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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.

SUBMITTER: McGinnity CJ

PROVIDER: S-EPMC8248344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: In phenylketonuria (PKU), elevated blood phenylalanine (Phe) concentrations are considered to impair transport of large neutral amino acids (LNAAs) from blood to brain. This impairment is believed to underlie cognitive deficits in PKU via different mechanisms, including reduced cerebral protein synthesis. In this study, we investigated the hypothesis that impaired LNAA influx relates to reduced cerebral protein synthesis. METHODS: Using positron emission tomography, L-[1-11C]-tyrosine (11C-Tyr) brain influx and incorporation into cerebral protein were studied in 16 PKU patients (median age 24, range 16 - 47 years), most of whom were early and continuously treated. Data were analyzed by regression analyses, using either 11C-Tyr brain influx or 11C-Tyr cerebral protein incorporation as outcome variable. Predictor variables were baseline plasma Phe concentration, Phe tolerance, age, and 11C-Tyr brain efflux. For the modelling of cerebral protein incorporation, 11C-Tyr brain influx was added as a predictor variable. RESULTS: 11C-Tyr brain influx was inversely associated with plasma Phe concentrations (median 512, range 233 - 1362 ?mol/L; delta adjusted R2=0.571, p=0.013). In addition, 11C-Tyr brain influx was positively associated with 11C-Tyr brain efflux (delta adjusted R2=0.098, p=0.041). Cerebral protein incorporation was positively associated with 11C-Tyr brain influx (adjusted R2=0.567, p<0.001). All additional associations between predictor and outcome variables were statistically nonsignificant. CONCLUSIONS: Our data favour the hypothesis that an elevated concentration of Phe in blood reduces cerebral protein synthesis by impairing LNAA transport from blood to brain. Considering the importance of cerebral protein synthesis for adequate brain development and functioning, our results support the notion that PKU treatment be continued in adulthood. Future studies investigating the effects of impaired LNAA transport on cerebral protein synthesis in more detail are indicated.

Dataset Information

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

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