Phenylalanine effects on brain function in adult phenylketonuria

Objective To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adult phenylketonuria patients. Methods In this prospective cross-sectional study, early-treated phenylketonuria patients older than 30 years and age and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were in addition evaluated in a subset of 10 patients. Results Nineteen phenylketonuria patients (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures and atrophy in putamen and right thalamus compared to controls. In CSF, Phenylketonuria patients exhibited higher Aβ1-42 (p = 0.003), T-Tau (p < 0.001) and P-Tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001) motor evoked potential latency (r = 0.48, p = 0.030) and parietal lobe atrophy. Conclusions Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical and imaging alterations in adult phenylketonuria patients