Transcript Slide 1

Executive Abilities in Individuals
with Phenylketonuria
Desiree A. White, PhD
Research supported by National Institute of Child Health & Human
Development and BioMarin Pharmaceutical. Consultation and speaker
fees accepted from BioMarin Pharmaceutical and Merck Serono.
“Numerous advances have been made in our
understanding of metabolic disorders over the
last century, but optimal outcomes have not
been achieved… We stand now on the cusp of
a new era of PKU research and treatment. It is
time that we thoroughly reevaluate our
understanding of PKU so that we may take
advantage of current innovations in
neuropsychological assessment, scientific
technologies, and treatment options that hold
promise for improving quality of life for
individuals with PKU.”
[White Waisbren van Spronsen 2010]
Overview
• Brain function
• Executive abilities
• Recommendations
• Discussion
Neuropathology of PKU:
Dopamine
Phenylalanine
(Phe)
PAH
BH4
Tyrosine
(Tyr)
Dopamine
(DA)
• Phenylalanine (Phe) converted to tyrosine
(Tyr) by phenylalanine hydroxylase (PAH) in
presence of tetrahydrobiopterin (BH4)
• Tyr converted to dopamine (DA), an essential
neurotransmitter in function of frontal cortex
which subserves executive abilities
[For an overview, de Groot et al 2010]
Neuropathology of PKU:
White Matter
Myelin increases speed
of neural transmission
Image from McKinstry
Washington University
Mallinckrodt Institute of Radiology
White matter
irregularities
Neuron
Myelin
Sheath
Cell
Body
Axon
[For an overview, Anderson Leuzzi 2010]
Diffusion Tensor Imaging (DTI)
Brain Region
Prefrontal Cortex
Centrum Semiovale *
Parietal-Occipital Cortex *
Optic Radiation
Putamen
Corpus Callosum *
Thalamus
Hippocampus
* Improvement following
treatment with BH4
White et al in preparation
Executive Abilities
• Definition: Maintenance & coordination of
information processing leading to higher
order thought & action
• Executive abilities play critical role in:
School performance
Employment
Social skill
Treatment
• Executive subcomponents:
Inhibitory Control
Monitoring
Working Memory
Strategic Processing
[For a review, Christ Huijbregts de Sonneville White 2010]
Inhibitory Control
Suppressing information or actions that
would otherwise interfere with the
efficient attainment of a goal
Inhibitory Control
Go/No-Go Task
Number of Errors
40
35
30
Control
PKU
25
* Significantly
more errors
32*
25
20
15
10
5
0
[Christ et al 2006]
Go
No-Go
Response Monitoring
Detection of errors
& adjustments in
behavior to facilitate
performance
Response Monitoring
Go/No-Go Task
800
700
RT (ms)
600
Control
PKU
681
617*
500
400
448
* Significantly
less post-error
slowing
449
300
200
100
0
Go RT
[Araujo et al 2009]
Post-Error RT
Working Memory
Maintenance & manipulation of
information for brief periods
Facilitates a range of abilities
Vocabulary
Reading
Mathematics
Spelling
Comprehension
Conversation
Working Memory
Recognition Span Task
Memory Span
6
5
*Significantly
lower span
5.2
Control
PKU
4.6*
4
3.9
3.8
3.4*
3
3.3*
2
1
0
Verbal
B N G
[White et al 2002]
Object
Spatial
Age-Related Difficulty
in Working Memory
8
Control
PKU
Average Span
7
6
5
4
3
2
5
6
7
8
9
10
11
12
13
Age (yrs)
[White et al 2002]
14
15
16
17
18
Strategic Processing
Flexibly evaluating
& altering plans to
perform tasks with
optimal efficiency
Age-Related Difficulty in Strategy Use
List Learning Task
8
Control
PKU
Cluster Score
7
6
* Significantly less
clustering for older
but not younger PKU
5
7.1
4.7*
4
3
2.7
2
1
0
1.6
2.3
2.3
2.2
1.6
Trial 1
Trial 5
Younger (<11 yrs)
[White et al 2001]
Trial 1
Trial 5
Older (≥11 yrs)
bananas
jacket
watermelon
peaches
strawberries
sweater
grapes
shorts
balloons
belt
puzzle
blocks
crayons
hat
marbles
Strategic Processing
Number Produced
Verbal Fluency Task
22
20
18
16
14
12
10
8
6
4
2
0
19.8
16.6*
* Significantly fewer
words & switches
10.4
Control
PKU
10.3
8.4*
8.0*
7.0
5.2*
Words Switches
Food/Drink Fluency
[Banerjee et al 2011]
Words Switches
Letter Fluency
Food/Drink
Apple
Peach
Milk
Soda
Bread
Salsa
Jelly
Letter
Sit
Set
Shelf
Ship
Slate
Skate
State
Age-Related Difficulty in Strategy Use
Verbal Fluency Task: Food/Drink
Number Switches
20
Control
PKU
18
16
14
12
10
8
6
4
2
0
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Age (yrs)
[Banerjee et al 2011]
PERFORMANCE
Developmental Trajectories
STATIC
IMPROVING
WORSENING
AGE
TYPICAL
DEVELOPMENT
COMPROMISED
DEVELOPMENT
Optimizing Outcomes
• Maintain Phe control across the lifespan
• Discuss and formally screen for
problems in cognitive, psychiatric, &
adaptive function in metabolic clinic
• Refer to psychologist, psychiatrist, or
neuropsychologist if problems identified
• Coordinate treatment recommendations
among all health care professionals
Screening for Problems in Clinic
 Executive Abilities
• BRIEF-P
Behavior Rating Inventory
• BRIEF
of Executive Function
• BRIEF-A
 Social-Emotional Function
• BASC-II
Behavior Assessment System
for Children – II
Child Behavior Checklist
Beck Anxiety Inventory
Beck Depression Inventory – II
Brief Symptom Inventory
• CBCL
• BAI
• BDI-II
• BSI
 Adaptive Function
• ABAS
Adaptive Behavior Assessment System
[Waisbren White 2010]
Ratings of Executive Behavior
Behavior Rating Inventory of Executive Function
% in Severe Range
25
20
21
18
15
10
5
0
5
Control
[Anderson et al 2002]
Hydrocephalus
PKU
Recommendations: General
(Repeating myself)
• Maintain Phe control across the lifespan
• Discuss and formally screen for
problems in cognitive, psychiatric, &
adaptive function in metabolic clinic
• Refer to psychologist, psychiatrist, or
neuropsychologist if problems identified
• Coordinate treatment recommendations
among all health care professionals
Recommendations: Evaluation
• School evaluation for special services for
children with learning differences
• Neuropsychological evaluation for
assessment of specific areas of cognition
• Psychological evaluation & counseling for
social & behavioral difficulties
• Psychiatric evaluation for medication if
warranted for ADHD or depression
Recommendations: School
•
•
•
•
•
•
•
•
Structured school environment
Small class with one-on-one instruction
Arrange environment to enhance attention
Extra time to complete tests/assignments
Divide work into small, manageable units
Written instructions for reference
Time to repeatedly review material
Present material in multiple modalities
Recommendations: Home
• Maintain regular routine
• Keep calendar of daily activities
• Choose specific locations for important
items (calendar, backpack, car keys)
• Remind to “stop, look, & think” before
beginning tasks
• Alert to key points in conversation &
before transitions between activities
Recommendations: Home
• Instruct through brief statements rather
than complicated directives
• Monitor performance as multiple steps
of tasks are completed
• Assist in determining the most organized
approach before beginning a task
• Suggest cues and meaningful organizers
• Generate checklists for organization
• Remind to complete one task before
moving to another
Recommendations: Home
 Encourage & provide opportunities for
independent completion of tasks
 Avoid punitive consequences when
tasks are not completed independently
 Provide praise & concrete rewards for
perseverance & completion of tasks
 Use time out & restriction of privileges
effectively (choose your battles!)