ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt


The aim of this study is to evaluate the neuropsychological status in a cohort of children with early and continuously treated phenylketonuria in Assiut, Upper Egypt. The study was implemented in seventy-eight phenylketonuria (PKU) children. Only 34 patients met the inclusion criteria. Investigated patients were evaluated according to detailed history, neurological examination, Childhood Autism Rating Scale, full scale Intelligence Quotient, attention deficit hyperactivity disorder, electroencephalography and magnetic resonance imaging (MRI). This study concluded that the prognosis for early diagnosed children with PKU treated from the first weeks of life is generally good. However, they are at increased risk for neurological complications and behavioral problems. So, neonatal screening for PKU is highly recommended in Egypt, for early detection and management. In addition, neuropsychological and MRI assessments in PKU children should be done.

This is a preview of subscription content, access via your institution.


  1. 1.

    Følling A (1934) Über Ausscheidung von Phenylbrenztraubensäure im Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Hoppe Seylers Z Physiol Chem. 227:169–176

    Article  Google Scholar 

  2. 2.

    MacLeod EL, Ney DM (2010) Nutritional management of phenylketonuria. Ann Nestlé (Engl). 68:58–69

    Article  Google Scholar 

  3. 3.

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

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Brumm VL, Bilder D, Waisbren SE (2010) Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab 99(Suppl 1):S59–S63

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Brumm VL, Azen C, Moats RA, Stern AM, Broomand C, Nelson MD, Koch R (2004) Neuropsychological outcome of subjects participating in the PKU adult collaborative study: a preliminary review. J Inherit Metab Dis 27:549–566

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Surtees R, Blau N (2000) The neurochemistry of phenylketonuria. Eur J Pediatr 159:S109–S113

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Scarabino T, Popolizio T, Tosetti M, Montanaro D, Giannatempo GM, Terlizzi R, Pollice S, Maiorana A, Maggialetti N, Carriero A, Leuzzi V, Salvolini U (2009) Phenylketonuria: white-matter changes assessed by 3.0-T magnetic resonance (MR) imaging, MR spectroscopy and MR diffusion. Radiol Med. 114:461–474

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Jones SJ, Turano G, Kriss A, Shawkat F, Kendall B, Thompson AJ (1995) Visual evoked potentials in phenylketonuria: association with brain MRI, dietary state, and IQ. J Neurol Neurosurg Psychiatry 59:260–265

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Scriver CR, Kaufman S (2001) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, pp 1667–1724

    Google Scholar 

  10. 10.

    Williams RA, Mamotte CD, Burnett JR (2008) Phenylketonuria: an inborn error of metabolism. Clin Biochem Rev 29:31–40

    PubMed Central  PubMed  Google Scholar 

  11. 11.

    Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal Investigators; Centers for Disease Control and Prevention (2012) Prevalence of autism spectrum disorders–Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill Summ. 61(3):1–19

  12. 12.

    Kuehn BM (2007) CDC: autism spectrum disorders common. JAMA 297:940

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Manzi B, Loizzo AL, Giana G, Curatolo P (2008) Autism and metabolic diseases. J Child Neurol 23:307–314

    Article  PubMed  Google Scholar 

  14. 14.

    Saad K, Hammad E, Abdel-rahman AA, Sobhy KM (2013) Autistic symptoms in late diagnosed phenylketonuric children in Upper Egypt. J Neur Res 3(3–4):122–129

  15. 15.

    Chen CH, Hsiao KJ (1989) A Chinese classic phenylketonuria manifested as autism. Br J Psych 155:251–253

    CAS  Article  Google Scholar 

  16. 16.

    Steiner CE, Acosta AX, Guerreiro MM, Marques-de-Faria AP (2007) Genotype and natural history in unrelated individuals with phenylketonuria and autistic behavior. Arq Neuropsiquiatr 65(2A):202–205

    Article  PubMed  Google Scholar 

  17. 17.

    Moss J, Howlin P (2009) Autism spectrum disorders in genetic syndromes: implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. J Intel Dis Res. 53:852–873

    CAS  Article  Google Scholar 

  18. 18.

    Caglayan AO (2010) Genetic causes of syndromic and non-syndromic autism. Dev Med Child Neurol 52:130–138

    Article  PubMed  Google Scholar 

  19. 19.

    Antshel KM, Waisbren SE (2003) Developmental timing of exposure to elevated levels of phenylalanine is associated with ADHD symptom expression. J Abnorm Child Psychol 31:565–574

    Article  PubMed  Google Scholar 

  20. 20.

    Antshel KM (2010) ADHD, learning, and academic performance in phenylketonuria. Mol Genet Metab 99(S1):S52–S58

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Melika LK (1998) The Stanford Binet Intelligence Scale. Arabic Examiner’s Handbook, 4th edn. Dar El-Maref Publishing, Cairo

    Google Scholar 

  22. 22.

    American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR. American Psychiatric Association, Washington, DC

    Google Scholar 

  23. 23.

    Schopler E, Reichller R, Renner BR (1994) The Childhood Autism Rating Scale CARS. Western Psychological Services, Los Angeles

    Google Scholar 

  24. 24.

    Rellini E, Tortolani D, Trillo S, Carbone S, Montecchi F (2004) Childhood Autism Rating Scale CARS, and Autism Behavior Checklist ABC, correspondence and conflicts with DSM-IV criteria in diagnosis of autism. J Autism Dev Disord 34:703–708

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Perry A, Condillac RA, Freeman NL, Dunn-Geier J, Belair J (2005) Multi-site study of the Childhood Autism Rating Scale (CARS) in five clinical groups of young children. J Autism Dev Disord 355:625–634

    Article  Google Scholar 

  26. 26.

    Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157:824–830

    CAS  Article  PubMed  Google Scholar 

  27. 27.

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

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Crossley LH, Anderson PJ (2010) Neuropsychological functioning in early-treated phenylketonuria—a review. Ann Nestlé (Engl). 68:78–88

    Article  Google Scholar 

  29. 29.

    McCandless DW (2012) Epilepsy: animal and human correlations. Springer, New York

    Google Scholar 

  30. 30.

    González MJ, Gutiérrez AP, Gassió R, Fusté ME, Vilaseca MA, Campistol J (2011) Neurological complications and behavioral problems in patients with phenylketonuria in a follow-up unit. Mol Genet Metab 104:S73–S79

  31. 31.

    Yalaz K, Vanli L, Yilmaz E, Tokatli A, Anlar B (2006) Phenylketonuria in pediatric neurology practice: a series of 146 cases. J Child Neurol 21:987–990

    Article  PubMed  Google Scholar 

  32. 32.

    Thompson AJ, Tillotson AJ, Smith I et al (1993) Brain MRI changes in phenylketonuria; associations with dietary status. Brain. 116:811–821

    Article  PubMed  Google Scholar 

  33. 33.

    Cleary MA, Walter JH, Wraith JE, Jenkins JP, Alani SM, Tyler K, Whittle D (1994) Magnetic resonance imaging of the brain in phenylketonuria. Lancet 344:87–90

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Toft PB, Lou HC, Krägeloh-Mann I, Andresen J, Güttler F, Guldberg P, Henriksen O (1994) Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia. J Inherit Metab Dis 17:575–583

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Weglage J, Pietsch M, Fünders B, Koch HG, Ullrich K (1995) Neurological findings in early treated phenylketonuria. Acta Paediatr 84:411–415

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Landvogt C, Mengel E, Bartenstein P, Buchholz HG, Schreckenberger M, Siessmeier T, Scheurich A, Feldmann R, Weglage J, Cumming P, Zepp F, Ullrich K (2008) Reduced cerebral fluoro-l-dopamine uptake in adult patients suffering from phenylketonuria. J Cereb Blood Flow Metab 28:824–831

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Goldman-Rakic PS (1998) The cortical dopamine system: role in memory and cognition. Adv Pharmacol 42:707–711

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Arnold GL, Vladutiu CJ, Orlowski CC, Blakely EM, DeLuca J (2004) Prevalence of stimulant use for attentional dysfunction in children with phenylketonuria. J Inherit Metab Dis 27(2):137–143

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Posner J, Gorman D, Nagel BJ (2009) Tyrosine supplements for ADHD symptoms with comorbid phenylketonuria. J Neuropsychiatry Clin Neurosci 21:228–230

    Article  PubMed  Google Scholar 

  40. 40.

    Baieli S, Pavone L, Meli C, Fiumara A, Coleman M (2003) Autism and phenylketonuria. J Autism Dev Disord 33:201–204

    Article  PubMed  Google Scholar 

  41. 41.

    Zafeiriou DI, Ververi A, Vargiami E (2007) Childhood autism and associated comorbidities. Brain Dev 29:257–272

    Article  PubMed  Google Scholar 

  42. 42.

    Okado N (1999) Mechanisms for formation and maintenance of synapses mediated by biogenic amines: pathogenesis and therapy of mental retardation and developmental disabilities by genetic and epigenetic factors. Kaibogaku Zasshi. 74:351–362

    CAS  PubMed  Google Scholar 

  43. 43.

    Anderson PJ, Wood SJ, Francis DE, Coleman L, Warwick L, Casanelia S, Anderson VA, Boneh A (2004) Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol 46:230–238

    Article  PubMed  Google Scholar 

  44. 44.

    Anderson PJ, Leuzzi V (2010) White matter pathology in phenylketonuria. Mol Genet Metab 99:3–9

    Article  Google Scholar 

  45. 45.

    Christ SE, Steiner RD, Grange DK, Abrams RA, White DA (2006) Inhibitory control in children with phenylketonuria. Dev Neuropsychol. 30:845–864

    Article  PubMed  Google Scholar 

  46. 46.

    Anderson PJ, Wood SJ, Francis DE, Coleman L, Anderson V, Boneh A (2007) Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol. 32(2):645–668

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

All authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author information



Corresponding author

Correspondence to Khaled Saad.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Saad, K., Elserogy, Y., Abdel rahman, A.A. et al. ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt. Acta Neurol Belg 115, 657–663 (2015).

Download citation


  • Phenylketonuria
  • ADHD
  • Autism
  • Children