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.
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Executive Abilities in Individuals with Phenylketonuria Desiree A. White, PhD Research supported by National Institute of Child Health & Human Development.
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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
• Recommendations
• 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
BH4
PhenylalaninePAH
DopamineTyrosine(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-Go0
5
10
15
20
25
30
35
40
25
32*
ControlPKU
Num
ber
of
Err
ors
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 (
ms)
[Araujo et al 2009]
* Significantly less post-error
slowing
Response Monitoring
Go/No-Go Task
Maintenance & manipulation of information for brief periods