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

https://doi.org/10.1016/j.ymgme.2010.08.003Get rights and content

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.

Introduction

Aromatic L-amino acid decarboxylase (AADC; EC 4.1.1.28, also known as dopa decarboxylase) is an essential enzyme in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine. AADC converts both 5-hydroxytryptophan (5-HTP) into serotonin and 3,4-dihydroxyphenylalanine (L-dopa) into dopamine, requiring pyridoxal-5-phosphate (activated vitamin B6) as co-factor. Dopamine is further metabolized towards norepinephrine (NE) and epinephrine (E) (Fig. 1). AADC-deficiency is a rare autosomal recessive disorder, characterized by developmental delay, prominent motor abnormalities, oculogyric crises and autonomic features [1], [2]. Prognosis is poor, and available treatment options like dopamine agonists, vitamin B6 and monoamine oxidase (MAO; EC 1.4.3.4) inhibitors only have marginal therapeutic effect [3], [4]. Diagnosis of AADC-deficiency is made by analysis of cerebrospinal fluid (CSF), the determination of AADC-enzyme activity in plasma, and mutation analysis [3], [5]. In urine, vanillactic acid (VLA), a breakdown product of L-dopa, is increased and may alert clinicians to perform additional investigations [5], [6].

In a number of AADC-deficient patients normal or increased levels of urinary dopamine are reported [6], [7], [8], [9], [10]. This apparently paradoxical finding has not been studied systematically before. Although dopamine is not uniquely synthesized in the nervous system, its biosynthesis is essentially mediated by AADC irrespective of the site of production. The kidneys synthesize dopamine by AADC after uptake of L-dopa in the cortical peripheral tubular epithelium (PTE) cells. The intrarenal autocrine–paracrine dopamine system is critical for sodium homeostasis [11], [12], [13] However, the finding of normal or increased levels of urinary dopamine remains unexplained [10].

We aimed to find a genetic or metabolic explanation for normal or increased levels of urinary dopamine in AADC-deficiency. Identification of alternative metabolic pathways for dopamine synthesis, different from that mediated by AADC, might reveal a potential therapeutic target for patients with AADC-deficiency. Furthermore, better understanding of peripheral dopamine synthesis will shed light on the underlying mechanisms of AADC-deficiency and may contribute to the development of therapeutic strategies in dopamine deficient ailments. Potential alternative metabolic pathways for dopamine production are depicted in Fig. 1, with 3-methoxytyrosine (3-MTYR) and tyramine shown as possible alternative substrates, and cytochrome P450 2D6 (CYP2D6) and tyrosinase shown as possible alternative enzymes involved in dopamine formation.

3-MTYR has been described in several publications to serve as an alternative substrate for dopamine formation [14], [15], [16]. Hydroxylation of tyramine leads to dopamine production. Tyrosinase is essential in melanin formation (Fig. 1) and tyrosinase deficiency results in albinism. Protein expression is thought to be highly confined to cells containing melanosomes [17]. Catecholamine synthesis was noted in pigmented tyrosine hydroxylase (TH; EC 1.14.16.2) deficient mice, suggesting a role for tyrosinase in the dopamine production by using tyrosine as substrate [18], [19]. Although AADC is still required in this alternative metabolic pathway of catecholamine synthesis (Fig. 1), these data support our hypothesis of existing alternative pathways for dopamine production in the absence of one of the key enzymes (in this case, TH). Interestingly, tyrosinase may also use tyramine as substrate for dopamine production. Since mushroom tyrosinase may convert tyramine to dopamine [20], [21], we investigated if human tyrosinase could be responsible for renal dopamine biosynthesis in AADC-deficiency by studying its expression in peripheral human tissues including kidney. The other enzyme tested, CYP2D6, is described to hydroxylate tyramine to dopamine in human liver and brain [22], [23].We investigated if this reaction also occurs in kidneys and therefore could be an explanation for normal or increased levels of urinary dopamine in AADC-deficiency.

Section snippets

Materials and methods

We collected urinary dopamine levels of AADC-deficient patients and searched for a genotype/phenotype correlation in this group. Peripheral dopamine production was investigated in several human and rat tissues and AADC-dependency of dopamine production in human kidney cortex was investigated by applying AADC-inhibitors. Furthermore, alternative metabolic pathways were tested to find possible AADC-independent ways of dopamine formation. The collection and use of laboratory data were in

Phenotype and genotype of 20 AADC-deficient patients

Patient characteristics are shown in Table 1. Urinary dopamine levels were obtained from 20 patients with AADC-deficiency with confirmed mutations. Eight patients were from European descent, one from Arabic descent and 11 from Asian descent. Mean age at time of investigation was five years and six months (range: three months to 26 years). Only one patient used medication (L-dopa) during the time of analysis. Three patients had decreased levels of urinary dopamine (Pt 1–3), seven patients had

Discussion

We confirmed that the majority of patients with AADC-deficiency (85%) have normal or increased levels of urinary dopamine excretion. In fact, even the patients with hypodopaminuria still excrete substantial amounts of dopamine. Genotype/phenotype correlations do not explain this finding. In our search for alternative metabolic pathways, we found that tyramine can be converted to dopamine by rat renal microsomes, presumably by CYP2D isoforms. Other alternative metabolic pathways for dopamine

Acknowledgments

We thank the referring clinicians for sharing patient material and J.D.A. Olivier, PhD, Donders Institute for Cognition, Brain and Behavior, Department of cognitive neuroscience: Molecular neurobiology, Radboud University Nijmegen Medical Centre, for providing animal material. This work was financially supported by the AADC Research Trust and Hersenstichting Nederland/Benny Vleerlaag Fonds (2009(2)-80).

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