Skip to main content
SpringerLink
Log in

Predictability and inconsistencies in the cognitive outcome of early treated PKU patients

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease’s biomarkers. We collected biochemical data from 65 ETPKU patients (diagnostic blood Phe > 360 μmol/l) who were assessed twice for IQ (Wechsler Intelligence Scale) during their lifetime (mean age: 10.2 and 19.6 years, respectively). Results show that in ETPKU patients IQ over the second decade of life remained stable in about half of the patients (51%); while the rest experienced a gain (7 to 15 points) or loss (7 to 28 points) in IQ scores (23 and 26% respectively) whatever the quality of metabolic control was. The main factor affecting the second IQ was the value of the first IQ (p < 0.000) whose effect overruled that of the markers of metabolic control. Looking at the developmental trajectory of our ETPKU patients, the present study disclosed a remarkable interindividual variability in their cognitive outcome and also an inconsistent linkage between cognitive performances and biochemical control, thus supporting the hypothesis of an individual resilience or vulnerability to Phe in young adult ETPKU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. Critical difference (T2-T1) = zalpha*SDtest score*SQRT((1-rtt1) + (1-rtt2)); where: T1 and T2 = IQ total scores at time-point 1 and 2, respectively; zalpha = z-score (standard normal distribution) corresponding to alpha level (z0.05 = 1.96); SDtest score = standard deviation of the test score; rtt1 and rtt2 = test-retest reliability for T1 and T2, respectively.

References

  • Beasley MG, Costello PM, Smith I (1994) Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971. Q J Med 87:155–160

    CAS  PubMed  Google Scholar 

  • Bilder DA, Burton BK, Coon H et al (2013) Psychiatric symptoms in adults with phenylketonuria. Mol Genet Metab 108:155–160

    Article  CAS  PubMed  Google Scholar 

  • Blau N, van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427

    Article  CAS  PubMed  Google Scholar 

  • Crone MR, van Spronsen FJ, Oudshoorn K et al (2005) Behavioural factors related to metabolic control in patients with phenylketonuria. J Inherit Metab Dis 28:627–637

    Article  CAS  PubMed  Google Scholar 

  • DeRoche K, Welsh M (2008) Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function. Dev Neuropsychol 33(4):474–504. https://doi.org/10.1080/87565640802101482

  • Hindley CB, Owen CF (1978) The extent of individual changes in I.Q. For ages between 6 months and 17 years, in a British longitudinal sample. J Child Psychol Psychiatry 19(4):329–350

    Article  CAS  PubMed  Google Scholar 

  • Hindley CB, Owen CF (1979) An analysis of individual patterns of DQ and IQ curves from 6 months to 17 years. Br J Psychol 70:273–293

    Article  Google Scholar 

  • Holtzman NA, Kronmal RA, van Doorninck W, Azen C, Koch R (1986) Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. N Engl J Med 314(10):593–8

  • Hujibregts SC, de Sonneville LM, Licht R, van Spronsen FJ, Sergeant JA (2002) Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J Inherit Metab Dis 25:419–430

    Article  Google Scholar 

  • Koch R, Azen CG, Friedman EG, Williamson ML (1982) Preliminary report on the effects of diet discontinuation in PKU. J Pediatr 100(6):870–875

    Article  CAS  PubMed  Google Scholar 

  • Koch R, Burton B, Hoganson G et al (2002) Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 25:333–346

    Article  CAS  PubMed  Google Scholar 

  • Leuzzi V, Mannarelli D, Manti F et al (2014) Age related psychophysiological vulnerabilità to phenylalanine in phenylketonuria. Front Pediatr 2:57. https://doi.org/10.3389/fped.2014.00057

  • Manti F, Nardecchia F, Chiarotti F, Carducci C, Carducci C, Leuzzi V (2016) Psychiatric disorders in adolescent and young adult patients with phenylketonuria. Mol Genet Metab 117(1):12–18. https://doi.org/10.1016/j.ymgme.2015.11.006

  • Mastrangelo M, Chiarotti F, Berillo L et al (2015) The outcome of white matter abnormalities in early treated phenylketonuric patients: a retrospective longitudinal long-term study. Mol Genet Metab 116(3):171–177. https://doi.org/10.1016/j.ymgme.2015.08.005

  • Menard S (1995) Applied logistic regression analysis: Sage University series on quantitative applications in the social sciences. Sage, Thousand Oaks

    Google Scholar 

  • Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR (2007) Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev 17:91–101

    Article  CAS  PubMed  Google Scholar 

  • Nardecchia F, Manti F, Chiarotti F, Carducci C, Carducci C, Leuzzi V (2015) Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: a longitudinal study. Mol Genet Metab 115(2–3):84–90

    Article  CAS  PubMed  Google Scholar 

  • National Institutes of Health Consensus Development Panel (2001 Oct) National Institutes of Health consensus development conference statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 108(4):972–982

    Article  Google Scholar 

  • Palermo L, Geberhiwot T, MacDonald A, Limback E, Hall SK, Romani C (2017) Cognitive outcomes in early-treated adults with phenylketonuria (PKU): a comprehensive picture across domains. Neuropsychology 31:255–267

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramus SJ, Forrest SM, Pitt DD, Cotton RG (1999) Genotype and intellectual phenotype in untreated phenylketonuria patients. Pediatr Res 45(4 Pt 1):474–481

    Article  CAS  PubMed  Google Scholar 

  • Romano C, Balsamo A, Burroni M, Cardillo A, Carnevale F, Caruso U, Cerone R, Ciatti R, Cioni M, Corbetta C, Dotti L, Impellizzeri A, Lelli A, Leuzzi V, Lilliu F, Pagliardini S, Piazzi S, Principi R, Salardi S, Schiaffino MC (1997) Diagnosis, classification, basis of treatment of hyperphenylalaninemias. Riv Ital Ped 23:1040–1044

    Google Scholar 

  • Romani C, Palermo L, MacDonald A, Limback E, Hall SK, Geberhiwot T (2017) The impact of phenylalanine levels on cognitive outcomes in adults with phenylketonuria: effects across tasks and developmental stages. Neuropsychology 31:242–254

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith I, Beasley MG, Ades AE (1990) Intelligence and quality of dietary treatment in phenylketonuria. Arch Dis Child 65:311–316

    Article  Google Scholar 

  • Smith I, Beasley MG, Ades AE (1991) Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 66:311–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith I, Wolff OH (1974) Natural history of phenylketonuria and influence of early treatment. Lancet 2(7880):540–544

    Article  CAS  PubMed  Google Scholar 

  • Sullivan JE (2001) Emotional outcome of adolescents and young adults with early and continuously treated phenylketonuria. J Pediatr Psychol 26:477–484

    Article  CAS  PubMed  Google Scholar 

  • Trefz FK, Cipcic-Schmidt S, Koch R (2000) Final intelligence in late treated patients with phenylketonuria. Eur J Pediatr 159(Suppl 2):S145–S148

    Article  PubMed  Google Scholar 

  • van Spronsen FJ, Huijbregts SC, Bosch AM, Leuzzi V (2011) Cognitive, neurophysiological, neurological and psychosocial outcomes in early-treated PKU-patients: a start toward standardized outcome measurement across development. Mol Genet Metab 104:S45–S51. https://doi.org/10.1016/j.ymgme

  • van Spronsen FJ, van Wegberg AM, Ahring K et al (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. https://doi.org/10.1016/S2213-8587(16)30320-5

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Walter JH, White FJ, Hall SK et al (2002) How practical are recommendations for dietary control in phenylketonuria? Lancet 360:55–57

    Article  CAS  PubMed  Google Scholar 

  • Wechsler D (1997) Wechsler adult intelligence scale- revised (WAIS-R), New York, The Psychological Corporation, 1981. Italian version, C. Laicardi, A. Orsini, Scala di intelligenza Wechsler per adulti, Organizzazioni Speciali, Firenze

  • Wechsler D (2006) Wechsler intelligence scale for children III (WISC-III), New York, The Psychological Corporation, 1991. Italian version, A. Orsini, L. Picone, Scala di intelligenza Wechsler per bambini- terza edizione, Organizzazioni Speciali, Firenze

  • Wechsler D (1986) Wechsler intelligence scale for children Revived (WISC-R), New York, The Psychological Corporation, 1974. Italian version, V. Rubini, F. Padovani, Scala di intelligenza Wechsler per bambini- riveduta, Organizzazioni Speciali, Firenze

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

    Article  CAS  PubMed  Google Scholar 

  • Weglage J, Pietsch M, Denecke J, Sprinz A, Feldmann R, Grenzebach M, Ullrich K (1999) Regression of neuropsychological deficits in early-treated phenylketonurics during adolescence. J Inherit Metab Dis 22(6):693–705

  • Weglage J, Ullrich K, Pietsch M, Fünders B, Zass R, Koch HG (1996) Untreated non-phenylketonuric-hyperphenylalaninaemia: intellectual and neurological outcome. Eur J Pediatr 155(Suppl 1):S26–S28

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics and Child Neurology and Psychiatry, Sapienza University of Rome, Via dei Sabelli 108, 00185, Rome, Italy

    Filippo Manti, Francesca Nardecchia & Vincenzo Leuzzi

  2. Department of Pediatrics, University of Milan, San Paolo Hospital, Santi Paolo e Carlo ASST, Via Antonio Di Rudinì 8, 20142, Milan, Italy

    Sabrina Paci, Silvia Dalmazzone, Graziella Cefalo, Elisabetta Salvatici & Giuseppe Banderali

  3. Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Flavia Chiarotti

  4. Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy

    Claudia Carducci & Carla Carducci

Authors
  1. Filippo Manti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Nardecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabrina Paci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Flavia Chiarotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Carducci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carla Carducci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Silvia Dalmazzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Graziella Cefalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elisabetta Salvatici
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giuseppe Banderali
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vincenzo Leuzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vincenzo Leuzzi.

Ethics declarations

Conflict of interest

F. Manti, F. Nardecchia, S. Paci, F. Chiarotti, C. Carducci, C. Carducci, S. Dalmazzone, G. Cefalo, E. Salvatici, G. Banderali, and V. Leuzzi declare that they have no conflict of interest.

Informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. Informed consent was obtained from all patients for being included in the study.

Additional information

Responsible Editor: Georg Hoffmann

Filippo Manti and Francesca Nardecchia wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Electronic supplementary material

Table S1

(DOCX 26 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manti, F., Nardecchia, F., Paci, S. et al. Predictability and inconsistencies in the cognitive outcome of early treated PKU patients. J Inherit Metab Dis 40, 793–799 (2017). https://doi.org/10.1007/s10545-017-0082-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-017-0082-y

Search

Navigation