Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria

To determine the prevalence of and identify subjects with phenylketonuria (PKU; phenylalanine hydroxylase deficiency) responsive to 6R-tetrahydrobiopterin (BH4) and to establish selection criteria for potential treatment with BH4.

Blood phenylalanine levels from 557 newborns and children with various degrees of PKU (blood phenylalanine, 301 to 4743 micromol/L) challenged with BH4 (20 mg/kg of body weight) were analyzed at 8 and 24 hours after BH4 administration. The 2 modalities were compared in terms of phenylalanine reduction.

The overall prevalence of BH4 responsiveness within patients with PKU for blood phenylalanine reductions of 20%, 30%, 40%, and 50% was 48%, 38%, 31%, and 24%, respectively, using the 8-hour modus and 55%, 46%, 41%, and 33%, respectively, using the 24-hour modus. Using the 30% cutoff, BH4 responsiveness was similar regardless of the modality in patients with mild hyperphenylalaninemia (79% to 83% responders), mild PKU (49% to 60% responders), and classical PKU (7% to 10% responders).

BH4 responsiveness is more prevalent than was previously assumed, particularly in patients with mild hyperphenylalaninemia and mild PKU. Depending on the severity of hyperphenylalaninemia, selection criteria for the potential treatment with BH4 may range from 20% to 40% blood phenylalanine reduction after 24 hours.