| Summary: | Phenylketonuria (PKU) is a metabolic disease in which depletion of hepatic phenylalanine hydroxylase results in incomplete conversion of the essential amino acid phenylalanine to tyrosine. All protein contains phenylalanine which in PKU is toxic to the immature nervous system. Brain damage and mental handicap generally ensue but can be averted by restriction of dietary phenylalanine. Cognitive tests are used to monitor development and thus treatment outcome. Diet therapy prevents intellectual retardation, but mean IQ falls below age-standards and neuropsychological deficits are found in the executive domain. Questions thus remain about how to optimise treatment. This thesis summarises the history of PKU, reviews the neuropsychological literature, presents an empirical analysis of the IQ subtest profile in children representative of the treated classical PKU population and compares subjects from this group with healthy controls on measures of executive function. The historical and neuropsychological overviews concluded that early treatment practices almost certainly compromised cognitive development. The empirical studies replicated the finding that IQ in treated PKU is significantly depressed, but also indicated that adherence to present United Kingdom treatment guidelines normalises verbal but not spatial ability. Evidence from attentional measures suggested that impaired decision-making speed and poor response inhibition might underlie cognitive deficits found in treated PKU such as poor performance on executive tasks and certain measures of spatial skill. This idea is consistent with the hypothesis that executive functioning is specifically deficient, possibly as a consequence of dopamine depletion in prefrontal cortex. Support for the prefrontal executive hypothesis is at present patchy and circumstantial. Further research is required to establish its validity and whether executive deficit in treated PKU has a bearing on everyday adjustment in the individual patient. Until this is done, national treatment guidelines should not be revised downward.
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