Urinary Dopamine in AADC Deficiency

Inside the brain of patients with AADC deficiency the amount of dopamine and serotonin is very low. This is because the AADC enzyme is responsible for the production of both dopamine and serotonin. Surprisingly however, it was noticed in 1998 that some patients with AADC deficiency have normal or even high levels of dopamine in their urine. This suggested that at least some AADC patients do have the ability to produce large amounts of dopamine and understanding this could help find a new treatment to increase dopamine production in the brain. Because of this Dr Marcel Verbeek and Dr Michel Willemsen set out to discover how these patients had high amounts of dopamine in their urine.

Firstly, they wanted to determine if the amount of dopamine in the urine was related to the patient’s mutation(s). This was not found to be the case and indeed different patients with exactly the same mutations had low, normal or high levels of dopamine in the urine. Secondly, different potential pathways for the production of dopamine were investigated. Two chemicals called tyramine and 3-O-methyldopa can potentially be converted to dopamine by alternative metabolic pathways not involving AADC. However, it was found that extracts from human kidney were not able to produce dopamine from either of these two chemicals. There are also two enzymes called tyrosinase and CYP2D6 that under certain circumstances are able to produce dopamine. Tyrosinase was not detectable in human kidney. However, in a special preparation of rat kidney CYP2D6 activity was detected, although the level of activity was thought to be too low to be responsible for the high amount of dopamine in the urine of some AADC patients.

Next, in different parts of the human body the amount of AADC was measured. It was found that the amount of AADC protein and activity was highest in the kidney. It is known that AADC patients do still retain a very low level of AADC activity and so it was considered whether this “residual” activity was enough to produce dopamine in the urine. Samples of blood and urine were taken from two patients with AADC deficiency and the levels of dopamine as well as its precursor L-dopa and its metabolites were measured. Importantly, the rate of kidney filtration of each patient was also measured. Using all of these measurements it was calculated that urinary dopamine could have been produced by AADC using L-dopa in the blood as a substrate. This led to the conclusion that the small amount of AADC activity in AADC patients in combination with the high levels of L-dopa in the blood is sufficient to produce normal or high levels of dopamine in the kidney that is then released in the urine.

This project demonstrated important differences in dopamine production between the brain and other organs of the body, highlighting the importance of directly measuring dopamine and serotonin metabolites in brain cerebral spinal fluid (CSF) during the diagnosis of AADC deficiency. In particular urine analysis of a patient with AADC deficiency may be misleading.

The AADC Research Trust awarded 34,000 EUR to Marcel Verbeek and Michel Willemsen at the Radboud University Nijmegen Medical Centre, Netherlands, to fund this project that was completed in 2011.

Work from this project was published in the following publications:

Wassenberg T., Willemsen M. A. A. P., Geurtz P. B. H., Lammens M., Verrijp K., Wilmer M., Lee W. T., Wevers R. A. and Verbeek M. M. (2010) Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: The unsolved paradox. Molecular Genetics and Metabolism 101, 349-356.



Wassenberg T., Monnens L. A., Geurtz B. P., Wevers R. A., Verbeek M. M. and Willemsen M. A. (2012) The paradox of hyperdopaminuria in aromatic L-amino acid deficiency explained. JIMD Reports 4, 39-45. FULL FREE TEXT AVAILABLE.


What the Founder & Managing Director, Lisa Flint, says about this project…Urinary Dopamine

When the Trust began in 2006 one of its main aims was to simplify the whole diagnostic process and find better treatment strategies’ for children suffering with AADC deficiency.  The brilliant Dr Marcel Verbeek and Dr Michel Willemsen, from Radboud University in the Netherlands, joined us on this mission.  We are eternally grateful to their commitment to this and other projects and their discoveries superbly enhance our knowledge of this disease.