This study explored the hypothesis that children with early-treated phenylketonuria (PKU) are selectively impaired on executive function measures, even when still on diet. The rationale for this hypothesis is that even mild elevations in phenylalanine (Phe) can lead to lower central levels of biogenic amines, including dopamine (DA). We hypothesize that this mild DA depletion causes subtle prefrontal dysfunction, which in turn affects executive functions such as set maintenance, planning, and organized search. 11 preschool early-treated PKU children (M age = 4.64) and a sample of age- and IQ-matched unaffected peers (n = 11) were evaluated on a battery of executive function (EF) measures. In addition, a "non-executive function" task, recognition memory, was administered to all subjects. Group comparisons demonstrated that PKU children were significantly impaired on an executive function composite score; there were no group differences, however, in recognition memory. These results supported the hypothesized specific deficit in executive function. Furthermore, within the PKU group the executive function composite score was significantly negatively correlated with concurrent phenylalanine levels, even after controlling for the correlation between IQ and executive function skills. This second finding provides support for the proposed biochemical mechanism underlying the specific cognitive deficits.

This study explored the hypothesis that children with early-treated phenylketonuria (PKU) are selectively impaired on executive function measures, even when still on diet. The rationale for this hypothesis is that even mild elevations in phenylalanine (Phe) can lead to lower central levels of biogenic amines, including dopamine (DA). We hypothesize that this mild DA depletion causes subtle prefrontal dysfunction, which in turn affects executive functions such as set maintenance, planning, and organized search. 11 preschool early-treated PKU children (M age = 4.64) and a sample of age- and IQ-matched unaffected peers (n = 11) were evaluated on a battery of executive function (EF) measures. In addition, a "non-executive function" task, recognition memory, was administered to all subjects. Group comparisons demonstrated that PKU children were significantly impaired on an executive function composite score; there were no group differences, however, in recognition memory. These results supported the hypothesized specific deficit in executive function. Furthermore, within the PKU group the executive function composite score was significantly negatively correlated with concurrent phenylalanine levels, even after controlling for the correlation between IQ and executive function skills. This second finding provides support for the proposed biochemical mechanism underlying the specific cognitive deficits.

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During 1967-1983, the Maternal and Child Health Division of the Public Health Services funded a collaborative study of 211 newborn infants identified on newborn screening as having phenylketonuria (PKU). Subsequently, financial support was provided by the National Institute of Child Health and Human Development (NICHD). The infants were treated with a phenylalanine (Phe)-restricted diet to age 6 years and then randomized either to continue the diet or to discontinue dietary treatment altogether. One hundred and twenty-five of the 211 children were then followed until 10 years of age. In 1998, NICHD scheduled a Consensus Development Conference on Phenylketonuria and initiated a study to follow up the participants from the original Collaborative Study to evaluate their present medical, nutritional, psychological, and socioeconomic status. Fourteen of the original clinics (1967-1983) participated in the Follow-up Study effort. Each clinic director was provided with a list of PKU subjects who had completed the original study (1967-1983), and was asked to evaluate as many as possible using a uniform protocol and data collection forms. In a subset of cases, magnetic resonance imaging and spectroscopy (MRI/MRS) were performed to study brain Phe concentrations. The medical evaluations revealed that the subjects who maintained a phenylalanine-restricted diet reported fewer problems than the diet discontinuers, who had an increased rate of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity. Psychological data showed that lower intellectual and achievement test scores were associated with dietary discontinuation and with higher childhood and adult blood Phe concentrations. Abnormal MRI results were associated with higher brain Phe concentrations. Early dietary discontinuation for subjects with PKU is associated with poorer outcomes not only in intellectual ability, but also in achievement test scores and increased rates of medical and behavioural problems.

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