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

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.