Neurocognitive Functioning in PKU Susan Waisbren Ph D

Neurocognitive Functioning in PKU Susan Waisbren, Ph. D 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

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

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

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 = 178) (n = 137) 0– 4 5– 9 Adapted from Table 2 of Walter JH, et al. Lancet. 2002; 360: 55– 57. (n = 98) (n = 77) 10– 14 15– 19

WHY PROBLEMS? • THE DOPAMINE HYPOTHESIS

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

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

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

Children with PKU on diet have significantly lower IQ than unaffected peers and sibling controls n = 21 n = 26 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.

EXECUTIVE FUNCTIONING DEFICITS (n = 80) (n = 45) (n = 44) *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.

ATTENTION PROBLEMS (n = 38) *P < 0. 006 as compared to children with diabetes mellitus Arnold GL, et al. J Inherit Metab Dis. 2004; 27: 137– 143. (n = 76)

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

ORGANIZATION AND MEMORY 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.

IMPULSE CONTROL * (n = 23) (n = 26) *p < 0. 05 compared to control Christ et al. , 2006

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

EMOTIONAL AND BEHAVIORAL OUTCOMES DEPRESSION ANXIETY

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.

AGORAPHOBIA Score on AAL Scale† Blood Phe level and score on AAL Scale† are significantly correlated rs = 0. 43 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.

WHY? • THE MYELIN HYPOTHESIS

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

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.

META-ANALYSIS SUMMARY Meta-analysis of 11 studies demonstrates deficits in multiple cognitive domains large medium small 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.

SCHOOL PROBLEMS *P = 0. 028 vs controls Gassio R, et al. Pediatr Neurol. 2005; 33: 267– 271.

KEY POINT #2: PSYCHOLOGICAL ASSESSMENT IS IMPORTANT

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]

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

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

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

KEY POINT #3: STRATEGIES FOR MANAGING CHALLENGES IN PKU

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

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

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 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. Example High Variability IQ = 92 Mean* (389 μmol/L) ± SD† (325 μmol/L)

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

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

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!

THANK YOU!