title: Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker.
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).
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Genetics Division, Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. syano@usc.edu
authors.forename: Shoji
authors.initials: S
authors.lastname: Yano
authors.forename: Kathryn
authors.initials: K
authors.lastname: Moseley
authors.forename: Colleen
authors.initials: C
authors.lastname: Azen
mesh_terms: D000328:Adult; D000368:Aged; D021542:Amino Acids, Neutral / Q000008:administration & dosage / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood* / Q000652:urine; D018592:Cross-Over Studies; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008550:Melatonin / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008875:Middle Aged; D010661:Phenylketonurias / Q000188:drug therapy / Q000378:metabolism*; D055815:Young Adult
chemical_list: D021542:Amino Acids, Neutral; D015415:Biomarkers; D008550:Melatonin