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

Neurocognitive Functioning in PKU Susan Waisbren, PhD Children’s Hospital Boston. HIGH HOPES!. KEY POINTS. EVEN TREATED CHILDREN AND ADULTS EXPERIENCE NEUROPSYCHOLOGICAL EFFECTS PSYCHOLOGICAL ASSESSMENTS ARE IMPORTANT THERE ARE STRATEGIES FOR IMPROVING FUNCTIONING IN PKU.

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

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  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

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

  4. 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

  5. (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.

  6. WHY PROBLEMS? • THE DOPAMINE HYPOTHESIS

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. (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.

  12. (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.

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

  14. * 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.

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

  16. 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

  17. EMOTIONAL AND BEHAVIORAL OUTCOMES DEPRESSION ANXIETY

  18. 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.

  19. 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.

  20. WHY? • THE MYELIN HYPOTHESIS

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

  22. 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.

  23. 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.

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

  25. KEY POINT #2: PSYCHOLOGICAL ASSESSMENT IS IMPORTANT

  26. 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]

  27. 4 YEARS Pre-School Assessments • Wechsler Preschool and Primary Scale of Intelligence (WPPSI) • Visual-motor skills • Behavior • Attention

  28. 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

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

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

  31. INFANTS AND TODDLERS • EARLY INTERVENTION • PLAY THERAPY • PARENT AS EDUCATOR

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

  33. 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.

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

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

  36. 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!

  37. THANK YOU!

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