title: Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.
abstract: Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established.
  
  
  
  In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria.
  
  
  
  Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured.
  
  
  
  Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine.
  
  
  
  The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria.
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands.
authors.forename: Danique
authors.initials: D
authors.lastname: van Vliet
authors.affiliation: Department of Molecular Neurobiology, University of Groningen, Groningen Institute for Evolutionary Life Sciences, Groningen, Netherlands.
authors.forename: Vibeke M
authors.initials: VM
authors.lastname: Bruinenberg
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands.|Department of Molecular Neurobiology, University of Groningen, Groningen Institute for Evolutionary Life Sciences, Groningen, Netherlands.
authors.forename: Priscila N
authors.initials: PN
authors.lastname: Mazzola
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Martijn Hjr
authors.initials: MH
authors.lastname: van Faassen
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: de Blaauw
authors.affiliation: Department of Psychology and Centro "Daniel Bovet," "La Sapienza" University, Fondazione Santa Lucia, Rome, Italy; and.|Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Pascucci
authors.affiliation: Department of Psychology and Centro "Daniel Bovet," "La Sapienza" University, Fondazione Santa Lucia, Rome, Italy; and.|Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Puglisi-Allegra
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: M Rebecca
authors.initials: MR
authors.lastname: Heiner-Fokkema
authors.affiliation: Department of Molecular Neurobiology, University of Groningen, Groningen Institute for Evolutionary Life Sciences, Groningen, Netherlands.
authors.forename: Eddy A
authors.initials: EA
authors.lastname: van der Zee
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, Netherlands; f.j.van.spronsen@umcg.nl.
authors.forename: Francjan J
authors.initials: FJ
authors.lastname: van Spronsen
mesh_terms: D021542:Amino Acids, Neutral / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004032:Diet; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010649:Phenylalanine / Q000008:administration & dosage; D010661:Phenylketonurias / Q000188:drug therapy*; D012701:Serotonin / Q000378:metabolism
chemical_list: D021542:Amino Acids, Neutral; D018377:Neurotransmitter Agents; D012701:Serotonin; D010649:Phenylalanine; D004298:Dopamine
keywords: brain biochemistry; inborn error of metabolism; large neutral amino acids; mouse model; neurotransmitters; pathophysiology; phenylketonuria; treatment