A Retrospective Case Series Analysis of the Relationship Between Phenylalanine: Tyrosine Ratio and Cerebral Glucose Metabolism in Classical Phenylketonuria and Hyperphenylalaninemia

Abstract

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [¹⁸F]fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [¹⁸F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [¹⁸F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe.

Keywords: [18F]fluorodeoxyglucose PET; hyperphenylalaninemia; intellectual function; phenylalanine:tyrosine ratio; phenylketonuria.

FIGURE 1

Examples of patterns of glucose metabolism revealed by [¹⁸F]FDG PET. The panel on the left depicts the mean of two patients who had scans that were reported as normal. The panel on the right depicts marked, widespread frontotemporoparietal hypometabolism sparing the occipital cortex, seen in patient 6, a 40-year-old male with full-scale IQ of 90 who ceased adherence to the low phenylalanine diet before he reached 10 years of age. His most recent blood spot phenylalanine measurement prior to the scan was 1200 μmol/ml. Based on 25 phenylalanine and 22 tyrosine measurements, his mean ± standard deviation historical phenylalanine was 877.2 ± 183.6 μmol/ml, and his Phe:Tyr ratio was 89.2 ± 52.6.