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Randomized Controlled Trial
. 2013 May;162(5):999-1003.
doi: 10.1016/j.jpeds.2012.10.015. Epub 2012 Nov 16.

Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker

Shoji Yano  1 , Kathryn Moseley, Colleen Azen
Affiliations
Randomized Controlled Trial

Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker

Shoji Yano et al. J Pediatr. 2013 May.

Abstract

Objective: To determine whether levels of melatonin in blood and urine can serve as a peripheral biomarker to reflect brain serotonin synthesis in individuals with phenylketonuria (PKU).

Study design: We measured the levels of melatonin, a serotonin metabolite in the pinealocytes, in the blood and urine of individuals with PKU in a randomized double-blind placebo controlled crossover study consisting of three 3-week phases in 10 adults with PKU: phase 1 (washout), phase 2 (supplementation of large neutral amino acid [LNAA] tablets or placebo), and phase 3 (alternate supplementation). An overnight protocol to measure blood melatonin and urine 6-sulfatoxymelatonin and dopamine in first void urine specimens was conducted after each phase for subjects with PKU and once in 10 controls.

Results: Significantly lower concentrations of these neurotransmitter metabolites were observed in subjects with PKU after phase 1 compared with controls (serum melatonin P = .008, urine melatonin P = .0043, urine dopamine P < .0001), with significant increases after LNAA supplementation compared with the placebo phase (serum melatonin P = .0008, urine melatonin P = .0008, urine dopamine P = .0005). The mean tryptophan/LNAA and tyrosine/LNAA ratios were markedly lower in subjects with PKU compared with controls, and these ratios were significantly increased in the LNAA phase compared with the placebo phase (P = .016, P = .0003, respectively). Blood phenylalanine levels in subjects with PKU were not significantly different between placebo and LNAA phases (P = .74).

Conclusion: Blood and urine melatonin levels may serve as biomarkers reflecting brain serotonin synthesis in subjects with PKU. Because this cannot be evaluated using blood phenylalanine levels, it may provide information on neurotransmitter metabolism for optimal dietary management.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Melatonin over time. P values are from Wilcoxon rank sum test comparing PKU after washout phase with controls.
Figure 2.
Figure 2.
Urine 6-sulfatoxymelatonin and dopamine in controls and subjects with PKU. Column heights and error bars represent the mean and SEs, respectively. PKU-W, PKU-washout phase; PKU-P, PKU-placebo phase; PKU-A, PKU-LNAA supplemented phase.
Figure 3.
Figure 3.
Urine 6-sulfatoxymelatonin and Trp/LNAA ratio. Trp/LNAA is the ratio of Trp to the LNAAs (Trp, Tyr, Phe, histidine, threonine, valine, isoleucine, leucine, methionine).
Figure 4.
Figure 4.
Urine dopamine and Tyr/LNAA ratio. Tyr/LNAA is the ratio of Tye to the LNAAs (Trp, Tyr, Phe, histidine, threonine, valine, isoleucine, leucine, methionine).
See this image and copyright information in PMC

Comment in

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