1. ¹Department of Nuclear Medicine, University of Mainz, Mainz, Germany
2. ²Department of Pediatrics, University of Mainz, Mainz, Germany
3. ³Department of Nuclear Medicine, LM University of Munich, Munich, Germany
4. ⁴Department of Psychiatry, University of Mainz, Mainz, Germany
5. ⁵Department of Pediatrics, University of Münster, Münster, Germany
6. ⁶Institute of Stereological Research, Bispbjerg Hospital, Copenhagen, Denmark
7. ⁷Department of Pediatrics, University of Hamburg, Hamburg, Germany

Correspondence: Dr P Bartenstein, Department of Nuclear Medicine, University of Munich, Marchioninistrasse 15, München D-81377, Germany. E-mail: peter.bartenstein@med.uni-muenchen.de

Received 18 June 2007; Revised 17 September 2007; Accepted 19 September 2007; Published online 31 October 2007.

Abstract

Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. To test this hypothesis, we used positron emission tomography (PET) to measure the utilization of 6-[¹⁸F]fluoro-L-dopamine (FDOPA) in the brain of adult patients suffering from PKU and in healthy controls. Dynamic 2-h long FDOPA emission recordings were obtained in seven adult PKU patients (five females, two males; age: 21 to 27 years) with elevated serum Phe levels, but lacking neurologic deficits. Seven age-matched, healthy volunteers were imaged under identical conditions. The utilization of FDOPA in striatum was calculated by linear graphical analysis (k₃^S, min^-1), with cerebellum serving as a nonbinding reference region. The time to peak activity in all brain time–radioactivity curves was substantially delayed in the PKU patients relative to the control group. The mean magnitude of k₃^S in the striatum of the PKU patients (0.00520.0004 min^-1) was significantly lower than in the control group (0.00880.0009 min^-1) (P<0.001). There was no significant correlation between individual serum Phe levels and k₃^S. The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe. Assuming this competition to be spatially uniform, the relationship between striatum and cerebellum time–activity curves additionally suggests inhibition of DOPA efflux, possibly also due to competition from Phe. The linear graphical analysis shows reduced k₃^S in striatum, indicating reduced DOPA decarboxylase activity.