1. Urinary dopamine in aromatic L-amino acid decarboxylase deficiency
- Author
-
Tessa Wassenberg, Martijn J. Wilmer, Ron A. Wevers, Marcel M. Verbeek, Kiek Verrijp, M.H. Willemsen, P.B.H. Geurtz, Martin Lammens, Wang-Tso Lee, Pediatrics, Faculty of Medicine and Pharmacy, and Faculty of Economic and Social Sciences and Solvay Business School
- Subjects
Male ,Endocrinology, Diabetes and Metabolism ,Dopamine ,DNA Mutational Analysis ,Membrane transport and intracellular motility [NCMLS 5] ,Monophenol Monooxygenase/genetics ,Neuroinformatics [DCN 3] ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Perception and Action [DCN 1] ,3-Methoxytyramine ,Child ,Renal disorder [IGMD 9] ,Aromatic L-amino acid decarboxylase ,Chemistry ,Monophenol Monooxygenase ,Cytochrome P-450 CYP2D6/metabolism ,Tyramine ,Tyrosine decarboxylase ,Cytochrome P-450 CYP2D6 ,Aromatic-L-Amino-Acid Decarboxylases ,young adult ,Female ,Functional Neurogenomics [DCN 2] ,Dopamine/urine ,medicine.drug ,Adult ,medicine.medical_specialty ,Kidney Cortex ,Adolescent ,Child, preschool ,Monoamine oxidase ,RATS ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Internal medicine ,Tyramine/metabolism ,Genetics ,medicine ,Animals ,Humans ,Tyrosine/analogs & derivatives ,Molecular Biology ,Genetic Association Studies ,Catechol-O-methyl transferase ,Tyrosine hydroxylase ,Kidney Cortex/enzymology ,Infant ,Aromatic-L-Amino-Acid Decarboxylases/deficiency ,Tyrosine - Abstract
Contains fulltext : 87540.pdf (Publisher’s version ) (Closed access) 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. 01 december 2010
- Published
- 2010