Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase-deficient hyperphenylalaninaemia.

In recent years several studies on tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency have been published. The molecular mechanisms of BH4 responsiveness are not conclusively understood, but there is evidence that BH4 responsiveness in hyperphenylalaninaemia (HPA) depends on the patient's genotype and residual PAH activity. As a BH4 preparation will soon obtain marketing approval as an alternative treatment for phenylketonuria (PKU), it is particularly important to evaluate this treatment and to define criteria to identify patients with a potential benefit from it. Most of the patients found to be BH4-responsive suffered from mild PKU or mild hyperphenylalaninaemia (MHP) and some of these would not be treated at all in many countries. Of patients with moderate and classic forms of PKU, only a few were classified as responders and the clinical significance of the effect size may be small.