title: BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations.
abstract: In phenylketonuria (PKU), cerebral neurotransmitter deficiencies have been suggested to contribute to brain dysfunction. Present treatment aims to reduce blood phenylalanine concentrations by a phenylalanine-restricted diet, while in some patients blood phenylalanine concentrations also respond to cofactor treatment with tetrahydrobiopterin (BH4). Recently, a repurposing approach of BH4 was suggested to increase cerebral neurotransmitter synthesis. To investigate whether BH4 may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, we investigated blood prolactin concentrations-as a parameter of brain dopamine availability. We retrospectively compared blood prolactin in relation to blood phenylalanine concentrations of nine (male) BH4-responsive PKU patients, when being treated without and with BH4. Blood prolactin concentrations positively correlated to blood phenylalanine concentrations (p=0.002), being significantly lower with than without BH4 treatment (p=0.047). In addition, even in this small number of male patients, blood prolactin concentrations tended to be lower at increasing BH4 dose (p=0.054), while taking blood phenylalanine concentrations into account (p=0.002). In individual BH4-responsive patients, median blood prolactin concentrations were significantly lower while using BH4 than before using BH4 treatment (p=0.024), whereas median blood phenylalanine concentrations tended to be lower, but this did not reach statistical significance (p=0.107). Therefore, these data show that high blood phenylalanine in BH4-responsive PKU male patients seems to be associated with increased blood prolactin concentrations, suggesting reduced cerebral dopamine availability. Moreover, these data suggest that BH4 treatment in itself could decrease blood prolactin concentrations in a dose-responsive way, independent of blood phenylalanine concentrations. We conclude that these preliminary data indicate that BH4 treatment may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, possibly in a dose-dependent manner, but further research would be warranted.
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands; University of Groningen, Center of Behavior and Neurosciences, Department of Molecular Neurobiology, Groningen, The Netherlands.
authors.forename: Danique
authors.initials: D
authors.lastname: van Vliet
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Anjema
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: Jahja
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands; University of Groningen, Center of Behavior and Neurosciences, Department of Molecular Neurobiology, Groningen, The Netherlands.
authors.forename: Martijn J
authors.initials: MJ
authors.lastname: de Groot
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
authors.forename: Geertje B
authors.initials: GB
authors.lastname: Liemburg
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: M Rebecca
authors.initials: MR
authors.lastname: Heiner-Fokkema
authors.affiliation: University of Groningen, Center of Behavior and Neurosciences, Department of Molecular Neurobiology, Groningen, The 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, The Netherlands.
authors.forename: Terry G J
authors.initials: TG
authors.lastname: Derks
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands. Electronic address: f.j.van.spronsen@umcg.nl.
authors.forename: Francjan J
authors.initials: FJ
authors.lastname: van Spronsen
mesh_terms: D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D002648:Child; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D011388:Prolactin / Q000097:blood*; D012189:Retrospective Studies
chemical_list: D001708:Biopterins; D011388:Prolactin; C003402:sapropterin; D004298:Dopamine
keywords: Dopamine; Inborn error of metabolism; Neurotransmitters; Phenylketonuria; Prolactin; Tetrahydrobiopterin