Assessment of Tetrahydrobiopterin (BH₄) Responsiveness in Phenylketonuria

Objective

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.

Study design

Blood phenylalanine levels from 557 newborns and children with various degrees of PKU (blood phenylalanine, 301 to 4743 μmol/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.

Results

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).

Conclusions

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.

Abbreviations: BH₄, Tetrahydrobiopterin, HPA, Hyperphenylalaninemia, PAH, Phenylalanine hydroxylase, PKU, Phenylketonuria