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 mmol/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 mmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 mmol/L and $360 mmol/L performed more poorly than did controls across tasks. Patients with Phe levels #240 mmol/L performed significantly better than patients with levels between 240 and 360 mmol/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