The Journal of pediatrics

Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria.

PMID 24485821


To compare the neurocognitive outcomes of patients with phenylketonuria (PKU) to determine whether decreasing phenylalanine (Phe) levels to <240 is preferable to the use of 360 μmol/L as an upper-target Phe level. An additional aim was to establish the influence of biochemical indices other than Phe on neurocognitive outcomes. Patients with PKU (n = 63; mean age 10.8 ± 2.3 years) and healthy controls (n = 73; mean age 10.9 ± 2.2 years) performed computerized tasks measuring neurocognitive functions (inhibitory control, cognitive flexibility, and motor control). Lifetime and concurrent blood Phe levels, Phe-to-tyrosine ratio (Phe:Tyr), and Phe variations were examined in relation to neurocognitive outcomes using nonparametric tests and regression analyses. Patients with PKU with Phe levels ≤240 μmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 μmol/L and ≥360 μmol/L performed more poorly than did controls across tasks. Patients with Phe levels ≤240 μmol/L performed significantly better than patients with levels between 240 and 360 μmol/L on tasks measuring inhibitory control and cognitive flexibility. Absolute Phe levels and Phe variation were the best predictors of motor control, whereas Phe:Tyr were the best predictors of inhibitory control. The results of this study suggest that upper Phe targets should be lowered to optimize neurocognitive outcomes. Moreover, Phe variation and Phe:Tyr appear to be of additional value in treatment monitoring.

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L-Phenylalanine, United States Pharmacopeia (USP) Reference Standard