Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

In phenylketonuria (PKU) patients, early diagnosis by neonatal screening and immediate institution of a phenylalanine‐restricted diet can prevent severe intellectual impairment. Nevertheless, outcome remains suboptimal in some patients asking for additional treatment strategies. Tetrahydrobiopterin (BH 4 ) could be one of those treatment options, as it may not only increase residual phenylalanine hydroxylase activity in BH 4 ‐responsive PKU patients, but possibly also directly improves neurocognitive functioning in both BH 4 ‐responsive and BH 4 ‐unresponsive PKU patients. In the present review, we aim to further define the theoretical working mechanisms by which BH 4 might directly influence neurocognitive functioning in PKU having passed the blood‐brain barrier. Further research should investigate which of these mechanisms are actually involved, and should contribute to the development of an optimal BH 4 treatment regimen to directly improve neurocognitive functioning in PKU. Such possible repurposing approach of BH 4 treatment in PKU may improve neuropsychological outcome and mental health in both BH 4 ‐responsive and BH 4 ‐unresponsive PKU patients.