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A micromethod for measurement of blood phenylalanine is described. The procedure is advantageous in management of phenylketonuric children under treatment.

Early-treated children with PKU are protected from mental retardation. However, recent studies have found IQ loss in these children, especially after termination of the low phenylalanine diet. We have studied IQ and IQ change in 91 early-treated children with PKU and 29 untreated or partially treated children with mild hyperphenylalaninemia (MH) who have been followed for up to 22 years. Their most recent psychological evaluations were compared to similar assessments done 5 years previously. In children with PKU, age (10.8 ± 4.7 yrs.) was negatively correlated with IQ (mean IQ = 98.4 ± 16.7) (r=-.30, p=.002). With age controlled, the treatment variable that best predicted IQ was the percent of blood phenylalanine levels ≥ 16 mg/dl while on diet (r2=0.86). These results suggest that IQ is significantly affected by dietary control during treatment. Over a 5 year period, mean IQ changes were -4.3 ± 14.8 in children with PKU off-diet, +7.4 ± 14.1 in children with PKU on-diet, and +2.8 ± 10.5 in children with MH. IQ change did not correlate with IQ score. With age controlled, the best predictor of IQ loss was diet discontinuation (r2=.159); natural (pre- or post-diet) blood phenylalanine level was the second best predictor (r2=.083). This suggests that loss of IQ is greater in children who have terminated the diet, particularly in those with higher natural blood phenylalanine levels. These findings may have implications for the issue of diet continuation or discontinuation during school age years.

Forty-one patients with phenylketonuria (PKU) whose dietary therapy was discontinued at an average age of 6 years were placed on a phenylalanine restricted diet after 1 to 16 years of unrestricted diet. Resumption of diet was prompted by decline in academic achievement, behavior problems, loss of I.Q., abnormal changes in the EEG, tremors, eczema and body odor. Twenty-three patients failed to comply with diet restrictions even after as much as one year of counseling and their blood phenylalanine levels remained greater than 25mg/dl. Eighteen patients maintained some diet restrictions but they still reported excessive intake of phenylalanine, an average of 1370mg daily in the first two years and 700mg daily after 4 years. Average blood phenylalanine levels in this group were 17.8mg/dl after 2 years and 14.8mg/dl after 4 years indicating poor compliance. The limited degree of success with diet seemed to be related to the length of time off diet. The 23 patients who failed were on an unrestricted diet an average of 9 years compared to 4 years for the remaining 18 patients. This study indicates the difficulty in returning to a phenylalanine restricted diet, particularly in adolescents and young adults. Since the female PKU patients must return to diet prior to conception this problem may have serious implications for this population who is at risk for unplanned pregnancies.

We previously demonstrated that large changes in blood phenylalanine (phe) concentrations (500 - 2000 pM) decreased plasma L-DOPA, slowed brain electrical discharge and prolonged performance (Fed. Res. 20:112, 1986). In this study we ask whether moderately elevated plasma phe affects brain function. Six heterozygotes for phenylketonuria (PKU) and 2 normal controls were studied in a crossover, blinded protocol of 4, 2-week intervals. Volunteers ingested a constant diet of 40-50 mg/kg/day phe supplemented either with 100 mg/kg/day phe or placebo. On the last three days of each period the mean power frequency of three electroencephalograms (MPF) were measured. Plasma phe rose in both heterozygotes and controls on ingesting supplemental phe from a mean placebo phe concentration of 99 ± 20 to 140 ± 166 μM. The range of changes was from −200 to +400 μM. There was an inverse relationship between changes in plasma phe above 50 μM and changes in the MPF. By regression analysis 100 μM change in plasma phe produced an inverse change of 0.12 CPS in MPF. We conclude that plasma phe concentrations are raised by phe ingestion in both PKU heterozygotes and homozygous normal, and that alterations in brain electrical discharge are induced by intermediate changes in blood phe concentrations supporting a linear rather than threshold relationship to altered brain function.

To the Editor:— Since the discovery by Folling, in 1935, of phenylketonuria (PKU), the simple ferric chloride test of urine has been the universal method of detecting this disease in spite of serious limitations. These include (1) failure of young infants to produce a positive test until several weeks after birth, even though there is evidence that blood phenylalanine concentration increases rapidly in the first few days of life in this condition (Armstronget al., Proceedings of the Third International Neurochemical Symposium,1958, to be published) and (2) failure of older PKU cases to produce a positive ferric chloride test if blood phenylalanine levels are below approximately 20 mg. per cent. Obviously a simple method of detecting elevated phenylalanine blood levels should overcome these limitations. Recently, with the cooperation of Dr. William Welch, Director of the Laboratory at Newark State School, Newark, N.Y., we have had the opportunity to develop