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.

2. “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]

3. Overview Brain function Executive abilities Recommendations Discussion

4. Phenylalanine (Phe) converted to tyrosine (Tyr) by phenylalanine hydroxylase (PAH) in presence of tetrahydrobiopterin (BH 4 ) Tyr converted to dopamine (DA), an essential neurotransmitter in function of frontal cortex which subserves executive abilities BH 4 Phenylalanine PAH Dopamine Tyrosine (Phe) (Tyr)(DA) Neuropathology of PKU: Dopamine [For an overview, de Groot et al 2010]

5. Myelin increases speed of neural transmission [For an overview, Anderson Leuzzi 2010] Neuron Cell Body Axon Myelin Sheath Neuropathology of PKU: White Matter Image from McKinstry Washington University Mallinckrodt Institute of Radiology White matter irregularities

6. Diffusion Tensor Imaging (DTI) Brain Region Prefrontal Cortex Centrum Semiovale * Parietal-Occipital Cortex * Optic Radiation Putamen Corpus Callosum * Thalamus Hippocampus White et al in preparation * Improvement following treatment with BH 4

7. Definition: Maintenance & coordination of information processing leading to higher order thought & action Executive abilities play critical role in: School performanceSocial skill Employment Treatment Executive subcomponents: Inhibitory Control Working Memory Monitoring Strategic Processing Executive Abilities [For a review, Christ Huijbregts de Sonneville White 2010]

8. Suppressing information or actions that would otherwise interfere with the efficient attainment of a goal Inhibitory Control

9. Go/No-Go Task [Christ et al 2006] * Significantly more errors Inhibitory Control

10. Detection of errors & adjustments in behavior to facilitate performance Response Monitoring

11. [Araujo et al 2009] * Significantly less post-error slowing Response Monitoring Go/No-Go Task

12. Maintenance & manipulation of information for brief periods Facilitates a range of abilities Vocabulary Reading Mathematics Spelling Comprehension Conversation Working Memory

13. Recognition Span Task [White et al 2002] B N G *Significantly lower span Working Memory

14. [White et al 2002] Age-Related Difficulty in Working Memory

15. Flexibly evaluating & altering plans to perform tasks with optimal efficiency Strategic Processing

16. Younger (<11 yrs) Older (≥11 yrs) List Learning Task [White et al 2001] bananas jacket watermelon peaches strawberries sweater grapes shorts balloons belt puzzle blocks crayons hat marbles * Significantly less clustering for older but not younger PKU Age-Related Difficulty in Strategy Use

17. Verbal Fluency Task Food/Drink FluencyLetter Fluency Letter Sit Set Shelf Ship Slate Skate State * Significantly fewer words & switches Strategic Processing [Banerjee et al 2011] Food/Drink Apple Peach Milk Soda Bread Salsa Jelly

18. [Banerjee et al 2011] Age-Related Difficulty in Strategy Use Verbal Fluency Task: Food/Drink

19. STATICWORSENINGIMPROVING AGE PERFORMANCE Developmental Trajectories TYPICAL DEVELOPMENT COMPROMISED DEVELOPMENT

20. 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

21. 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 CBCLChild Behavior Checklist BAIBeck Anxiety Inventory BDI-IIBeck Depression Inventory – II BSIBrief Symptom Inventory  Adaptive Function ABASAdaptive Behavior Assessment System Behavior Rating Inventory of Executive Function

22. [Anderson et al 2002] Ratings of Executive Behavior Behavior Rating Inventory of Executive Function

23. 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)

24. 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

25. 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

26. 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

27. 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

28.  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