Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: effects of tryptophan and tyrosine supplementation

Abstract

Objective: To determine whether additional supplementation of tryptophan (Trp) and tyrosine (Tyr) improve serotonin and dopamine metabolism in individuals with phenylketonuria treated with large neutral amino acid (LNAA) tablets.

Study design: Ten adult individuals with phenylketonuria participated in a randomized, double-blind, placebo-controlled cross-over study consisting of three 3-week phases: washout, treatment with LNAA tablets plus supplementation with either Trp and Tyr tablets or placebo, and LNAA tablets plus the alternate supplementation. An overnight protocol to measure blood melatonin, a serotonin metabolite in the pinealocytes, and urine 6-sulfatoxymelatonin and dopamine in first-void urine specimens was conducted after each phase.

Results: Serum melatonin and urine 6-sulfatoxymelatonin and dopamine levels were increased in the LNAA phase (LNAA plus placebo) compared with the washout phase. Serum melatonin and urine 6-sulfatoxymelatonin were not increased in the active phase (LNAA plus Trp + Tyr) compared with the LNAA phase, although plasma Trp:LNAA was increased compared with the LNAA phase. Among 7 subjects with a plasma Trp/LNAA >0.03, a negative correlation between urine 6-sulfatoxymelatonin and plasma phenylalanine levels was observed (r = -0.072). Urine dopamine levels and plasma Tyr:LNAA were increased in the active phase compared with the LNAA phase.

Conclusion: Melatonin levels were not increased with the higher dose of Trp supplementation, but dopamine levels were increased with the higher dose of Tyr supplementation. Serotonin synthesis appears to be suppressed by high phenylalanine levels at the Trp hydroxylase level.

Figure 1.

Urine 6-sulfatoxymelatonin and dopamine in subjects with PKU (n=6).Error bars represent SE.Urine6-sulfatoxymelatonin was significantly increased in the LNAA phase compared with the washout phase (P = .0158); however, there was no significant difference between the LNAA phase and the LNAA + TT phase. Urine dopamine was significantly increased in the LNAA phase compared with the washout phase (P = .0009), and was further increased in the LNAA + TT phase compared with the LNAA phase (P = .0052).

Figure 2.

Urine 6-sulfatoxymelatonin and Trp:LNAA. All 10 study subjects are plotted, 8 of whom completed the LNAA and LNAA + TT phases. In all subjects, Trp:LNAA were increased in the LNAA + TT phase compared with the LNAA phase, although 6-sulfatoxymelatonin did not significantly increase. Subject S6 showed a continuous increase in urine 6-sulfatoxymelatonin with increasing Trp/LNAA (the highest ratio was <0.03). The other 7 subjects had a Trp/LNAA >0.03.

Figure 3.

Urine 6-sulfatoxymelatonin and plasma Phe levels for the 7 subjects with a Trp:LNAA >0.03 in the LNAA + TT phase. Urine 6-sulfatoxymelatonin level was negatively correlated with plasma Phe level (r = −0.72).

Figure 4.

Trp transporter and melatonin synthesis. Decreased serotonin synthesis in the CNS involves at least 2 steps. The first step is inhibition of transport of the precursor amino acid Trp by other LNAAs through competitive inhibition. The second step is inhibition of TPH by high Phe levels. AADC, aromatic L-amino acid decarboxylase.