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.