A Pilot Study of Fluorodeoxyglucose Positron Emission Tomography Findings in Patients with Phenylketonuria before and during Sapropterin Supplementation

Abstract

Background and PurposePET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy.MethodsWe enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects' Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake.ResultsNone of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca's and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation.ConclusionsFurther studies with a larger sample size are needed to confirm the above changes in both sapropterin non-responsive and responsive PKU patients.

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

“…CMR glc studies in human PKU patients are sparse and difficult to compare with those in animals due to a heterogeneous patient population with differences in age, diet, and clinical intervention. Global energy metabolism is, however, intact in PKU patients, as in the rats, and there are selective changes in relatively few brain structures but affected regions differ among the studies [38, 67–69]. …”

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“…The study was limited by a small sample size (5 subjects) and none had responded to sapropterin therapy; defined as 30% decrease in blood Phe level. In addition, gglucose metabolism also appeared depressed in the cerebellum and left parietal cortex while elevated in the frontal and anterior cingulate cortices as well as in left Broca's area and right superior lateral temporal cortex bilaterally [79] .…”

Tetrahydrobiopterin treatment in phenylketonuria: A repurposing approach

“…81 The role of such impaired cerebral energy metabolism on brain functioning in PKU is however largely unknown. Reduced cerebral energy metabolism has been suggested to relate to white matter abnormalities in PKU, 78 while increased cerebral glucose metabolism, which has been observed in particular brain areas in PKU patients, 77,80 has been suggested to reflect some compensatory mechanism. 77 The effect of BH 4 (at 20 mg/kg/day) on brain glucose metabolism as measured by FDG-PET has been investigated in one study in BH 4 -unresponsive PKU patients.…”

“…Reduced cerebral energy metabolism has been suggested to relate to white matter abnormalities in PKU, 78 while increased cerebral glucose metabolism, which has been observed in particular brain areas in PKU patients, 77,80 has been suggested to reflect some compensatory mechanism. 77 The effect of BH 4 (at 20 mg/kg/day) on brain glucose metabolism as measured by FDG-PET has been investigated in one study in BH 4 -unresponsive PKU patients. 77 This study showed that, after 4 months of BH 4 treatment, glucose metabolism in left Broca's and right lateral temporal cortices was increased, which was accompanied by enhanced performance in a phonemic fluency test.…”

“…77 The effect of BH 4 (at 20 mg/kg/day) on brain glucose metabolism as measured by FDG-PET has been investigated in one study in BH 4 -unresponsive PKU patients. 77 This study showed that, after 4 months of BH 4 treatment, glucose metabolism in left Broca's and right lateral temporal cortices was increased, which was accompanied by enhanced performance in a phonemic fluency test. Ficicioglu et al hypothesized that this could have been the result of BH 4 -induced vasodilation.…”