Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: The unsolved paradox
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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2020, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesSemi-quantitative detection of a vanillactic acid/vanillylmandelic acid ratio in urine is a reliable diagnostic marker for aromatic L-amino acid decarboxylase deficiency
2020, Molecular Genetics and MetabolismCitation Excerpt :However, the quantitative change is often subtle and a normal VLA concentration does not exclude AADC deficiency. Similarly, the concentration of the catecholamine degradation product VMA in the urine of AADC patients may be decreased, normal or increased and therefore does not provide any diagnostic value [16]. Overall, the determination of individual catecholamine metabolites in urine is not suitable to confirm or exclude AADC deficiency [1].
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2020, Pediatric NeurologyCitation Excerpt :A founder mutation (IVS6+4A>T) has been defined in East Asia, including Taiwan and China, and the prevalence of AADC deficiency in Taiwan has been estimated to be 1:32,000, but, until recently, the prevalence of the disorder outside of Taiwan had not been investigated.16 Approximately 120 individuals have been described and confirmed as unique cases of AADC deficiency.7,8,10,14,17-32 An additional 22 cases have been mentioned in the literature but were not confirmed as unique cases (i.e., it is unknown if these 22 additional cases represent 22 individual new patients or they involve multiple reports that describe a lesser number of patients, or perhaps were included in the initial 120 patients).