Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria

Objectives: 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.

Study design: 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.

Results: 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.

Conclusions: 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.