Localized proton magnetic resonance spectroscopy with short echo time (TE = 20 ms) was used to investigate biochemical changes in the cerebral white matter of 20 young adult patients (median 19 years) with phenylketonuria (PKU). Results were compared with those of a group of 12 age-matched healthy volunteers (median 25 years). Concentrations of N-acetyl-aspartate (NAA) and choline (Cho) relative to creatine (Cr) were unchanged. However, concentrations of inositol (Ins) relative to creatine were found to be significantly lower (P < 0.001) in the PKU patients (0.30 +/- 0.09 versus 0.57 +/- 0.17). Individual inositol concentrations did not correlate with age, diet, serum phenylalanine (Phe) levels or extent of pathological regions in the T2-weighted images. The lack of correlation with individual data suggests that the decreased inositol concentration could be related to a metabolic deficiency during fetal development. No signal from the phenyl ring protons of phenylalanine was detected in the PKU patients (phenylalanine serum concentration < or = 1.27 mM), which suggests that concentration of phenylalanine may be lower in brain than in serum.