Neurocognitive Functioning in PKU Susan Waisbren, PhD Children’s Hospital Boston

1. Neurocognitive Functioning in PKUSusan Waisbren, PhDChildren’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. Especially if Blood Phe not consistently in target range NEUROCOGNITIVE DEFICITS IN TREATED PKU • REDUCTIONS IN: • Executive Functioning • Memory • Planning • Attention • Organization • Mental Processing Speed • Behavior and Mood

6. (n = 178) (n = 77) (n = 137) (n = 98) 15–19 0–4 5–9 10–14 ADHERENCE TO TREATMENT • Nearly one in three PKU children under the age of 10 have blood Phe above recommended target range • Noncompliance increases as patients enter adolescence (n = 77) (n = 137) (n = 98) Adapted from Table 2 of Walter JH, et al. Lancet. 2002;360:55–57.

7. WHY PROBLEMS? • THE DOPAMINE HYPOTHESIS

8. EXECUTIVE FUNCTIONING AND THE DOPAMINE HYPOTHESIS Blood Brain Barrier Periphery (mostly liver) Brain PAH TH AADC Phenylalanine Tyrosine L-dopa Dopamine Tyrosine BH4 BH4 BH4 = tetrahydrobiopterin PAH = phenylalanine hydroxylase TH = tyrosine hydroxylase AADC = aromatic amino acid decarboxylase

9. basal ganglia frontal lobe prefrontal cortex dopamine pathways 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

10. DOPAMINE AND EXECUTIVE FUNCTION DEFICITS • Infants2 • Working memory • Behavioral inhibition • Children (7–14)3 • Impulse control • Attentional flexibility • Adults4 • Attention • Working memory • Verbal Fluency 1Van Zutphen KH, et al. Clin Genet. 2007;72:13-18. 2Diamond A, et al. Monogr Soc Res Child Dev. 1997;62:1-208. 3Huijbregts SC, et al. NeuroSci Biobehav Rev. 2002;26:697-712. 4Channon S, et al. Neuropsychology. 2004;18:613-620.

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

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

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

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

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

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

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

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

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

25. SCHOOL PROBLEMS *P = 0.028 vs controls 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 • 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 Example Low Variability IQ = 116 Example High Variability IQ = 92 Mean* (389 μmol/L) ±SD† (325 μmol/L) Mean* (412 μmol/L) ±SD† (166 μmol/L) *Lifetime blood Phe levels †Mean standard deviations for lifetime blood Phe levels Anastasoaie V, et al. Mol Genet Metab. 2008;95:17-20.

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

36. SAM SOCIAL SUPPORT POSITIVE ATTITUDES MANAGEABILITY Finkelson L, Bailey I, Waisbren SE. J Inherit Metab DIs. 2001; 24: 515-516.

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!