Phenylketonuria: High plasma phenylalanine decreases cerebral protein synthesis

Abstract

Left untreated, phenylketonuria biochemically results in high phenylalanine concentrations in blood and tissues, and clinically especially in severe mental retardation. Treatment consists of severe dietary restriction of phenylalanine with more or less normal intellectual outcome as result when started early enough. It is unclear whether treatment for life is necessary. A clear relationship between plasma phenylalanine concentrations and cerebral outcome exists, but the precise pathophysiological mechanism is not understood. In studies in mice with phenylketonuria, the cerebral protein synthesis rate is decreased when compared to controls. The aim of the present study was to determine the protein synthesis rate in relation to the plasma phenylalanine concentrations in-vivo in patients with phenylketonuria by positron emission tomography brain studies after an intravenous l-[1-(11)C]-tyrosine bolus. Results showed a significant negative relationship (R(2)=0.40, p<0.01) between plasma phenylalanine concentration and the cerebral protein synthesis rate in 19 patients with phenylketonuria. At increased plasma phenylalanine concentrations, i.e. above 600-800micromol/l, the cerebral protein synthesis rate is clearly decreased compared to lower phenylalanine concentrations. These data suggest that cerebral protein metabolism in untreated adults with phenylketonuria can be abnormal due to high plasma phenylalanine concentrations. Hence, we speculate that it is important to continue dietary treatment into adulthood, aiming at plasma phenylalanine concentrations <600-800micromol/l.