OBJECTIVES:

In PKU, elevated phenylalanine levels lead to cognitive disability. Early dietary management isa prerequisite for normal cognition. Herein we discuss data on the impact of PKU on cognition, among those receiving early dietary management.

METHODS:

An SLR was conducted following PRISMA guidelines (March 2023) using MEDLINE, EMBASE and Northern Lights databases. Observational studies in English assessing IQ among PKU patients receiving early dietary management (phenylalanine>600μmol/l at screening) were included. Mean Wechsler Intelligence Scale scores, overall and by subgroup if applicable, were extracted. The percentage of studies where patients had mean IQ scores <100 (the threshold for ‘average intelligence’) was tabulated. Differences in IQ between PKU and comparison samples in the same studies were explored.

RESULTS:

From 1,713 abstracts, 25 studies were included: 16 pediatric, 8 adult, and 1 pediatric/adult. Sample sizes ranged from 4-203. In children, mean (SD) IQ scores ranged from 87.9 (NR; single-center study describing IQ by diet), to 114.1 (15.9; single-center study describing long-term IQ development). Mean IQ was <100 for ≥1 subgroup in 83% of pediatric studies. Four studies included comparison groups; mean IQ scores ranged from 5.2 (sibling comparison) to 12.9-points (healthy comparison) higher than PKU groups. Six adult studies reported IQ<100. Differences between adult PKU patients and comparison groups, which reached 16.3 points, tended to be larger than differences among pediatric groups. The exception was among continuously diet-adherent adults, where a 2-point difference was observed. Considerable variability was noted in IQ estimates.

CONCLUSIONS:

As expected, individual IQ scores in PKU were variable. Despite this variability, most studies reported mean IQ scores <100. PKU cohorts tended to average lower than non-PKU cohorts – from 5-16.3 points lower. These data show that IQ is affected in PKU, even with early dietary management, indicating an opportunity for treatments that reduce phenylalanine levels for alleviating burden in PKU.