The impact of phenylalanine levels on cognitive outcomes in adults with phenylketonuria: Effects across tasks and developmental stages.

Abstract

Objective: Phenylketonuria (PKU) is due to an inability to metabolize the amino acid phenylalanine (Phe), leading to its accumulation in the brain. Phe levels can be controlled following a protein-free diet, but cognitive impairments are still present. A number of questions remain to be answered related to which type of metabolic control is important, the age when it is important, the cognitive functions which are most affected and, the best tests to use to monitor cognitive health. Method: We investigated the impact of metabolic control at different ages on cognitive performance in 37 early treated adults with PKU. Results: (a) Phe variation was as associated to performance as average Phe showing that stable dietary control is as important as strict control; (b) For some tasks, current and adult Phe were stronger predictors of performance than childhood or adolescent Phe, showing the importance of a strict diet even in adulthood; and (c) The relationship between performance and Phe levels varied depending on time and cognitive domain. For some functions (sustained attention, visuomotor coordination), Phe at the time of testing was the best predictor. While for other functions (visual attention, executive functions) there was a diminishing or stable relationship across time. Conclusion: Results show the importance of selecting the right tasks to monitor outcomes across ages, but also that the impact of bio-chemical disruptions is different for different functions, at different ages. We show how inherited metabolic diseases offer us a unique vantage point to inform our understanding of brain development and functioning.

Children and adolescents with phenylketonuria display fluctuations in their blood phenylalanine levels

“…Nevertheless, neurocognitive deficits have still been reported in individuals with PKU treated who were treated early and continuously with a phenylalanine-restricted diet. related to cognitive outcome in early and continuously treated PKU (15)(16)(17). We saw the well-known negative correlation of IQ with concurrent blood phenylalanine level in those patients in our study who had classic PKU.…”

“…Nevertheless, neurocognitive deficits have still been reported in individuals with PKU treated who were treated early and continuously with a phenylalanine‐restricted diet. According to Anastasoaie et al, Hood et al and Romani et al, the stability of blood phenylalanine levels may be related to cognitive outcome in early and continuously treated PKU .…”

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

“…The association of Phe levels with adult cognition may depend on the age at which metabolic control was measured and on the particular cognitive domain examined. A recent study showed that performance on verbal memory and learning, visuomotor coordination and sustained attention were better predicted by recent Phe levels than control during childhood, whereas performances on visuospatial processing and complex executive functions showed a stable association with metabolic control across different ages . Interestingly, a positive correlation has been found between striatal dopamine D 2/3 R receptor availability, with impulsivity and error rate in a cognitive flexibility task, while there was no correlation with working memory or inhibitory control.…”

“…A number of well‐controlled studies reported statistically significant deficits in patients compared with healthy control groups or normative populations across a range of neuropsychological and executive functions, including sustained and selective attention, working memory, response inhibition, and letter fluency . Two studies that performed extensive analyses on the same cohort of patients reported impairments in patients with ETPKU vs healthy controls, in the higher order executive functions, visuo‐spatial attention and visuo‐motor coordination, with significant variability across patients . Additionally, a recent study reported that compared with a control group, patients with ETPKU showed deficits in complex language tasks and were slower and less accurate in tasks requiring planning and strategic abilities .…”

Structural elucidation of novel biomarkers of known metabolic disorders based on multistage fragmentation mass spectra

“…The diagnosis and follow-up of PKU patients largely relies on the plasma concentration of phenylalanine in combination with the ratio of Phe to Tyr. However, adequate biochemical control of Phe levels does not directly translate into the desired clinical outcome (Romani et al 2017 andJahja et al 2017). For HMGCLD 3-hydroxyisovaleric acid, 3-hydroxyisovalerylcarnitine, 3-methylglutaconic acid, 3-hydroxy-3-methylglutaric acid, 3-methylcrotonylglycine, 3methylglutaric acid, and 3-methylglutarylcarnitine are known accumulating compounds.…”