Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

Mol Genet Metab. 2021 May;133(1):49-55. doi: 10.1016/j.ymgme.2021.02.008. Epub 2021 Mar 6.


Background: In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.

Methods: Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).

Results: BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.

Conclusion: BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.

Keywords: Phenylalanine; Phenylketonuria; Tetrahydrobiopterin; Tyrosine; Variation.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biopterin / adverse effects
  • Biopterin / analogs & derivatives*
  • Biopterin / pharmacology
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Child
  • Child, Preschool
  • Dried Blood Spot Testing
  • Female
  • Humans
  • Male
  • Phenylalanine / blood*
  • Phenylalanine Hydroxylase / antagonists & inhibitors
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / drug therapy*
  • Phenylketonurias / genetics
  • Phenylketonurias / pathology
  • Tyrosine / blood*


  • Biopterin
  • Tyrosine
  • Phenylalanine
  • Phenylalanine Hydroxylase
  • sapropterin