Phenylketonuria in mice and men

Phenylketonuria (PKU) is a hereditable metabolic disorder in which phenylalanine (Phe), a building block of protein, is not properly converted. When a low-protein diet starts early and is maintained for life, Phe will not build-up in the brain and severe cognitive problems can be avoided. The diet is difficult to maintain and some brain-related problems are still experienced by the patients. This makes research into new and/or additional treatment methods still very important. To be able to do this, it must be clear what the consequences of PKU are and what factors influence the outcome. In this thesis we show in a mouse model of PKU that the genetic background and gender of the mice is important for certain behavioral consequences of PKU. Furthermore, we show that PKU patients have more sleep-related problems compared to healthy relatives. These findings help us to develop new treatment strategies. Two possible candidates were investigated in this dissertation: 1) a specific group of nutrients that could relieve cognitive problems and 2) other building blocks of protein that should make it more difficult for Phe to enter the brain. The first treatment showed a positive effect on learning and memory in the PKU mouse model. The second treatment showed a promising improvement in the chemical messengers of the brain of the PKU mouse. This fundamental research is in principle the beginning towards new treatment strategies for PKU.