1. Neurocognitive Functioning in PKU Susan Waisbren, PhD Children’s Hospital Boston HIGH HOPES!

2. KEY POINTS EVEN TREATED CHILDREN AND ADULTS EXPERIENCE NEUROPSYCHOLOGICAL EFFECTS PSYCHOLOGICAL ASSESSMENTS ARE IMPORTANT THERE ARE STRATEGIES FOR IMPROVING FUNCTIONING IN PKU

4. KEY POINT # 1: EVEN TREATED CHILDREN AND ADULTS EXPERIENCE LEARNING DIFFICULTIES AND OTHER NEUROPSYCHOLOGICAL EFFECTS

5. NEUROCOGNITIVE DEFICITS IN TREATED PKU REDUCTIONS IN: Executive Functioning Memory Planning Attention Organization Mental Processing Speed Behavior and Mood Especially if Blood Phe not consistently in target range

6. Nearly one in three PKU children under the age of 10 have blood Phe above recommended target range Noncompliance increases as patients enter adolescence Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55–57. ADHERENCE TO TREATMENT 0–4 5–910–14 15–19 (n = 137) (n = 98) (n = 77) (n = 178) (n = 137) (n = 98) (n = 77)

7. WHY PROBLEMS? THE DOPAMINE HYPOTHESIS

8. EXECUTIVE FUNCTIONING AND THE DOPAMINE HYPOTHESIS BH 4 Phenylalanine PAH DopamineTyrosineL-dopa TH BH 4 AADC Tyrosine Periphery (mostly liver) Blood Brain Barrier Brain BH 4 = tetrahydrobiopterin PAH = phenylalanine hydroxylase TH = tyrosine hydroxylase AADC = aromatic amino acid decarboxylase

9. DOPAMINE: EXECUTIVE FUNCTION, EMOTION AND SOCIAL BEHAVIOR Neurotransmitter related to attention, mood, and movement Precursor to norepinephrine, epinephrine, and other neurotransmitters Image from http://nobelprize.org/nobel_prizes/medicine/laureates/2000/press.html prefrontal cortex dopamine pathways frontal lobe basal ganglia

10. DOPAMINE AND EXECUTIVE FUNCTION DEFICITS 1 Van Zutphen KH, et al. Clin Genet. 2007;72:13-18. 2 Diamond A, et al. Monogr Soc Res Child Dev. 1997;62:1-208. 3 Huijbregts SC, et al. NeuroSci Biobehav Rev. 2002;26:697-712. 4 Channon S, et al. Neuropsychology. 2004;18:613-620. Infants 2 Working memory Behavioral inhibition Children (7–14) 3 Impulse control Attentional flexibility Adults 4 Attention Working memory Verbal Fluency

11. Gassio R, et al. Pediatr Neurol. 2005;33:267–271. *Controls were age- and sex-matched † PKU patients (ages 7–19 years old) managed early and continuously with Phe-restricted diet n = 26n = 21 Children with PKU on diet have significantly lower IQ than unaffected peers n = 55 Koch R, et al. J Inherit Metab Dis. 1984;7:86-90. † and sibling controls

12. EXECUTIVE FUNCTIONING DEFICITS Anderson VA, et al. Child Neuropsychol. 2002;8(4):231-240. **Based on Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score. Severe range is > 1 SD above the mean (n = 80)(n = 45)(n = 44) *P < 0.001 compared to control

13. Arnold GL, et al. J Inherit Metab Dis. 2004;27:137–143. (n = 38) (n = 76) ATTENTION PROBLEMS *P < 0.006 as compared to children with diabetes mellitus

14. WORKING MEMORY *P <.05 compared to control White DA, et al. J Int Neuropsychol Soc. 2002;8:1-11. n = 20

15. * Younger < 11 yr Older ≥ 11 yr White DA, et al. Neuropsychol. 2001;15(2):221-229. n = 23 *P < 0.05 compared to control ORGANIZATION AND MEMORY California Verbal Learning Test

16. IMPULSE CONTROL *p < 0.05 compared to control Christ et al., 2006 (n = 23) (n = 26) *

17. EXECUTIVE FUNCTIONING IN PKU Planning diet Remembering Phe intake for records Remembering to take formula Helps with inhibiting responses, resisting foods not allowed on diet Maintaining supplies Monitoring blood Phe and making appropriate adjustments in intake

18. EMOTIONAL AND BEHAVIORAL OUTCOMES DEPRESSION ANXIETY

19. *P < 0.05 as compared to 18-year-old controls PSYCHIATRIC OUTCOMES IN ADULTS WITH PKU Adapted from Table 3 of Pietz J, et al. Pediatrics. 1997;99:345–350.

20. AGORAPHOBIA Blood Phe level and score on AAL Scale † are significantly correlated † From the Mobility Inventory, measuring avoidance behavior when alone (AAL) Blood Phenylalanine Level ( μ mol/L) Score on AAL Scale † Waisbren SE and Levy HL. J Inherit Metab Dis. 1991;14:755-764. r s = 0.43

21. WHY? THE MYELIN HYPOTHESIS

22. MYELIN INSULATES AXONS WHICH INCREASE THE SPEED OF PROCESSING OF NERVE SIGNALS Image from: http://kvhs.nbed.nb.ca/gallant/biology/schwann_myelin.html

23. WHITE MATTER HYPOTHESIS Individuals with PKU have abnormal white matter Abnormalities may be due to –Increased myelin turnover –Elevated water content –Disturbed myelin synthesis White matter abnormalities may reduce speed of processing leading to neurocognitive deficits observed with PKU Anderson P, et al. Devel Neuropsychol. 2007;32(2):645-668.

24. Range: Control 91–221; PKU 100–218 * Hedge’s g effect size with 95% confidence intervals small medium large META-ANALYSIS SUMMARY Adapted from Figure 1 of Moyle JJ, et al. Neuropsychol Rev. 2007;17(2):91–101. Meta-analysis of 11 studies demonstrates deficits in multiple cognitive domains

25. * P = 0.028 vs controls SCHOOL PROBLEMS Gassio R, et al. Pediatr Neurol. 2005;33:267–271.

26. KEY POINT #2: PSYCHOLOGICAL ASSESSMENT IS IMPORTANT

27. 6, 12, 18, 30 MONTHS Developmental Assessments Bayley Scales of Infant Development Emergent Language Skills Adaptive Behavior [Scores < 85 or Discrepancy between scores indicate need for Early Intervention]

28. 4 YEARS Pre-School Assessments Wechsler Preschool and Primary Scale of Intelligence (WPPSI) Visual-motor skills Behavior Attention

29. SCHOOL AGE (6-7 YEARS AND EVERY 3 YEARS THEREAFTER) Wechsler Intelligence Scale for Children (WISC-IV) or Wechsler Abbreviated Intelligence Scale (WASI) Achievement Executive Functioning and Attention Processing Speed Visual-Motor Adaptive behavior and mood

30. ADOLESCENCE & ADULTHOOD Wechsler Abbreviated Scale of Intelligence Achievement Executive Functioning Processing Speed Anxiety & Depression Adaptive Behavior Transition to Adult Care Maternal PKU

31. KEY POINT #3: STRATEGIES FOR MANAGING CHALLENGES IN PKU

32. INFANTS AND TODDLERS EARLY INTERVENTION PLAY THERAPY PARENT AS EDUCATOR

33. SCHOOL AGE REMEDIAL HELP CHUNKING DICTATING LISTS & CALENDARS VERBAL LEARNERS SLOW DOWN INSTRUCTIONS TEST MODIFICATIONS MONITOR BLOOD PHE

34. STABILITY OF BLOOD PHE Anastasoaie V, et al. Mol Genet Metab. 2008;95:17-20. Mean* (412 μ mol/L) ± SD † (166 μ mol/L) Mean* (389 μ mol/L) ± SD † (325 μ mol/L) *Lifetime blood Phe levels † Mean standard deviations for lifetime blood Phe levels Example Low Variability IQ = 116Example High Variability IQ = 92 Correlation of SD of blood Phe levels with FSIQ was -0.36 (p=.058) FSIQ decreased 4.3 points with 1 point increase in SD of blood Phe

35. ADOLESCENTS & YOUNG ADULTS TUTORS EXTENDED TIME OR UNTIMED TESTING CHOOSE CLASSES CAREFULLY PSYCHOTHERAPY REDUCE BLOOD PHE

36. S OCIAL SUPPORT POSITIVE A TTITUDES M ANAGEABILITY Finkelson L, Bailey I, Waisbren SE. J Inherit Metab DIs. 2001; 24: 515-516. SAM

38. TAKE AWAY MESSAGES EVEN TREATED INDIVIDUALS FACE CHALLENGES – DON’T BLAME THE VICTIM ASSESSMENT IS THE FIRST STEP TOWARD MANAGING THE CHALLENGES STRATEGIES EXIST FOR NEARLY EVERY SITUATION – THERE IS NEVER NOTHING MORE TO BE DONE BECAUSE WE HAVE HIGH HOPES!

39. THANK YOU!