residual renal AADC-activity combined with high substrate availability of l-dopa leads to normal or elevated levels of urinary dopamine is tested and verified using 24-h urine collection of two AADC-deficient patients.

Renal dopamine is a major regulator of natriuresis and plays a crucial role in the maintenance of sodium homeostasis. Therefore, the preservation of sufficient renal AADC-activity in AADC deficiency might be crucial for survival of AADC-deficient patients.

In this study, we underpinned an empirical finding with theory, thereby putting a clinical observation into its physiological context. Our study stresses the difference – not qualitatively but quantitatively – between dopamine production in the central nervous system and peripheral organs. Furthermore, this study clarifies the so far unexplained observation that neurotransmitter profiles in urine should be interpreted with extreme caution in the diagnostic work-up of patients suspected to suffer from neurometabolic disorders.

Competing interests: None declared.

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Abbreviations

AADC:

Aromatic l-amino acid decarboxylase

COMT:

Catechol O-methyltransferase

CSF:

Cerebrospinal fluid

GFR:

Glomerular filtration rate

HVA:

Homovanillic acid

l-dopa:

l-3,4-Dihydroxyphenylalanine

MAO:

Monoamine oxidase

PTE:

Proximal tubular epithelium

VLA:

Vanillactic acid

References

  • Abeling NG, Brautigam C, Hoffman GF et al (2000) Pathobiochemical implications of hyperdopaminuria in patients with aromatic L-amino acid decarboxylase deficiency. J Inherit Metab Dis 23:325–328

    Article  PubMed  CAS  Google Scholar 

  • Aperia AC (2000) Intrarenal dopamine: a key signal in the interactive regulation of sodium metabolism. Annu Rev Physiol 62:621–647

    Article  PubMed  CAS  Google Scholar 

  • Barhelmebs M, Mbou P, Stephan D, Grima M, Imbs JL (1993) Renal dopamine excretion in healthy volunteers after oral ingestion of L-dopa. Fundam Clin Pharmacol 7:11–16

    Article  Google Scholar 

  • Baines AD, Drangova R, Hatcher C (1980) Dopamine production in isolated glomeruli and tubules from rat kidney. Can J Physiol Pharmacol 63:155–158

    Article  Google Scholar 

  • Brun L, Ngu LH, Keng WT et al (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75:64–71

    Article  PubMed  CAS  Google Scholar 

  • Chan YL (1976) Cellular mechanisms of renal tubular transport of L-dopa and its derivates in the rat: microperfusion studies. J Pharmacol Exp Ther 199:17–24

    PubMed  CAS  Google Scholar 

  • Chen L, Zhuang X (2003) Transgenic mouse models of dopamine deficiency. Ann Neurol 54(Suppl 6):S91–102

    Article  PubMed  CAS  Google Scholar 

  • Eisenhofer G, Aneman A, Friberg P et al (1997) Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab 82:3864–3871

    Article  PubMed  CAS  Google Scholar 

  • Fiumara A, Brautigam C, Hyland K et al (2002) Aromatic L-amino acid decarboxylase deficiency with hyperdopaminuria. Clinical and laboratory findings in response to different therapies. Neuropediatrics 33:203–208

    Article  PubMed  CAS  Google Scholar 

  • Goldstein DS, Eisenhofer G, Kopin IJ (2003) Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther 305:800–811

    Article  PubMed  CAS  Google Scholar 

  • Ibarra FR, Armando I, Nowicki S et al (2005) Dopamine is metabolised by different enzymes along the rat nephron. Pflugers Arch 450:185–191

    Article  PubMed  CAS  Google Scholar 

  • Moreira-Rodrigues M, Sampaio-Maia B, Pestana M (2009) Renal dopaminergic system activity in rat remnant kidney up to twenty-six weeks after surgery. Life Sci 27:409–414

    Article  Google Scholar 

  • Pestana M, Jardim H, Correia F, Vieira-Coelho MA, Soares-da-Silva P (2001) Renal dopaminergic mechanisms in renal parenchymal diseases and hypertension. Nephrol Dial Transplant 16(Suppl 1):53–59

    Article  PubMed  CAS  Google Scholar 

  • Quinones H, Collazo R, Moe OW (2004) The dopamine precursor L-dihydroxyphenylalanine is transported by the amino acid transporters rBAT and LAT2 in renal cortex. Am J Physiol Renal Physiol 287:F74–80

    Article  PubMed  CAS  Google Scholar 

  • Sampaio-Maia B, Serrao P, Vieira-Coelho MA, Pestana M (2003) Differences in the renal dopaminergic system activity between Wistar rats from two suppliers. Acta Physiol Scand 178:83–89

    Article  PubMed  CAS  Google Scholar 

  • Sampaio-Maia B, Moreira-Rodrigues M, Pestana M (2006) Role of chronic inhibition of dopamine-metabolizing enzymes in the regulation of renal sodium and phosphate excretion in the rat remnant kidney. Nephron Physiol 103:14–24

    Article  Google Scholar 

  • Soares-da-Silva P, Fernandes MH (1990) Synthesis and metabolism of dopamine in the kidney. Am J Hypertension 3:7S–10S

    CAS  Google Scholar 

  • Soares-da-Silva P, Vieira-Coelho MA, Serrao MP (1997) Uptake of L-3,4-dihydroxyphenylalanine and dopamine formation in cultured renal epithelial cells. Biochem Pharmacol 54:1037–1046

    Article  PubMed  CAS  Google Scholar 

  • Soares-da-Silva P, Pestana M, Ferreira A, Damasceno A, Polonia J, Cerqueira-Gomes M (2000) Renal dopaminergic mechanisms in renal parenchymal diseases, hypertension, and heart failure. Clin Exp Hypertens 22:251–268

    Article  PubMed  CAS  Google Scholar 

  • Verbeek MM, Geurtz PB, Willemsen MA, Wevers RA (2007) Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes. Mol Genet Metab 90:363–369

    Article  PubMed  CAS  Google Scholar 

  • Vieira-Coelho MA, Soares-da-Silva P (1998) Uptake and intracellular fate of L-DOPA in a human intestinal epithelial cell line: Caco-2. Am J Physiol 275:C104–112

    PubMed  CAS  Google Scholar 

  • Wang Y, Berndt TJ, Gross JM, Peterson MA, So MJ, Knox FG (2001) Effect of inhibition of MAO and COMT on intrarenal dopamine and serotonin and on renal function. Am J Physiol Regul Integr Comp Physiol 280:R248–54

    PubMed  CAS  Google Scholar 

  • Wassenberg T, Willemsen MA, Geurtz PB et al (2010) Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox. Mol Genet Metab 101:349–356

    Article  PubMed  CAS  Google Scholar 

  • Willemsen MA, Verbeek MM, Kamsteeg EJ et al (2010) Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain 133:1810–1822

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Radboud University Nijmegen Medical Centre, Donders Centre for Brain, Cognition and Behaviour, Nijmegen, The Netherlands

    Tessa Wassenberg & Marcel M. Verbeek

  2. Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Neurochemistry Laboratory, 830 LGEM, Nijmegen, The Netherlands

    Ben P. B. H. Geurtz, Ron A. Wevers & Marcel M. Verbeek

  3. Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Leo A. H. Monnens

  4. Department of Pediatric Neurology, Radboud University Nijmegen Medical Centre, Donders Centre for Brain, Cognition and Behaviour, 820, 9101, 6500 HB, Nijmegen, The Netherlands

    Michèl A. A. P. Willemsen

Authors
  1. Tessa Wassenberg
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  2. Leo A. H. Monnens
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  3. Ben P. B. H. Geurtz
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  4. Ron A. Wevers
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  5. Marcel M. Verbeek
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  6. Michèl A. A. P. Willemsen
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Corresponding author

Correspondence to Michèl A. A. P. Willemsen .

Editor information

Editors and Affiliations

    Additional information

    Communicated by: John H Walter.

    Appendices

    Take-Home Message

    The combination of residual renal AADC-activity and pathologic increases of l-dopa substrate availability explains normo- to hyperdopaminuria in AADC-deficient patients.

    Details of Contributions of Individual Authors

    T. Wassenberg as first author had primary responsibility in conducting and reporting the work described in the chapter.

    L. Monnens has contributed in development of hypothesis and calculation.

    B. Geurtz contributed to development and conduct of laboratory investigations.

    M. Verbeek and R. Wevers contributed to development of laboratory investigations and carried out critical assessment of the manuscript.

    M. Willemsen serves as guarantor for the article and had primary responsibility in conception and design of hypothesis.

    Competing Interest Statement

    Marcel Verbeek served as a consultant for Schering-Plough Corp. (until 2009) and received research support from Schering-Plough Corp., the AADC Research Trust, Hersenstichting Nederland, Internationale Stichting Alzheimer Onderzoek, Zon-MW, and the Center for Translational Molecular Medicine. The other authors have nothing to disclose.

    Details of Funding

    This work was supported by the AADC Research Trust (UK) and Hersenstichting Nederland/ Benny VleerlaagFonds (2009(2)-80). Study sponsors had no input into the study design, data collection, or writing of the manuscript.

    Details of Ethical Approval

    Informed parental consent and approval of the Medical Ethical Committee of the Radboud University Nijmegen were obtained for this study.

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    © 2011 SSIEM and Springer-Verlag Berlin Heidelberg 2011

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    Wassenberg, T., Monnens, L.A.H., Geurtz, B.P.B.H., Wevers, R.A., Verbeek, M.M., Willemsen, M.A.A.P. (2011). The Paradox of Hyperdopaminuria in Aromatic l-Amino Acid Deficiency Explained. In: JIMD Reports - Case and Research Reports, 2012/1. JIMD Reports, vol 4. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_84

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    • DOI: https://doi.org/10.1007/8904_2011_84

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    • Publisher Name: Springer, Berlin, Heidelberg

    • Print ISBN: 978-3-642-25751-3

    • Online ISBN: 978-3-642-25752-0

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