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Cognitive profile and mental health in Phenylketonuria

Cognitive profile and mental health in Phenylketonuria

Phenylketonuria (PKU) is known to have a devastating effect on intellectual development early in life resulting in an IQ of <30-40, severe behavior problems and severe epilepsy if treatment is not started soon after birth.1 Some patients (~1-2%) seem to escape from the severe mental delay in development when not treated2 – the exact number of these patients is not accurately known, as all patients are – and should be – treated as soon as possible after neonatal screening.3

Studies show that continuously treated patients (from neonatal screening onwards) have a normal IQ (within the range 80–120), but always with a decrease of about 4–10 points compared with the control population.4,5 One might be surprised by the relatively large difference between studies showing either a small or a relatively larger decrease in IQ within the studied PKU patients compared with control populations within the same project. Part of this may be due to the educational level of the control groups or perhaps the adequacy of treatment in the PKU population studied. Some of the differences may also be due to the way IQ is tested. Is language development tested as well? Does the method describe verbal and performance total IQ? Although IQ is a well-known outcome measure, differences exist between the various methods used.a

In the 1970s and 80s, IQ was the most important gauge of neurocognitive outcome, but from the 90s, executive function (EF) became the more important outcome.6 Gradually, the importance of verbal development has been realized,7 and, especially for adults, other aspects of mental health have been recognized.8 Acknowledging the differences in IQ, the differences in measures for EF are even greaterb as EF encompasses neurocognitive abilities (the less complex: inhibitory control, working memory, cognitive flexibility, and the more complex abilities: strategic thinking, organization and planning). All these functions have been found to be abnormal in various studies at various ages in patients with PKU. Parts of these functions are also tested with IQ, but not all. Originally, EF was thought to be ‘only’ concerned with the prefrontal area of the brain. Now, not only other parts of the brain (temporal, parietal) are considered to be important for these abilities, but also the connections between various parts of the brain.9 Part of the discussion (especially in adults) is whether the differences found between adult patients with PKU and adult controls are due to executive functions or are just differences in velocity.10-12 Smith et al have shown that speed matters, but that PKU patients have a specific pattern of neurocognitive function.12

As well as neurocognitive outcome, behavioral aspects have also been studied,13 although more focus has been on psychiatric problems.14 However, these issues, as well as social skills are important for patients in their day-to-day functions.15 Together, these aspects cover mental health and show that mental health in patients with PKU is not that bad but still not optimal. Indeed, when compared with some other inborn errors of metabolism for which there is no treatment, the outcome in PKU patients is adequate. On the other hand, there is still an increasing number of publications showing that less adequate treatment during adulthood is not without danger to PKU adults, and that dietary treatment, although socially disabling, does dramatically improve the outcome (see reference 4).

What does all this mean?

It definitely means that the most important part of the PKU pathophysiology – i.e., brain dysfunction - can be prevented by the combination of neonatal screening and treatment. But even if treated well, there is still a non-optimal EF that is largely dependent on metabolic control, and metabolic control is increasingly advised to be very strict, especially in childhood and early puberty.3-5,16,17 Other existing treatments that decrease the blood phenylalanine concentration are the chaperone treatment with sapropterin dicholoride,1 and lately the treatment with phenylalanine ammonia lyase,18,19 while other treatments such as the use of large neutral amino acids20-22 and the medical blockade of the transport of phenylalanine into the brain,23 may in the future also prove to be of help to further optimize the outcome of these patients.



  1. Examples include the Intelligence and Development Scales (IDS), the Reynolds Intellectual Assessment Scales (RIAS), the Snijders-Oomen Nonverbal Intelligence Test (SON), the Wechsler Intelligence Scale for Children (WISC), the Terman revised WISC. the Standford-Binet test, the WPPSI, the Beayley, the BSID and BOS (both Bayley development scales). In addition, some tests, and in particular the WISC have variants: WISC-II, III, IV and now V.
  2. Apart from the well-known batteries CANTAB and ANT, there are a large number of specific tests (s.a. Tower of London, Tower of Hanoi, Stroop test, one-back, two-back, three-back etc.). Some more or less measure the same abilities, but not all.



  1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet 2010 Oct 23;376(9750):1417-27.
  2. van Vliet D, van Wegberg AMJ, Ahring K, et al. Can untreated PKU patients escape from brain dysfunction? A systematic review. Orphanet J Rare Dis. Accepted for publication.
  3. van Spronsen FJ, van Wegberg AM, Ahring K, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 2017 Sep;5(9):743-56.
  4. van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 2017 Oct 12;12(1):162.
  5. Jahja R, Huijbregts SC, de Sonneville LM, et al. Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. J Pediatr 2014 Apr;164(4):895-9.e2.
  6. Huijbregts SC, Gassió R, Campistol J. Executive functioning in context: Relevance for treatment and monitoring of phenylketonuria. Mol Genet Metab 2013;110 Suppl:S25-30.
  7. Hawks ZW, Strube MJ, Johnson NX, et al. Developmental trajectories of executive and verbal processes in children with phenylketonuria. Dev Neuropsychol 2018;43(3):207-18.
  8. Jahja R, Huijbregts SCJ, de Sonneville LMJ, et al. Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study. Neuropsychology 2017 May;31(4):437-47.
  9. Christ SE, Huijbregts SC, de Sonneville LM, White DA. Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab 2010;99 Suppl 1:S22-32.
  10. Channon S, Mockler C, Lee P. Executive functioning and speed of processing in phenylketonuria. Neuropsychology. 2005 Sep;19(5):679-86.
  11. Albrecht J, Garbade SF, Burgard P. Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria: A meta-analysis. Neurosci Biobehav Rev 2009 Mar;33(3):414-21.
  12. Romani C, MacDonald A, De Felice S, Palermo L. Speed of processing and executive functions in adults with phenylketonuria: Quick in finding the word, but not the ladybird. Cogn Neuropsychol 2018 May-Jun;35(3-4):171-98.
  13. Smith I, Knowles J. Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr 2000 Oct;159 Suppl 2:S89-93.
  14. Bilder DA, Noel JK, Baker ER, et al. Systematic review and meta-analysis of neuropsychiatric symptoms and executive functioning in adults with phenylketonuria. Dev Neuropsychol 2016 May-Jun;41(4):245-60.
  15. Jahja R, van Spronsen FJ, de Sonneville LMJ, et al. Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study. J Inherit Metab Dis 2016 May;39(3):355-62.
  16. Burgard P, Ullrich K, Ballhausen D, et al. Issues with European guidelines for phenylketonuria. Lancet Diabetes Endocrinol 2017 Sep;5(9):681-3.
  17. van Spronsen FJ, van Wegberg AMJ, Ahring K, et al. Issues with European guidelines for phenylketonuria - Authors' reply. Lancet Diabetes Endocrinol 2017 Sep;5(9):683-4.
  18. Longo N, Harding CO, Burton BK, 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 2014 Jul 5;384(9937):37-44.
  19. Harding CO, Amato RS, Stuy M, et al; PRISM-2 Investigators. Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial. Mol Genet Metab 2018 May;124(1):20-6.
  20. van Spronsen FJ, de Groot MJ, Hoeksma M, et al. Large neutral amino acids in the treatment of PKU: from theory to practice. J Inherit Metab Dis 2010 Dec;33(6):671-6.
  21. van Vliet D, Bruinenberg VM, Mazzola PN, et al.Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model. Am J Clin Nutr 2016 Nov;104(5):1292-1300.
  22. van Vliet D, van der Goot E, Bruinenberg VM, et al. Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice. J Nutr Biochem 2018 Mar;53:20-7.
  23. Belanger AM, Przybylska M, Gefteas E, et al. Inhibiting neutral amino acid transport for the treatment of phenylketonuria. JCI Insight. 2018 Jul 26;3(14).pii:121762. [Epub ahead of print].

Francjan Van Spronsen

Pediatrician metabolic diseases, Associate Professor Pediatrics
Beatrix Children's Hospital
University of Groningen
Groningen, Netherlands
executive function
mental health