Executive Abilities in Individuals with Phenylketonuria

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. Neuropathology of PKU: Dopamine PAH Tyrosine Phenylalanine Dopamine BH4 (Phe) (Tyr) (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]

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

6. Diffusion Tensor Imaging (DTI) * Improvement following treatment with BH4 White et al in preparation

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

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

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

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

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

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

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

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

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

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

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

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

19. Developmental Trajectories PERFORMANCE STATIC IMPROVING WORSENING AGE TYPICAL DEVELOPMENT COMPROMISED DEVELOPMENT

20. 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

21. Screening for Problems in Clinic • 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 [Waisbren White 2010]

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

23. 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

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. 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

26. 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

27. 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

28. 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!)

29. Thanks!