Phenotyping and treatment of phenylketonuria.

We are troubled by some assumptions in the Seminar on phenylketonuria by Nenad Blau and colleagues (Oct 23, p 1417),1 which conflict with what we have experienced in our department. Accurate phenotyping must be the first step in planning a patient's treatment. This cannot be done with a single measurement of blood phenylalanine concentration, which fluctuates continuously and widely.2 Owing to the combined effect of genetic and peristatic (eg, bodyweight, age, and dietary intake) determinants of hyperphenylalaninaemia in phenylketonuria, patients affected by variants of different severity can have similar blood phenylalanine concentrations. The other phenotyping method mentioned by Blau and colleagues—ie, assessment of dietary tolerance at 5 years of age, when feeding is an active process and the diet highly composite—is too late and very laborious. We have found that tolerance for dietary phenylalanine can be easily assessed in the first months of life with appropriate and simple procedures (immediate phenylalanine washout, and increasing phenylalanine intake). Unlike other methods, such assessment allows a clear-cut definition of the phenotype, unambiguously fitting that predicted by genotyping.3 Experimental results cannot be validated if they are not reproducible. This is the case in the assessment of tetrahydrobiopterin responsiveness in phenylketonuria. In one study,4 about 10% of patients were still considered responders against an initial figure of 60–80%, the same patients seemed to be alternatively responders or not, and cofactor administration induced either a decrease (44% of patients) or an increase (32%) in blood phenylalanine concentration. By means of a quantitative and self-controlled study of patients who differ only by one variable—ie, tetrahydrobiopterin challenge—we have found that cofactor administration does not alter phenylalanine metabolism in phenylketonuria.5 We fear that reiteration of inappropriate procedures will hamper the assessment of new treatments for phenylketonuria. We declare that we have no conflicts of interest.