Reduced Cerebral Fluoro-l-Dopamine Uptake in Adult Patients Suffering from Phenylketonuria

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-[ 18 F]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 (k 3 S , min À1 ), 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 k 3 S in the striatum of the PKU patients (0.0052 ± 0.0004 min À1 ) was significantly lower than in the control group (0.0088±0.0009 min À1 ) (P < 0.001). There was no significant correlation between individual serum Phe levels and k 3 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 k 3 S in striatum, indicating reduced DOPA decarboxylase activity.

Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria

“…The specific mechanism leading to the presence of these ADHD symptoms in persons with PKU is currently unknown; however, it may be caused by a direct toxic effect of phenylalanine levels. It has also been suggested that reduced tyrosine levels in PKU may decrease dopamine and norepinephrine production in the central nervous system [24,25,49,50]. Results of this clinical trial population showed a correlation between serum phenylalanine levels and inattention scores in sapropterin responders and has been discussed in the primary publication [27], but in the pooled population of responders and nonresponders, this correlation was weak.…”

Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria

“…Because Phe shares a common transport system across the blood brain barrier with tyrosine and tryptophan, elevated Phe levels also limit the entry of these amino acids into the central nervous system (Pardridge & Choi, 1986). As precursors to the neurotransmitters dopamine/ neuroepinephrine and serotonin, low tyrosine and tryptophan levels, respectfully, in the CNS can impact the critical regulation of mood, anxiety, and cognition provided by these neurotransmitters (Burlina, Bonafé, Ferrari, Suppiej, & Zacchello, 2000;Landvogt et al, 2008;Stahl, 2000). This dynamic phenomenon involving concurrent Phe has the potential to affect adults with early-and late/untreated PKU and may subsequently contribute to improvements associated with Phe reduction in either group that relate to mood, anxiety, behavior, and functioning.…”

Phenylketonuria: Brain Phenylalanine Concentrations Relate Inversely to Cerebral Protein Synthesis

“…The logistical challenge of this set-up reduced the number of subjects willing to participate. Thus, 6 out of the previously reported 10, 11 16 patients underwent MRS scanning in addition to PET scanning. One may wonder whether plasma concentrations of LNAAs, in particular of Phe, remained stable throughout the study.…”

“…15 Furthermore, two clinical radioisotope studies support an inhibitory effect of elevated plasma Phe concentrations on blood-to-brain transport of non-Phe LNAAs in PKU patients. 16,21 Specifically, elevated plasma Phe concentrations were shown to reduce uptake of 75 Se-selenomethionine 21 and were associated with reduced apparent blood-to-brain transport of 6-[ 18 F]-L-dihydroxyphenylalanine, 16 a substance which, like the LNAAs, is transported across the BBB by the LNAA type-I transporter.…”

“…9,10 The LNAAs compete for transport across the blood-brain barrier (BBB) mediated by the LNAA type-I transporter (a SLC7A5:SLC3A2 heterodimer). [14][15][16] This facilitated transport appears to be the only physiologically significant route for LNAA transport from blood to brain, as diffusion-mediated transport of LNAAs across the BBB is hindered by the extensive presence of tight junctions between endothelial cells. [17][18][19] Still, the contribution of diffusion-mediated LNAA transport to total LNAA BBB transport in PKU patients remains to be investigated.…”