Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox.

Abstract

INTRODUCTION:

In aromatic L-amino acid decarboxylase (AADC) deficiency, a neurotransmitter biosynthesis defect, paradoxical normal or increased levels of urinary dopamine have been reported. Genotype/phenotype correlations or alternative metabolic pathways may explain this remarkable finding, but were never studied systematically.

METHODS:

We studied the mutational spectrum and urinary dopamine levels in 20 patients with AADC-deficiency. Experimental procedures were designed to test for alternative metabolic pathways of dopamine production, which included alternative substrates (tyramine and 3-methoxytyrosine) and alternative enzymes (tyrosinase and CYP2D6).

RESULTS/DISCUSSION:

In 85% of the patients the finding of normal or increased urinary levels of dopamine was confirmed, but a relation with AADC genotype could not be identified. Renal microsomes containing CYP2D were able to convert tyramine into dopamine (3.0 nmol/min/g protein) but because of low plasma levels of tyramine this is an unlikely explanation for urinary dopamine excretion in AADC-deficiency. No evidence was found for the production of dopamine from 3-methoxytyrosine. Tyrosinase was not expressed in human kidney.

CONCLUSION:

Normal or increased levels of urinary dopamine are found in the majority of AADC-deficient patients. This finding can neither be explained by genotype/phenotype correlations nor by alternative metabolic pathways, although small amounts of dopamine may be formed via tyramine hydroxylation by renal CYP2D6. CYP2D6-mediated conversion of tyramine into dopamine might be an interesting target for the development of new therapeutic strategies in AADC-deficiency.

• Authors: T Wassenberg, M A A P Willemsen, P B H Geurtz, M Lammens, K Verrijp, M Wilmer, W T Lee, R A Wevers, M M Verbeek
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 101 Issue 4 Pg. 349-56 (Dec 2010) ISSN: 1096-7206 [Electronic] United States
• PMID: 20832343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Tyrosine
• Cytochrome P-450 CYP2D6
• Monophenol Monooxygenase
• Aromatic-L-Amino-Acid Decarboxylases
• 3-methoxytyrosine
• Dopamine
• Tyramine

Topics

• Adolescent
• Adult
• Animals
• Aromatic-L-Amino-Acid Decarboxylases (deficiency, genetics, metabolism)
• Child
• Child, Preschool
• Cytochrome P-450 CYP2D6 (metabolism)
• DNA Mutational Analysis
• Dopamine (urine)
• Female
• Genetic Association Studies
• Humans
• Infant
• Kidney Cortex (enzymology)
• Male
• Monophenol Monooxygenase (genetics, metabolism)
• Rats
• Tyramine (metabolism)
• Tyrosine (analogs & derivatives, metabolism)
• Young Adult