A personalized medicine approach for phenylketonuria patients

Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in the European-descended population. PKU is due to defects in the hydroxylation reaction of the phenylalanine (Phe) to tyrosine that is governed by the enzyme phenylalanine hydroxylase (PAH). The synthetic form of the natural cofactor tetrahydrobiopterin (BH4), sapropterin dihydrochloride, acts as a pharmacological chaperone and corrects the biochemical phenotype in patients with milder forms of the disease termed BH4-responsive PAH-deficiency. A significant gap of knowledge concerns the enzymatic function associated with PAH genotypes. Case Study / Methods: PAH genotype data was collected and systematized as a database available online. The activity landscapes method was used to determine PAH function in living cells as a result of most common PAH genotypes. Results: In the PAH activity landscapes database (http://pah-activitylandscapes.org/) we have collected country-specific information on over 9700 PAH genotypes. For the 50 most common genotypes PAH activity landscapes were performed. Depicting enzyme activity of variant PAH proteins as activity landscapes allows for the determination of the optimal working range of the protein in the functional metabolic and therapeutic context. The binding of the pharmacological chaperone BH4 depends on the patient's Phe concentration. Retrospective data evaluation of BH4-testing in patients has set the basis for a model in which enzyme function depends not only on the genotype but also on a patient's metabolic state and the dosage of a potential treatment with BH4. Conclusion / Discussion: Using only the standard protocol for BH4-loading test and disregarding the patient's PAH genotype may lead to false-negative testing results. Therefore, there is a need for employing a holistic approach that would guide pediatricians to personalize BH4-loading tests and dietary treatment schemes. The information resulting from PAH activity landscapes allows to create individualized treatment regimens. Keywords: BH4, enzyme activity, functional analysis