By Eva Gross Friedman, Colleen G. Azen, M.S., Richard Koch, M.D., and the Writing Committee for the PKU Collaborative Study
This randomized study was conducted in two phases: phase A compared randomly assigned strict (TG1: 1.5-5.4 mg/dL) versus moderate (TG2: 5.4-9.9 mg/dL) restriction of phenylalanine (Phe) intake during the first 6 years of life. Phase B investigated diet continuation versus discontinuation after the age of 6 years. Non-PKU full natural siblings of the PKU index cases constituted the control group. The study designs for both investigations have been published (Williamson, Dobson, Koch, 1977; Koch, Azen, Friedman, et al., 1982). Subjects with PKU were identified by newborn screening, treated within the first 120 days of birth, and underwent confirmatory challenge by 1 year.
The Phe-restricted diet was based on Lofenelac, a casein hydrolysate, and was designed to provide a balance of nutrients with adequate protein, calories, and other essential amino nutrients. Good growth of those in both TG1 and TG2 was evidence of the adequacy of nutrient intake (Acosta, Trahms, Wellman, et al., 1983).
Blood Phe levels were measured weekly during the first year and monthly thereafter. These serial Phe levels were then summarized into Indices of Dietary Control (IDC). IDC-1 was the median of Phe levels during specific periods, and IDC-2 was the area under the curve of Phe over time. Other summary measures included rate of rise in blood Phe levels above 900 mmol/L through 6 years of age (Williamson, Koch, Azen, et al., 1981), total exposure to Phe levels above 900 mmol/L, and age after which Phe levels consistently exceeded a specified value-i.e., 900 mmol/L (Holtzman, Kronmal, van Doorninck, 1986).
Of the 167 confirmed infants with PKU who were initially enrolled in the collaborative study, 133 completed phase A, and 118 completed phase B through age 10. When the study concluded, 96 had completed 12-year evaluations. The subjects were predominantly Caucasian (96 percent); 43 percent were first-born, and 57 percent were male. Of the mothers, 16 percent were younger than 20 years of age at the birth of the child. The mean parent Weschler Adult Intelligence Scale (WAIS) score was 109 (SD=13) for 109 fathers, and 106 (SD=12) for 120 mothers.
For both groups, the mean 6-month IDC-1 values rose during phase A. Although TG1 values were generally below those of TG2, mean values exceeded the target range after 6 months of age for TG1 and after 36 months of age for TG2. The average rate of increase in Phe levels per year was 67.9 mmol/L for TG1 and 57.1 mmol/L for TG2. Twenty percent of the children in TG1 and 30 percent of those in TG2 had exceeded 900 mmol/L by the age of 6 years. Furthermore, many children who were "on diet" had blood Phe levels well above the target ranges, even during phase A. Holtzman and colleagues defined loss of dietary control to have occurred when IDC-1 rose above 900 mmol/L and remained there for three consecutive 6-month periods (Holtzman, Kronmal, van Doorninck, 1986).
The children in this sample exhibited an overall prevalence of congenital anomalies (9.3 percent) that was not significantly different from the figure for the general population (Johnson, Koch, Peterson, et al., 1978). Nineteen of the 161 children with PKU had abnormal electroencephalograms (EEG) shortly after birth that became normal by 1 year of age in all but 2 children (Blaskovics, Engel, Podosin, et al., 1981).
Annual assessments of height, weight, and head circumference through 4 years of age compared favorably with national norms (Holm, Kronmal, Williamson, et al., 1979). No significant differences were noted at any age between the PKU sample and a cohort of 184 normal children followed by the Fels Research Institute . However, the girls with PKU had a significantly greater increase in weight at later ages than did girls in the Fels group. This trend was still apparent at 8 years of age. Higher serum Phe levels were found to be positively correlated with weight, particularly for girls ( p<.001), perhaps reflecting poorer diet adherence in those with more rapid weight gain (McBurnie, Kronmal, Schuett, et al., 1991).
Cognitive Development and Academic Achievement
At age 6 the average intelligence quotient (IQ) score was 98 (SD=16). Significant predictors of IQ scores were mother's IQ score, age at initiation of treatment, and rate of increase in IDC, which together accounted for 36 percent of the total variation in IQ score (Williamson, Koch, Azen, et al., 1981). By the time subjects were 10 years of age, Holtzman and colleagues found that the age at which control of Phe was lost was the best, and often the only, significant predictor of the deficit in Wechsler Intelligence Scale for Children (WISC) IQ scores, Wide Range Achievement Test (WRAT) achievement, and behavior test scores between the child with PKU and other family members. A followup report on the subjects confirmed these findings at 12 years of age (Azen, Koch, Friedman, et al., 1991). Table 1 depicts mean IQ score from ages 6 through 12 years for children with PKU grouped by age at loss of dietary control.
The greatest discrepancies between the scores of the children with PKU and other family members occurred in those who lost dietary control before age 6, whereas those who lost control between 6 and 10 years of age had the greatest change in scores from age 6. Those still in control maintained their scores at 6 years of age in all areas except arithmetic. Arithmetic scores declined more than 10 points in all groups.
Table 1. Mean IQ at ages 6 to 12 years for children with PKU grouped by age at which control of blood Phe below 900 mmol/L was lost
*S-B: Stanford Binet, 1972 Norms.
†WISC: Wechsler Intelligence Scale for Children
‡WISC-R: Wechsler Intelligence Scale for Children (Revised).
|Age Lost Control||Age/Test||N||Mean||SD|
|Before age 6||6-year S-B*
|Between 6 and 10||6-year S-B
|After age 10||6-year S-B
|After age 10 and low Phe||6-year S-B
In addition to IQ and WRAT scores, the collaborative study evaluated perception and language development using the Bender Gestalt Test and the Illinois Test of Psycholinguistic Abilities (ITPA) at various ages. Those who continued on the diet and maintained control of their blood Phe levels had better mean scores than those who discontinued, but both groups had declining scores, similar to the pattern observed for arithmetic scores (Fishler, Azen, Henderson, et al., 1987). Among 112 children with PKU for whom school history data were collected, 32 percent were having mild to severe problems by the first grade, including repeating a grade or spending at least half of each day in special classes. By the fourth grade, 34 percent were at least 1 year below modal grade.
Comparison With Siblings
The non-PKU control group comprised 163 children from 91 families, allowing for within-family paired comparisons on cognitive tests. Table 2 presents these results at the ages at which siblings were tested.
Table 2. Paired comparisons between children with PKU and their unaffected siblings on psychological test scores at various ages
*Bender Perceptual Maturity scores are month equivalents.
|Psychological Test||Age at Test||Number of Pairs||Mean Scores PKU||Mean Scores Sib||Sib-PKU
|Stanford-Binet, 1972 norms||4 years||36||94||99||5||<0.02|
|Frostig Perceptual Quotient||5 years||51||94||103||9||<0.001|
|Bender Perceptual Maturity*||7 years||40||79||84||5||<0.05|
|ITPA Psycholinguistic Quotient||7 years||42||97||101||4||NS|
|WISC verbal scale||8 years||57||101||105||5||0.034|
|WISC performance scale||8 years||58||101||108||7||<0.001|
|WISC full scale||8 years||57||101||107||6||0.005|
|WRAT reading||8 years||54||101||107||6||0.006|
|WRAT spelling||8 years||54||100||104||4||NS|
|WRAT arithmetic||8 years||54||96||100||4||0.007|
Children with PKU scored significantly below their siblings on all tests except WRAT spelling at 8 years and the ITPA at 7 years (Fishler, Azen, Henderson, et al., 1987). The sibling-PKU differences were correlated with IDC at the time of the test and/or the age at loss of dietary control, except for the Frostig and ITPA tests. Children who maintained control of their blood Phe levels at least through 8 years of age had scores comparable with those of their siblings on all tests (Holtzman, Kronmal, van Doorninck, 1986).
The U.S. PKU Collaborative Study provided answers to several basic questions regarding treatment for PKU, namely, that the Phe-restricted diet is a safe and effective method of treatment, that continuation of the diet throughout childhood is recommended, and that early initiation of treatment and maintenance of good control of Phe levels in the early years of life are crucial.
Although IQ scores remain relatively stable after diet discontinuation, other areas of cognitive functioning (such as reading and spelling) may be more sensitive to rising Phe levels. Other areas, such as arithmetic, language, and perception, appear to be problematic for all children with PKU, at least in the ranges of Phe control seen in these children. Too few children in the study maintained Phe levels in the ranges of 120 to 360, or even 600 mmol/L, to address whether stricter control would have prevented even these subtle deficits.
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