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.

Metabolomic changes in children with autism

“…Some researchers have proposed that imbalances or abnormalities in the phenylalanine-to-tyrosine ratio might affect neurotransmitter levels, potentially contributing to certain aspects of ASD symptomatology. The high ratio observed in children with autism is due to the failure of phenylalanine to be converted to tyrosine and, consequently, to dopamine in the brain[ 69 ]. The high levels of phenylalanine and tyrosine were not observed only in children with ASD but also observed in their parents and siblings[ 70 ].…”

Engineering Organoids for in vitro Modeling of Phenylketonuria

“…Indeed, correlation between antioxidant status and blood L-Phe levels in PKU patients has also been challenging to obtain, explaining the number of patients with good dietary adherence that still present neuronal damage ( Rausell et al, 2019 ). Data that support such hypothesis include the observation of cerebral glucose hypometabolism in eleven adult PKU patients ( McGinnity et al, 2021 ) which is known to scale with oxidative stress in preclinical Alzheimer’s disease (AD) patients ( Mosconi et al, 2008 ). Therefore, oxidative stress might be an important neurodegeneration-inducing mechanism in PKU, possibly contributing to the neuropathology of late onset neurological and psychological impairments observed even in early diagnosed and uninterruptedly treated PKU adults.…”