Ricerc@Sapienza

Phenylketonuria (PKU) is caused by the deficiency of the hepatic enzyme Phenylalanine Hydroxylase, which catalyses the conversion of the aminoacid Phenylalanine (Phe) into Tyrosine. Clinical manifestations of the disease are due to the accumulation of Phe in the brain. Indeed, untreated PKU is associated with intellectual disability, autism, seizures, and motor deficits. Early-treatment of PKU is aimed at decreasing the blood Phe concentration, which is considered to be correlated with brain Phe concentrations. Despite the favorable clinical outcome of early treated PKU patients, a lower than expected intelligence quotient (IQ) and neuropsychological and psychiatric problems, neuroimaging alterations remain challenging aspects of the disease and the possible targets for future improvement of the treatment. On the other hand, due to the difficulty to adhere to the diet in adulthood, many patients discontinue or relax the diet and nevertheless show a completely normal cognitive functioning. This remarkable variability in the outcome suggests the existence of an individual vulnerability to Phe, which cannot be deduced from the biochemical phenotype of the disease. Discovering possible biomarker of such susceptibility or resilience may help in personalizing the therapy and improve the outcome of the disease. The aim of present project is to explore the variation of brain connectivity in adult PKU patients under different values of blood and brain Phe. Two following neuropsychological, morphological (brain MRI), functional (resting state fMRI), and biochemical (brain 1H-MRS) will be performed in 10 subjects affected by classical PKU (diagnostic blood Phe level > 1200 µmol/l) at interval of 4 weeks. The two examinations will be planned in order to collect individual data under a low ( 500 µmol/l) levels of blood Phe, respectively. We expect to characterize individual variation denoting age-related and/or subject-related vulnerability to Phe.