Neurocognitive%20Functioning%20in%20PKU%20Susan%20Waisbren,%20PhD%20Children

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Neurocognitive Functioning in PKUSusan Waisbren,
PhDChildrens Hospital Boston
HIGH HOPES!
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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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(No Transcript)
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KEY POINT 1 EVEN TREATED CHILDREN AND ADULTS
EXPERIENCE LEARNING DIFFICULTIES AND OTHER
NEUROPSYCHOLOGICAL EFFECTS
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NEUROCOGNITIVE DEFICITS IN TREATED PKU

• REDUCTIONS IN
• Executive Functioning
• Memory
• Planning
• Attention
• Organization
• Mental Processing Speed
• Behavior and Mood

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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 137)
(n 77)
(n 98)
Adapted from Table 2 of Walter JH, et al. Lancet.
20023605557.
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WHY PROBLEMS?

• THE DOPAMINE HYPOTHESIS

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EXECUTIVE FUNCTIONING AND THE DOPAMINE HYPOTHESIS
Blood Brain Barrier
Periphery (mostly liver)
Brain
PAH
TH
AADC
Phenylalanine
Dopamine
Tyrosine
L-dopa
Tyrosine
BH4
BH4
BH4 tetrahydrobiopterin PAH phenylalanine
hydroxylase TH tyrosine hydroxylase AADC
aromatic amino acid decarboxylase
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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/medi
cine/laureates/2000/press.html
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DOPAMINE AND EXECUTIVE FUNCTION DEFICITS

• Infants2
• Working memory
• Behavioral inhibition

• Children (714)3
• Impulse control
• Attentional flexibility

• Adults4
• Attention
• Working memory
• Verbal Fluency

1Van Zutphen KH, et al. Clin Genet.
20077213-18. 2Diamond A, et al. Monogr Soc Res
Child Dev. 1997621-208. 3Huijbregts SC, et al.
NeuroSci Biobehav Rev. 200226697-712. 4Channon
S, et al. Neuropsychology. 200418613-620.
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Children with PKU on diet have significantly
lower IQ than unaffected peers
and sibling controls
n 26
n 21
n 55
n 55

Controls were age- and sex-matched PKU patients
(ages 719 years old) managed early and
continuously with Phe-restricted diet
Gassio R, et al. Pediatr Neurol. 200533267271.
Koch R, et al. J Inherit Metab Dis. 1984786-90.
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EXECUTIVE FUNCTIONING DEFICITS
P lt 0.001 compared to control
Based on Behavior Rating Inventory of Executive
Function (BRIEF) global executive composite
score. Severe range is gt 1 SD above the mean
Anderson VA, et al. Child Neuropsychol.
20028(4)231-240.
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ATTENTION PROBLEMS
P lt 0.006 as compared to children with diabetes
mellitus
Arnold GL, et al. J Inherit Metab Dis.
200427137143.
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WORKING MEMORY
n 20
n 20
P lt .05 compared to control
White DA, et al. J Int Neuropsychol Soc.
200281-11.
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ORGANIZATION AND MEMORY
n 23
n 23
Younger lt 11 yr Older 11 yr
California Verbal Learning Test
P lt 0.05 compared to control
White DA, et al. Neuropsychol. 200115(2)221-229.
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IMPULSE CONTROL

(n 23)
(n 26)
p lt 0.05 compared to control
Christ et al., 2006
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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

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EMOTIONAL AND BEHAVIORAL OUTCOMES
DEPRESSION
ANXIETY
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PSYCHIATRIC OUTCOMES IN ADULTS WITH PKU

P lt 0.05 as compared to 18-year-old controls
Adapted from Table 3 of Pietz J, et al.
Pediatrics. 199799345350.
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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.
199114755-764.
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WHY?

• THE MYELIN HYPOTHESIS

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MYELIN INSULATES AXONS WHICH INCREASE THE SPEED
OF PROCESSING OF NERVE SIGNALS
Image from http//kvhs.nbed.nb.ca/gallant/biology
/schwann_myelin.html
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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.
200732(2)645-668.
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META-ANALYSIS SUMMARY
Meta-analysis of 11 studies demonstrates deficits
in multiple cognitive domains
Range Control 91221 PKU 100218 Hedges g
effect size with 95 confidence intervals
Adapted from Figure 1 of Moyle JJ, et al.
Neuropsychol Rev. 200717(2)91101.
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SCHOOL PROBLEMS
P 0.028 vs controls
Gassio R, et al. Pediatr Neurol. 200533267271.
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KEY POINT 2 PSYCHOLOGICAL ASSESSMENT IS
IMPORTANT
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6, 12, 18, 30 MONTHS Developmental Assessments

• Bayley Scales of Infant Development
• Emergent Language Skills
• Adaptive Behavior
• Scores lt 85 or Discrepancy between scores
  indicate need for Early Intervention

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4 YEARS Pre-School Assessments

• Wechsler Preschool and Primary Scale of
  Intelligence (WPPSI)
• Visual-motor skills
• Behavior
• Attention

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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

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ADOLESCENCE ADULTHOOD

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

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KEY POINT 3 STRATEGIES FOR MANAGING
CHALLENGES IN PKU
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INFANTS AND TODDLERS

• EARLY INTERVENTION
• PLAY THERAPY
• PARENT AS EDUCATOR

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SCHOOL AGE

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

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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.
20089517-20.
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ADOLESCENTS YOUNG ADULTS

• TUTORS
• EXTENDED TIME OR UNTIMED TESTING
• CHOOSE CLASSES CAREFULLY
• PSYCHOTHERAPY
• REDUCE BLOOD PHE

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

• EVEN TREATED INDIVIDUALS FACE CHALLENGES DONT
  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!

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THANK YOU!