Executive Abilities in Individuals

with PhenylketonuriaDesiree 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• Recommendation

s• Discussion

• 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

BH4Phenylalanine

PAHDopamineTyrosine

(Phe) (Tyr) (DA)

Neuropathology of PKU: Dopamine

[For an overview, de Groot et al 2010]

Myelin increases speed of neural transmission

[For an overview, Anderson Leuzzi 2010]

Neuron

CellBody

Axon

MyelinSheath

Neuropathology of PKU: White Matter

Image from McKinstryWashington University

Mallinckrodt Institute of Radiology

White matterirregularities

Diffusion Tensor Imaging (DTI)

Brain RegionPrefrontal Cortex Centrum Semiovale * Parietal-Occipital Cortex * Optic Radiation Putamen Corpus Callosum * Thalamus Hippocampus

White et al in preparation

* Improvement following treatment with BH4

• Definition: Maintenance & coordination of information processing leading to higher order thought & action

• Executive abilities play critical role in: School performance Social skillEmployment Treatment

• Executive subcomponents:Inhibitory Control Working Memory Monitoring Strategic Processing

Executive Abilities

[For a review, Christ Huijbregts de Sonneville White 2010]

Suppressing information or actions that would otherwise interfere with the

efficient attainment of a goal

Inhibitory Control

Go No-Go05

10152025303540

25

32*

ControlPKU

Num

ber o

f Erro

rs

Go/No-Go Task

[Christ et al 2006]

* Significantly more errors

Inhibitory Control

Detection of errors & adjustments in behavior to facilitate performance

Response Monitoring

Go RT Post-Error RT0

100

200

300

400

500

600

700

800

448

681

449

617*

ControlPKU

RT (m

s)

[Araujo et al 2009]

* Significantly less post-error

slowing

Response Monitoring

Go/No-Go Task

Maintenance & manipulation of information for brief periodsFacilitates a range of abilities

VocabularyReadingMathematicsSpellingComprehensionConversation

Working Memory

Verbal Object Spatial0

1

2

3

4

5

6

5.2

3.9 3.8

4.6*

3.4* 3.3*

ControlPKU

Mem

ory

Span

Recognition Span Task

[White et al 2002]

B N G

*Significantly lower span

Working Memory

5 6 7 8 9 10 11 12 13 14 15 16 17 182

3

4

5

6

7

8ControlPKU

Age (yrs)

Aver

age

Span

[White et al 2002]

Age-Related Difficulty in Working Memory

Flexibly evaluating & altering plans to perform tasks with optimal efficiency

Strategic Processing

Younger (<11 yrs) Older (≥11 yrs)

Trial 1 Trial 5 Trial 1 Trial 5012345678

1.6

2.72.3

7.1

1.62.3 2.2

4.7*

ControlPKU

Clus

ter S

core

List Learning Task

[White et al 2001]

bananasjacket watermelonpeaches strawberriessweater grapesshortsballoonsbeltpuzzleblockscrayonshatmarbles

* Significantly less clustering for older

but not younger PKU

Age-Related Difficulty in Strategy Use

Words Switches Words Switches02468

10121416182022

19.8

10.4 10.3

7.0

16.6*

8.4* 8.0*

5.2*

ControlPKU

Num

ber P

rodu

ced

Verbal Fluency Task

Food/Drink Fluency Letter Fluency

LetterSitSet

ShelfShipSlateSkateState

* Significantly fewer words & switches

Strategic Processing

[Banerjee et al 2011]

Food/DrinkApplePeachMilkSodaBreadSalsaJelly

6 7 8 9 10 11 12 13 14 15 16 17 18 19 2002468

101214161820

ControlPKU

Age (yrs)

Num

ber S

witc

hes

[Banerjee et al 2011]

Age-Related Difficulty in Strategy Use

Verbal Fluency Task: Food/Drink

STATIC WORSENINGIMPROVING

AGE

PERF

ORM

ANCE

Developmental Trajectories

TYPICALDEVELOPMENT

COMPROMISEDDEVELOPMENT

• 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

Optimizing Outcomes

Screening for Problems in Clinic

[Waisbren White 2010]

Executive Abilities• BRIEF-P• BRIEF• BRIEF-A

Social-Emotional Function• BASC-II Behavior Assessment System

for Children – II• CBCL Child Behavior Checklist• BAI Beck Anxiety Inventory• BDI-II Beck Depression Inventory – II• BSI Brief Symptom Inventory

Adaptive Function• ABAS Adaptive Behavior Assessment System

Behavior Rating Inventory of Executive Function

Control Hydro-cephalus

PKU0

5

10

15

20

25

5

18

21

% in

Sev

ere

Rang

e

[Anderson et al 2002]

Ratings of Executive BehaviorBehavior Rating Inventory of Executive Function

• 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: General (Repeating myself)

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

• 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: School

• 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!)

Recommendations: Home

Thanks!