Pathologic changes in the brain of untreated phenylketonuria (PKU) patients occur in structures that develop post-natally, i.e. in myelination of subcortical white matter and spinal cord and in the growth of axons, dendrites and synapses in cerebral cortex. In addition, a small minority of brains show evidence of progressive white matter degeneration (leucodystrophy). The pathologic changes are thought to be due to toxic effects of phenylalanine and/or its metabolites. It is assumed that they can be prevented by dietary therapy during infancy and childhood, but direct confirmation by neuropathologic studies is lacking. The recently discovered genetic mouse mutant Pah(enu2) provides an excellent animal model in which effects of PKU on brain development, including dendritic and synaptic development in cerebral cortex, can be assessed. In human PKU, there needs to be neuropathologic study of the brains from PKU patients, particularly adults, with a history of dietary therapy. Special attention needs to be paid to the study of white matter in such cases, in view of recent reports of white matter lesions on MRI despite dietary treatment.
Conclusion: Careful correlation is needed between neuropathology, magnetic resonance imaging white matter changes, dietary history and clinical findings. Finally, neuropathologic investigation is needed to determine whether progressive degeneration of the white matter (leucodystrophy) poses a risk to adults in whom dietary therapy has been discontinued.