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

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.

Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes.

BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder characterised by developmental delay, motor retardation and autonomic dysfunction. Very low concentrations in cerebrospinal fluid (CSF) of homovanillic acid (HVA) and 5-hydroxy indole acetic acid (5-HIAA) are suggestive, but not specific, for this disorder. Confirmation of the diagnosis AADC deficiency is then required by enzyme activity measurement or genetic analysis. METHODS: We describe assays for plasma AADC enzyme activity using both of its substrates, 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (L-dopa). We measured AADC activity in controls, AADC deficient patients and heterozygotes. RESULTS: AADC enzyme activity in control plasma on average is a factor 8-12 higher with L-dopa as substrate than with 5-HTP. Both substrates of AADC compete for the same active site of the enzyme resulting in equally decreased residual enzyme activities in AADC deficient patients. In AADC deficient patients, the enzyme activity towards both substrates, L-dopa and 5-HTP, are equally decreased, as are the CSF concentrations of HVA, 5-HIAA and MHPG, whereas heterozygotes have intermediate AADC activity levels. CONCLUSIONS: The presently described assays for AADC activity measurement allow an efficient, reproducible and non-invasive way to confirm the diagnosis of AADC deficiency. Since AADC enzyme activity is much higher with L-dopa as a substrate, this method is to be preferred over activity measurement with 5-HTP as a substrate for diagnostic purposes.