1. Understanding and Managing the Neurocognitive and Psychiatric Issues Associated with PKU

6. Dietary Compliance and Blood Phe Levels in Patients with PKU Over Time % Patients Above Recommended Blood Phe Level Walter, et al. Lancet . 2002;360:55-7. N = 178 N = 137 N = 98 N = 77

10. Vulnerable Neurocognitive Domains Moyle, et al. Neuropsychol Rev . 2007;17(2):91-101. Motor Skills Information Processing Speed Inhibitory Control Working Memory Attention IQ PKU

12. IQ in Patients with PKU Comparison to Peer Group 1 Comparison to Siblings 2 P < 0.0001 P < 0.001 N = 21 N = 55 N = 55 N = 26 IQ (Wechsler Intelligence Scale) 1) Gassio, et al. Pediatr Neurol . 2005;33(4):267-71. 2) Koch, et al. J Inherit Metab Dis . 1984;7(2):86-90.

13. Impact of Blood Phe Levels on IQ N = 3361 Waisbren, et al. Mol Genet Metabol . 2007;92:63-70. Observation Period Blood Phe Levels ( μ mol/L) Lifetime IQ Loss for Each 100 μ mol/L ↑ in Blood Phe 0 - 12 years old 423 - 750 1.3 - 3.1 points Lifetime 394 - 666 1.9 - 4.1 points

16. Role of Executive Function in Self-Management Executive Task Plan diet Maintain supplies of formula and supplements Record phe intake Resist restricted foods (inhibitory control) Take blood phe levels Adjust diet based on blood phe levels

19. Executive Function in Patients with PKU vs. Control Group Leuzzi, et al. J Inherit Metab Dis . 2004;27(2):115-25. P < 0.001 P < 0.05

20. Working Memory in Patients with PKU vs. Control Group P < 0.05 (all domains) Mean Span White, et al. J Int Neuropsychol Soc . 2002;8:1-11.

21. Inhibitory Control in Patients with PKU vs. Control Group * P < 0.05 vs. control * Number of Errors Christ, et al. Dev Neuropsychol . 2006;30(3):845-64.

22. Strategic Planning in Patients with PKU vs. Normative Data P < 0.05 vs. normative data * * N = 15 VanZutphen, et al. Clin Genet . 2007;72(1):13-8. Test Score

23. Information Processing Speed in Patients with PKU vs. Control Group Anderson, et al. Dev Neuropsychol . 2007;32(2):645-68. Test Score Time to Rapid Retrieval P < 0.01 vs. control (all domains)

24. Memory and Learning Impairments in Patients with PKU White, et al. Neuropsychol . 2001;15(2):221-9. Words Recalled * P < 0.05 vs. control * California Verbal Learning Test Patients up to 11 y.o. Patients ≥ 11 y.o.

28. Academic Difficulties in Patients with PKU vs. Control Group * P < 0.05 vs. control * % Students Gassio, et al. Pediatr Neurol . 2005;33(4):267-71.

30. Neurocognitive Testing * BRIEF-P (preschool version) is available for children aged 2-5 years old. Christ, et al. Mol Genet Metabol . 2010;99(S1):22-32. Janzen, et al. Mol Genet Metabol . 2010;99(S1):47-51. Neurocognitive Domain Test / Assessment Intelligence / IQ Wechsler intelligence scale Executive function • Working memory, attention • Inhibitory control, cognitive flexibility • Planning / organization Behavior rating inventory of executive function (BRIEF*) • Digit span; self-ordered pointing test; trail making test • Stroop color-word test; Wisconsin card sorting test; tower tasks; test of everyday attention for children • Rey-Osterreith complex figure test; tower tasks Non-executive function • Information processing speed • Motor skills • Memory and learning • Symbol digit coding; finger tapping test; trail making test • Purdue test; Peabody developmental motor scales • California verbal learning test; Rey learning tests Academic performance Teacher/parent reports; academic testing Social-emotional adjustment Quality of life questionnaires

34. Psychiatric Symptoms in PKU ↓ Positive Emotions Less joy, happiness, confidence, autonomy, social competence ↑ Negative Emotions More depression, anxiety, phobias, social isolation Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Feillet, et al. Mol Genet Metabol . 2010;99(S1):79-85.

35. Psychiatric Symptoms in PKU Brumm, et al. Mol Genet Metabol . 2010;99(S1):59-63. Untreated Individual Early-Treated Child Early-Treated Adult Aggression Attention problems Decreased positive emotions Anxiety Decreased autonomy Depression Autistic behaviors Decreased social competence Generalized anxiety Depression Less achievement motivation Lack of autonomy Hyperactivity Low self-esteem Low self-esteem Impaired social skills School problems Phobias Psychotic symptoms Social isolation/withdrawal Social withdrawal Social maturity deficits

36. Psychiatric Symptoms in Patients with PKU vs. Control Group Pietz, et al. Pediatrics . 1997;99(3):345-50. Percent of Adult Patients Reporting Symptom P < 0.05 vs. control (all domains) % % % % % % % % % %

38. Stimulant Use for ADHD in Patients with PKU vs. Control Group Control group = patients with diabetes mellitus Arnold, et al. J Inherit Metab Dis . 2004;27(2)137-43. Control Group (N = 76) PKU (N = 38) Percent of patients using stimulants for ADHD ( P < 0.006) ADHD symptoms were associated with higher blood phe levels

42. Assessment by Non-Psychologists Psychological Realm Test / Assessment Adaptive functioning Adaptive behavior assessment system (ABAS-II) Behavior Behavior assessment system for children (BASC-II) Executive function Behavior rating inventory of executive function (BRIEF) (BRIEF-P = preschool version for children aged 2-5 years old)