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

Abstract

Background

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.

Methods

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).

Results

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.

Conclusions

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.

Impact

  • 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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References

  1. 1.

    Blau, N., Van Spronsen, F. J. & Levy, H. L. Phenylketonuria. Lancet 376, 1417–1427 (2010).

    CAS  Article  Google Scholar 

  2. 2.

    Van Spronsen, F. J. Phenylketonuria: a 21st century perspective. Nat. Rev. Endocrinol. 6, 509–514 (2010).

    Article  Google Scholar 

  3. 3.

    Kure, S. et al. Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. J. Pediatr. 135, 375–378 (1999).

    CAS  Article  Google Scholar 

  4. 4.

    De Groot, M. J., Hoeksma, M., Blau, N., Reijngoud, D. J. & Van Spronsen, F. J. Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol. Genet. Metab. 99, S86–S89 (2010).

    Article  Google Scholar 

  5. 5.

    Longo, N. et al. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet 384, 37–44 (2014).

    CAS  Article  Google Scholar 

  6. 6.

    Harding, C. O. et al. Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol. Genet. Metab. 124, 20–26 (2018).

    CAS  Article  Google Scholar 

  7. 7.

    Goldfinger, M. et al. Partial rescue of neuropathology in the murine model of PKU following administration of recombinant phenylalanine ammonia lyase (pegvaliase). Mol. Genet. Metab. 122, 33–35 (2017).

    CAS  Article  Google Scholar 

  8. 8.

    Enns, G. M. et al. Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol. Genet. Metab. 101, 99–109 (2010).

    CAS  Article  Google Scholar 

  9. 9.

    Moyle, J. J., Fox, A. M., Arthur, M., Bynevelt, M. & Burnett, J. R. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol. Rev. 17, 91–101 (2007).

    CAS  Article  Google Scholar 

  10. 10.

    Albrecht, J., Garbade, S. F. & Burgard, P. Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: a meta-analysis. Neurosci. Biobehav. Rev. 33, 414–421 (2009).

    CAS  Article  Google Scholar 

  11. 11.

    Huijbregts, S. C., De Sonneville, L. M., Van Spronsen, F. J., Licht, R. & Sergeant, J. A. The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance versus manipulation-functions of working memory. Neurosci. Biobehav. Rev. 26, 697–712 (2002).

    CAS  Article  Google Scholar 

  12. 12.

    Waisbren, S. E. et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol. Genet. Metab. 92, 63–70 (2007).

    CAS  Article  Google Scholar 

  13. 13.

    Weglage, J. et al. Neurocognitive functioning in adults with phenylketonuria: results of a long term study. Mol. Genet. Metab. 110, S44–S48 (2013).

    CAS  Article  Google Scholar 

  14. 14.

    Jahja, R. et al. Long-term follow-up of cognition and mental health in adult phenylketonuria: a PKU-COBESO study. Behav. Genet. 47, 486–497 (2017).

    Article  Google Scholar 

  15. 15.

    Van Spronsen, F. J. et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 5, 743–756 (2017).

    Article  Google Scholar 

  16. 16.

    Vockley, J. et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet. Med. 16, 188–200 (2014).

    CAS  Article  Google Scholar 

  17. 17.

    Jahja, R., Huijbregts, S. C., De Sonneville, L. M., Van der Meere, J. J. & Van Spronsen, F. J. Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J. Pediatr. 164, 895–899 (2014).

    CAS  Article  Google Scholar 

  18. 18.

    Viau, K. S. et al. Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria. J. Inherit. Metab. Dis. 34, 963–971 (2011).

    CAS  Article  Google Scholar 

  19. 19.

    Huijbregts, S. C. J. et al. Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations. Neuropsychologia 40, 7–15 (2002).

    CAS  Article  Google Scholar 

  20. 20.

    Posner, M. I. & Rothbart, M. K. Temperament and brain networks of attention. Philos. Trans. R. Soc. Lond. B Biol. Sci. 373, 20170254 (2018).

    Article  Google Scholar 

  21. 21.

    Somerville, L. H. & Casey, B. J. Developmental neurobiology of cognitive control and motivational systems. Curr. Opin. Neurbiol. 20, 236–241 (2010).

    CAS  Article  Google Scholar 

  22. 22.

    Burgard, P., Rey, F., Rupp, A., Abadie, V. & Rey, J. Neuropsychologic functions of early treated patients with phenylketonuria, on and off diet: results of a cross-national and cross-sectional study. Pediatr. Res. 41, 368–374 (1997).

    CAS  Article  Google Scholar 

  23. 23.

    Van der Schot, L. W., Doesburg, W. H. & Sengers, R. C. The phenylalanine response curve in relation to growth and mental development in the first year of life. Acta Paediatr. 407, 68–69 (1994).

    Article  Google Scholar 

  24. 24.

    Smith, I., Beasley, M. G. & Ades, A. E. Intelligence and quality of dietary treatment in phenylketonuria. Arch. Dis. Child. 65, 472–478 (1990).

    CAS  Article  Google Scholar 

  25. 25.

    Jahja, R. et al. Mental health and social functioning in early treated phenylketonuria: the PKU-COBESO study. Mol. Genet. Metab. 110, S57–S61 (2013).

    CAS  Article  Google Scholar 

  26. 26.

    Feldmann, R., Denecke, J., Grenzebach, M. & Weglage, J. Frontal lobe-dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults. J. Inherit. Metab. Dis. 28, 445–455 (2005).

    CAS  Article  Google Scholar 

  27. 27.

    Weglage, J. et al. Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls. J. Inherit. Metab. Dis. 23, 487–496 (2000).

    CAS  Article  Google Scholar 

  28. 28.

    Kort, W. et al. Wechsler Intelligence Scale for Children-III-NL (Pearson Clinical and Talent Assessment, 2005).

  29. 29.

    Petermann, F. F. & Petermann, U. (eds.) HAWIK-IV 3rd edn (Huber, 2010).

  30. 30.

    McCabe, E. R., McCabe, L., Mosher, G. A., Allen, R. J. & Berman, J. L. Newborn screening for phenylketonuria: predictive validity as a function of age. Pediatrics 72, 390–398 (1983).

    CAS  PubMed  Google Scholar 

  31. 31.

    RStudio. RStudio: integrated development environment for R (version 1.1.453). http://www.rstudio.org (2012).

  32. 32.

    Eid, M., Gollwitzer, M. & Schmitt, M. Statistik und Forschungsmethoden Lehrbuch (Beltz, 2011).

  33. 33.

    Lenhard, W. & Lenhard, A. Hypothesis Tests for Comparing Correlations (Psychometrica, 2014).

  34. 34.

    Christ, S. E., Huijbregts, S. C., De Sonneville, L. M. & White, D. A. Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol. Genet. Metab. 99, S22–S32 (2010).

    CAS  Article  Google Scholar 

  35. 35.

    Huijbregts, S. C., Gassio, R. & Campistol, J. Executive functioning in context: Relevance for treatment and monitoring of phenylketonuria. Mol. Genet. Metab. 110, S25–S30 (2013).

    CAS  Article  Google Scholar 

  36. 36.

    DeRoche, K. & Welsh, M. Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function. Dev. Neuropsychol. 33, 474–504 (2008).

    Article  Google Scholar 

  37. 37.

    Cleary, M. et al. Fluctuations in phenylalanine concentrations in phenylketonuria: A review of possible relationships with outcomes. Mol. Genet. Metab. 110, 418–423 (2013).

    CAS  Article  Google Scholar 

  38. 38.

    Zeman, J. et al. Intellectual and school performance in adolescents with phenylketonuria according to their dietary compliance. The Czech-Slovak Collaborative Study. Eur. J. Pediatr. 155, S56–S58 (1996).

    Article  Google Scholar 

  39. 39.

    Gonzalez, M. J. et al. Neurological complications and behavioral problems in patients with phenylketonuria in a Follow-up Unit. Mol. Genet. Metab. 104, S73–S79 (2011).

    CAS  Article  Google Scholar 

  40. 40.

    Van Vliet, D. et al. Infants with Tyrosinemia Type 1: should phenylalanine be supplemented? JIMD Rep. 18, 117–124 (2015).

    Article  Google Scholar 

  41. 41.

    Van Vliet, K. et al. Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients. Orphanet J. Rare Dis. 14, 285 (2019).

    Article  Google Scholar 

Download references

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Affiliations

Authors

Contributions

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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Participants and/or parents gave written informed consent to participate in the study and for using their data in this report.

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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). https://doi.org/10.1038/s41390-021-01728-8

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