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Metabolic control during the neonatal period in phenylketonuria: associations with childhood IQ



In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence.


Overall phenylalanine concentration during the first month of life (total “area under the curve”), proportion of phenylalanine concentrations above upper target level (360 μmol/L) and proportion below lower target level (120 μmol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were <360 μmol/L, and lifetime and concurrent phenylalanine levels were correlated with IQ scores of 64 PKU patients (mean age 10.8 years, SD 2.9).


Overall phenylalanine concentration and proportion of phenylalanine concentrations >360 μmol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0–10 days, 11–20 days, 21–30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found.


In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control.


  • In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes.

  • Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria.

  • No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears “safe” with respect to later cognitive outcomes.

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Author information




G.B.L., S.C.J.H., F.R., J.G., M.B. and F.J.v.S. contributed to conception and design of the study and the analysis and interpretation of data. G.B.L., F.R., R.F., R.J. and U.O. contributed to acquisition of data. All authors contributed to drafting the article or revising it critically for intellectual content.

Corresponding author

Correspondence to Stephan C. J. Huijbregts.

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Competing interests

S.C.J.H. has participated in strategic advisory boards and received grants and honoraria as a consultant and/or speaker from Biomarin, Merck- Serono, Homology Medicines, and Nutricia. R.J. has received honoraria as a speaker and consultant from Merck- Serono and Biomarin. F.J.v.S. has received research grants, advisory board fees, and speaker’s honoraria from Nutricia Research, Merck-Serono, Biomarin, Codexis, Alexion, Vitaflo, MendeliKABS, Promethera, SOBI, APR, and ARLA Foods Int. G.B.L., F.R., R.F., J.W., U.O. and J.G.M.B. declared that they do not have potential conflicts of interest.

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Liemburg, G.B., Huijbregts, S.C.J., Rutsch, F. et al. Metabolic control during the neonatal period in phenylketonuria: associations with childhood IQ. Pediatr Res (2021).

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