Metabolic phenotypes of phenylketonuria. Kinetic and molecular evaluation of the Blaskovics protein loading test

Background: As part of the German Collaborative Study of Children Treated for Phenylketonuria (PKU), a three-day protein loading test was applied to children at 6 months of age. This load elicits three principal types of blood phenylalanine (Phe) response, with types I and III clinically corresponding to classic PKU and mild hyperphenylalaninaemia not requiring diet (MHP), respectively. An intermediate type II, clinically corresponding to mild PKU, is characterized by early decline of blood Phe from above 1200 μmol/L down to levels between 600 and 1200 μmol/L at 72 h. Aims: Unbiased classification and kinetic and molecular characterization of the intermediate Phe response; estimation of phenotypic variability of Phe disposal.Method: A kinetic model with zero-order protein synthesis and first-order rate of metabolic disposal of Phe is applied to 157 tests. Results: A model of exponentially saturated activation describes the acceleration of Phe disposal from day 1 to 3 in the intermediate type of response. Eleven of 14 p.Y414C functional hemizygotes and two of three p.R261Q homozygotes manifested this kinetic type. The rate estimates of Phe metabolic disposal differ widely in patients with identical PAH genotype, yet are highly correlated with the Phe level at 72 h.