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Concerns about the psychosocial risk of adults with early-treated phenylketonuria (ETPKU) are predicated on four sources of scientific data: (1) consistent documentation of increased behavioural risk in children with ETPKU; (2) recent evidence of neurocognitive impairment in adults with ETPKU; (3) reports of neuroimaging abnormalities in adults with ETPKU; and (4) preliminary evidence of increased rates of psychiatric disturbance in this population. We studied the psychosocial adjustment of 25 patients, aged 18 years and older, with ETPKU. On most psychosocial outcome measures, patients were indistinguishable from 15 sibling controls. However, on a self-report inventory of psychiatric symptoms, 20% of the patients demonstrated significant morbidity. Psychosocial outcome of these patients was unrelated to concurrent or historical biological dietary disease factors, unlike neurocognitive outcome. A strong relationship was demonstrated, however, between neurocognitive measures and psychosocial morbidity. These findings indicate that a significant minority of patients with ETPKU develop psychosocial difficulties with multiple clinical elevations on a psychiatric inventory. However, most adults with ETPKU cope with the challenges of young adulthood with the same degree of success as their unaffected siblings. Neuropsychological surveillance during childhood and adolescence is important in identifying patients at risk for both neurocognitive and psychosocial morbidity.

Twenty-five adults with phenylketonuria that was treated early were compared with 15 unaffected control siblings with respect to intellectual and neuropsychologic measures. Patients were found to have normal intelligence but were significantly lower than their control siblings on measures of intelligence, attention, and complex visuoconstructional ability. Stepwise multiple regression analyses found the patients' intellectual outcome to be best predicted by indexes reflecting early insult to the brain, whereas performance on a measure of novel problem solving was best predicted by concurrent serum phenylalanine level. Different pathophysiologic mechanisms may thus account for cognitive deficits in this population. These results provide further evidence of continuing benefits of dietary adherence into adulthood.

Early treatment of phenylketonuria by dietary phenylalanine restriction prevents brain damage. Behavioral and cognitive deficits occur when serum phenylalanine levels increase. Administration of valine, isoleucine, and leucine to patients with phenylketonuria may inhibit entry of phenylalanine into the brain and reduce its toxic effects on the central nervous system. Sixteen adolescents and young adults with phenylketonuria participated in double-blind trials in which a valine, isoleucine, and leucine mixture or a control mixture was given for four 3-month periods. Biochemical and neuropsychologic tests were carried out before and at the end of each period. Time to completion of a test that required substantial attention with mental processing (Attention Diagnostic Method) was faster during the valine, isoleucine, and leucine periods than during the control mixture periods. Improvement with valine, isoleucine, and leucine on a less demanding task (Continuous Performance Test) approached significance. These data lent support to the hypothesis that a regimen of valine, isoleucine, and leucine may help individuals unable to maintain low serum phenylalanine levels.

Serum phenylalanine (phe) concentrations during and following phe challenges and liver phenylalanine hydroxylase (PH) activity were compared in 13 phenylketonuric (PKU) patients. These patients were separated into two groups: eight patients with no detectable PH activity (PH degrees) and five patients with residual PH activity (PH-) ranging from 9 to 24% of the activity obtained in 10 non-PKU subjects. The rise in serum phe concentration during 3 days of oral loading did not differentiate the two groups. However, the difference in serum phe concentration of the PH degrees and PH- groups reached statistical significance at 24 h postloading (p less than 0.01). We concluded that combined results from multiple measurements during the oral challenge, namely serum phe concentration after termination of loading, serum phe clearance rate, post-loading phe tolerance index and urinary metabolite excretion, make a better indicator for predicting residual PH activity for the majority of PKU subjects than peak phe concentrations during phe challenge.

A supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluid-serum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15-40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed.

Recent behavioral data have demonstrated the importance of maintaining low phenylalanine concentrations beyond early childhood in patients with phenylketonuria, which can be a difficult task, particularly during adolescence. Administration of certain large neutral amino-acids (valine, isoleucine, leucine--VIL) appears to reduce phenylalanine concentrations in the cerebrospinal fluid of humans and in the brain of rats. The present study compared neuropsychological test-performance of six patients with phenylketonuria during periods of VIL administration and periods when this supplement was not given. Although individual responses to VIL were variable, there was an over-all improvement of about 1 1/2 SD in neuropsychological test performance during VIL treatment. Abstract reasoning and tactile motor problem-solving increased more than pure motor performance.

Albumaid XP, a phenylalanine-free protein hydrolysate, was used for treatment of five phenylketonuric infants born between January, 1970, and September, 1972. The results were compared with those obtained from the five infants most recently treated with Lofenalac in our clinic prior to 1970. Treatment was begun by 2 months of age in all instances. Satisfactory physical growth and mental development were achieved using either Albumaid XP or Lofenalac, and there were no major differences in the outcomes with either treatment. The two protein sources may be used interchangeably for treatment of phenylketonuria.

The decision to continue treatment for phenylketonuria (PKU) patients into adolescence and adulthood presents a challenge to nutritionists and other professionals who must motivate patients to maintain the diet and give them support. Nutrition needs must be assessed and then met by commercial low-phenylalanine formula and low-protein foods, while at the same time the amount of phenylalanine in the diet is severely limited. Combinations of products can be used to tailor the diet to individual needs, e.g., weight reduction. The objective is to allow the intellectually normal PKU patient to develop as socially normal a life-style as possible.