Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment

Some individuals with phenylketonuria (PKU) respond to pharmacologic treatment with tetrahydrobiopterin (BH4) by a reduction in the blood phenylalanine concentration. This can result in increased dietary tolerance for phenylalanine or, in rare instances, replacement of the phenylalanine-restricted diet. BH4 is now available as sapropterin dihydrochloride under the name KUVAN, a formulation of natural BH4. This commentary contains recommendations for determining responsiveness to sapropterin dihydrochloride. The recommendations include challenging with an initial daily dose of 20 mg/kg and blood phenylalanine determinations pre-challenge and on days 1, 7, and 14 with the option of an additional continuation to day 28 if required to clarify whether a response has occurred. An algorithm depicting this recommendation for the challenge is included. The most widely accepted standard of response is ⩾30% reduction in the blood phenylalanine concentration, but a lower degree of response might also be considered clinically meaningful in some individual circumstances. Issues include the potential treatment of those with mild hyperphenylalaninemia who are not on diet, challenging neonates who have hyperphenylalaninemia identified by newborn screening, and the use of sapropterin dihydrochloride in treatment of maternal PKU pregnancies. These recommendations are intended to provide a basis for the use of sapropterin dihydrochloride in the treatment of PKU but may be altered after close observation of treated patients and carefully performed research.