Tetrahydrobiopterin (BH4) increases phenylalanine hydroxylase (PAH) activity and can normalise the blood phenylalanine concentration in some patients with phenylketonuria. However, lack of precise methods for in-vivo PAH activity measurement makes the assessment of BH4 treatment effects only semi-quantitative.
The aim of the study was to establish a model for calculating absolute phenylalanine hydroxylase activity in newborns with phenylketonuria receiving BH4.
Methods: A mathematical equation for assessment of PAH activity in newborns was constructed with the use of previously published data on blood phenylalanine kinetics in adults (Kaufman, Proc Nat Acad Sci 1996;3160–4). Lower basic PAH activity and phenylalanine transamination activity, a higher amount of body water, dietary protein intake and phenylalanine tolerance in newborns with phenylketonuria were considered. The model was validated by means of a retrospective analysis of PAH activity in 10 newborns with phenylketonuria who received BH4.
Results: The equation ΔPhe/t = −0.9 k vPAH − 0.9 vTrans + Phefood was used for calculating PAH activity where ΔPhe/t is the blood phenylalanine increase rate, k is the PAH residual activity ratio, vPAH is the maximal phenylalanine hydroxylation rate in adults, vTrans is the phenylalanine transamination rate in adults, Phefood is the diet-related blood phenylalanine increase rate. The calculated in-vivo enzymatic activities correlated with published in-vitro data on PAH activities observed in the presence of mutations of the PAH gene. In three cases (patients heterozygous for BH4-responsive mutations) PAH activities higher than predicted were observed, which probably reflects BH4 responsiveness.
Conclusion: Our method allows for the estimation of absolute PAH activity in newborns with phenylketonuria and can be useful for measurement of the BH4 treatment effect.
Funding: Supported by government grant N40708032/3085.