Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Findings in Patients With Phenylketonuria Before and After KUVAN Therapy

Phenylketonuria (PKU) is an autosomal recessive disorder resulting from a deficiency of
phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine
hydroxylase is one of the three aromatic amino acid hydroxylases that utilizes
tetrahydrobiopterin (BH4) as cofactor. The published reports indicate that there is altered
energy metabolism in the brain of patients with PKU. Phenylalanine and its metabolites
appear to impair several aspects of brain energetics including: (1) Inhibition of glucose
uptake; (2) diminished glycosylation of cytoskeletal proteins; (3) Inhibition of pyruvate
kinase; and (4) reduced flux through the glycolysis. Studies in vivo with magnetic resonance
spectroscopy have demonstrated phenylalanine-responsive abnormalities in cerebral energy
metabolism.

PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures
regional glucose metabolic rate with high resolution and absolute quantitation. To date this
technology has been used only for single case reports or the investigation of white matter
abnormalities in small numbers of patients with PKU.

The aim of this pilot study is to determine if there are any changes in brain glucose
metabolism in the gray matter of patients with PKU and whether KUVAN (BH4) can improve such
deficits. This study will also elucidate the relationship between hyperphenylalaninemia,
phenylalanine intake in diet, altered brain glucose handling and the neurocognitive profile
of the patients with PKU before and after KUVAN therapy.