Abstract
Phenylketonuria (PKU) is a genetic disorder that causes altered biochemistry, resulting in downstream neurotransmitter dysregulation. Left untreated, this will result in severe intellectual disability and substantial white matter loss in the developing brain. Treatment via medically prescribed diet has seen this population develop normally in terms of standard IQ scores. However, children with early and continuously treated PKU remain at elevated risk of developing executive function (EF) impairments. Over 10 years ago, Diamond first proposed these residual impairments may result from a low dopamine environment in the developing brain, caused by a high phenylalanine to tyrosine (phe:tyr) ratio. Few experimental studies have followed up this hypothesis, as the research agenda remains focussed on phenylalanine-only measures. Further, the routine screening of tyrosine levels in these patients is highly variable. This study aimed to analyse children's EF development longitudinally against their lifetime biochemistry to ascertain which biochemical markers were most strongly associated with poor EF across two critical time points in development (early childhood and early adolescence). 17 children with PKU were assessed in 2002 on a battery of neuropsychological tests. In 2009 these children were reassessed on a select number of tests that have since been shown to be particularly sensitive in detecting EF deficits in this population. In the 2009 study, parents also filled out two questionnaires assessing EF and mood (the Behaviour Rating Inventory of Executive Function and Children's Depression Inventory); questionnaire data related to both children with PKU and their siblings in 2009 to allow for a between groups comparison. Both phenylalanine and phe:tyr ratio were shown to be associated with global impairments. A high phe:tyr ratio (a precursor to dopamine impairment) was more strongly associated with the residual EF deficits that remain problematic for this population. Current treatment for PKU centres around phenylalanine control; there may be another mechanism via the phe:tyr ratio leading to dopamine deficiencies that better accounts for residual EF deficits in this population. Future treatment may need to incorporate phe:tyr control to protect the developing brain. This research furthers our understanding of the possible dopaminergic basis of EF development.