Pathophysiology of phenylketonuria

The brain is the organ primarily affected by elevated phenylalanine (Phe) i n the disease phenylketonuria (PKU). The hallmark neuropathology of both th e untreated and treated PKU brains is hypomyelination or demyelination or b oth. Because cognitive deficits are present in untreated and treated indivi duals, the link between the observed neuropathology and cognitive deficits is important to ascertain. Two current models of the molecular events under lying the cognitive deficits are presented. The first model is based on the hypothesis that cognitive deficits in individuals with PKU result from a d eficiency of the neurotransmitter dopamine. Decreased levels of tyrosine in the PKU brain are believed to cause the low levels of dopamine. The possib le connections between reduced dopamine levels and the observed myelin defi cits are presented. However, as discussed, the link between the two remains elusive. The second model is based on the hypothesis that the primary insu lt to the PKU brain is loss of myelin and that this secondarily leads to ne uronal dysfunction. The function of myelin is reviewed, including evidence showing that myelin and the axon communicate with one another to form a fun ctional unit. Because the ability of the axon to conduct action potentials at normal speed is compromised when myelin is not formed or is lost, the la tter model has the capacity to account for both abnormalities and cognitive deficits. Current studies characterizing the neuropathology of the recentl y developed genetic mouse model for PKU, the PAH(enu2) mouse, are reviewed. Preliminary evidence is summarized that indicates that Phe specifically in hibits cholesterol metabolism in the oligodendrocyte, the cell that forms m yelin in the brain. Finally, areas of future, high-priority research are ou tlined. MRDD Research Reviews 1999;5:104-112. Published 1999 Wiley-Liss, In c.dagger.