Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art

Since 1999 an increasing number of patients with phenylalanine hydroxylase (PAH) deficiency are reported to be able to decrease their plasma phenylalanine (Phe) concentrations after a 6R-tetrahydrobiopterin (BH4) challenge. The majority of these patients have mild PKU or MHP (mild hyperphenylalaninemia) and harbour at least one missense mutation in the PAH gene associated with this phenotype. The rate of decrease and the lowest achieved Phe level vary between patients with different genotypes but appears to be similar in patients with the same genotype. A number of the mutations associated with BH4responsiveness have been studied in an ‘in vitro’ eukaryotic cell expression system leading to biosynthesis of a mutant PAH enzyme with some residual activity. Patients bearing mutations that cause severe structural distortion in the expressed protein (loss of function mutations), leading to undetectable PAH activity, are not responsive to BH4. These observations suggest that residual PAH activity (in vitro) is a prerequisite for BH4-responsiveness. However, an in vitro residual PAH activity is not a guarantee for in vivo BH4-responsiveness. Mechanisms behind this responsiveness could be relieve of decreased binding affinity for BH4, BH4-mediated increase of PAH gene expression or stabilization of the mutant enzyme protein by BH4. BH4responsive PAH-deficient patients have only been reported since 1999. For the western countries this is explained by the fact that the manufacturer changed the diastereoisomeric purity of the BH4 preparation from 69% of the natural 6R-BH4 (31% of 6S-BH4) to 99.5% 6R-BH4. The new findings on BH4-responsiveness may be of clinical relevance because these patients can be treated with BH4 with concomitant relief or withdrawal of the burdensome PKU diet. These observations warrant further clinical studies to assess efficacy, optimal dosage, and safety of BH4 treatment in this group. The data strongly emphasize the necessity of the BH4 loading test in patients detected in the newborn PKU screening.