Tetrahydrobiopterin (BH4) lowers blood phenylalanine (Phe) in individuals with PKU who are responders, but its effects on the brain and cognition have not been explored thoroughly. We examined blood Phe, microstructural white matter integrity, and executive abilities in 12 BH4 responders before (i.e., baseline) and after (i.e., follow-up) six months of treatment with BH4. Compared with baseline, Phe in these responders decreased by 51% during a 4week screening period after initiation of treatment and remained lowered by 37% over the 6month follow-up period. Significant improvements in white matter integrity, evaluated by mean diffusivity from diffusion tensor imaging, were also found following six months of treatment. Improvements in executive abilities were not identified, although six months may have been a period too brief for changes in cognition to follow changes in the brain. To our knowledge, our study is the first to explore relationships among Phe, white matter integrity, executive abilities, and BH4 treatment within a single study.

Original languageEnglish
Pages (from-to)213-217
Number of pages5
JournalMolecular genetics and metabolism
Issue number3
StatePublished - Nov 2013


  • Diffusion tensor imaging
  • Executive
  • Phenylketonuria
  • Sapropterin
  • Tetrahydrobiopterin
  • White matter


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