To the Editor:

In patients with phenylketonuria (PKU), blood phenylalanine concentration during childhood is the major determinant of cognitive outcome. Adolescents and young adults generally do not comply with recommendations for the monitoring and control of phenylalanine concentrations,1 and two thirds of pregnant women in the United States did not follow the diet before becoming pregnant.2

Recently it has been shown that some patients with PKU respond to the loading test with 6R-tetrahydrobiopterin (BH4) by lowering plasma phenylalanine concentrations and that these patients can be treated with BH4.3 BH4 is the natural cofactor of aromatic amino acid hydroxylases, and particular mutations in the phenylalanine hydroxylase gene may affect enzyme stability or its affinity for the BH4. We recently found that more than 60% of patients with plasma phenylalanine concentrations between 400 and 800 ÎĽmol/L respond to BH4 challenge and that the best results can be obtained with doses of 20 mg/kg body weight (Fig. 1).4 Oral supplementation with 10 mg BH4/kg reduced plasma phenylalanine concentrations below 360 ÎĽmol/L in most patients with mild forms of phenylalanine hydroxylase deficiency (Phe < 1200 ÎĽmol/L) and increased phenylalanine tolerance in some patients with classical PKU (Phe > 1200 ÎĽmol/L).

Fig. 1
figure 1

Percentage of patients with different degrees of hyperphenylalaninemia who responded to 6R-tetrahydrobiopterin challenge (20 mg/kg body weight) by lowering plasma phenylalanine levels by at least 30% within 8 hours.

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Our findings show the importance of the BH4 loading test in the diagnosis of BH4-responsive variants and open new prospects for the treatment of PKU and mild hyperphenylalaninemia. Replacement of the low-phenylalanine diet with the commercially available BH4 (Schircks Laboratories, Jona, Switzerland) may significantly improve compliance in adolescents and young adults with PKU variants and may solve some barriers that prevent control of blood phenylalanine levels in pregnant women with PKU. Thus BH4 may be a practical, but not inexpensive, alternative to control PKU.