Phenylketonuria: towards mechanism-based treatment

This thesis investigates the mechanisms by which phenylketonuria (PKU) results in brain dysfunction. PKU is an inherited disease characterized by impaired phenylalanine (Phe) metabolism, leading to severe mental retardation. When diagnosed early in life and adequately treated by a Phe-restricted diet, mental development is within normal ranges. However, outcome remains suboptimal, and the strict treatment reduces quality of life. We found that in PKU patients, higher blood Phe concentrations were associated with less 11C-tyrosine transport, which in turn was strongly related with less cerebral protein synthesis (CPS). Moreover, higher brain Phe concentrations were strongly associated with less CPS. These associations were further studied in a PKU mouse model. Untreated PKU mice showed several characteristic biochemical changes in blood and brain. Unexpectedly, these mice did not show learning and memory deficits in behavioral tasks. To clarify these phenotypic differences, we studied the pCREB/CREB signaling system, which connects biochemical markers to learning and memory. While the pCREB/CREB system was less active in PKU mice under baseline conditions, its activity normalized after behavioral testing. These results suggest that PKU mice maintain learning and memory by upregulating the pCREB/CREB system. In behavioral tasks associated with monoaminergic neurotransmitter signaling, PKU mice displayed several deficits, which were paralleled by reduced brain concentrations of these neurotransmitters. A monotherapeutic approach to restore these abnormalities was ineffective, suggesting that multiple interventions may be required. Together, our findings suggest several targets for developing mechanism-based therapies in PKU. Such therapies will likely improve treatment outcome and quality of life.