Report of the NIH Consensus Development Conference on Phenylketonuria (PKU): Screening & Management: Chapter III

3. What treatment regimens are used to prevent the adverse consequences of PKU? What is known about the effectiveness of these treatment and management strategies overall and with respect to variables such as time of initiation of dietary management, level of phenylalanine at various ages, methods for enhancing dietary compliance, duration of dietary management, and dietary regimen for women of childbearing age and other adults?

This section of the report addresses four major issues involving the treatment of individuals with phenylketonuria (PKU): 1) the nature of treatment regimens used to prevent the adverse consequences of PKU; 2) the efficacy of these treatments for improving cognitive functions, behavioral adjustment, and quality of life, particularly in relationship to the time of initiation of dietary management, influences of variations in phenylalanine (PHE) levels at different ages, and duration of dietary management; 3) issues involving adherence with dietary management, including barriers and obstacles, monitoring, and health care systems; and 4) factors specific to women with PKU who are of childbearing age, including effects specific to the mother and to the fetus.

What Treatment Regimens Are Used to Prevent the Adverse Consequences of PKU?

It is well-established that implementation of a diet restricted in PHE early in life can significantly reduce the mental deficiencies associated with this disease prior to dietary interventions. This section describes current practices in the United States and elsewhere with regard to the treatment of PKU. Specifically, we will review current practices with regard to a) blood levels of PHE indicating need for treatment; b) age of treatment initiation; c) recommended levels of PHE and tyrosine/PHE ratios in the blood; d) frequency of monitoring of blood levels; e) discontinuation of treatment; and f) future directions.

Deciding to initiate treatment

Most professionals agree that infants with blood PHE levels >600  µM/L (9.9 mg/dL) should be started on dietary treatment. Typically, infants with levels between 400 µM/L (6.6 mg/dL) and 600 µM (9.9 mg/dL) persisting for more than a few days are started on dietary therapy (Cockburn, et al., 1993; Seashore, et al., 1999; Smith, 1994). When infants have very high blood PHE levels (>900 µM/L, 14.9 mg/dL), all natural sources of PHE are eliminated for a few days and PHE levels are monitored daily until blood PHE levels in an acceptable range are achieved. There is not general agreement about 6 mg/dL (360 µM/L) as either a level at which to begin treatment or a treatment goal (Seashore et al., 1999).

Dietary treatment involves use of a medical food/formula, PHE free and nutritionally complete with 100-120 mg/kg/day tyrosine and total amino acid content of at least 3 g/kg/day for children under 24 months and maintained at 2 g/kg/day for children over 24 months. Phenylalanine is added to the diet, which is then adjusted according to blood PHE levels. Vitamin B12, folic acid, calcium, zinc, iron, and the calcium/phosphorous ratio need to be monitored (De Freitas et al., 1999). There is a lack of consensus regarding the role of tyrosine supplementation and micronutrients in treatment of PKU (Seashore et al., 1999). If a patient is identified with mild hyperphenylalaninemia, medical food/formula is not recommended if PHE levels remain < 400 µM/L (6.6 mg/dL) while on a natural protein diet. Lowering natural protein in the diet is not a recommended strategy.

Other common aspects of treatment include genetic counseling, education of females regarding risk for pregnancy, assessment of possible learning problems, on-going dietary management, adherence strategies, protocols for illness management, and specialist services. Some recommend that patient assessments, which include an evaluation of nutrient intake, growth, and general health should be conducted every 2-3 months during infancy, every 3-4 months to school age, and every 6 months thereafter (Cockburn et al., 1993). PKU is considered to be a spectrum disorder and individualized treatment based on assessments on daily PHE and energy intake and blood PHE levels is recommended. Over-restriction in diet can lead to malnutrition. Feeding problems are a concern among children with PKU (MacDonald et al., 1994).

Age of initiation of treatment

Since the 1960's, detection of PKU through newborn screening has allowed early initiation of dietary treatment. There is general agreement among professionals that dietary treatment of PKU should begin as soon as possible, ideally by the time the neonate is 14 days of age and no later than 20 days of age (Cockburn et al., 1993; Smith, 1994). A recent survey of parents, patients, and clinic directors regarding current practices indicated that 53% of patients started diet between 8-14 days after birth, whereas 10% were not started on treatment until after 30 days (Wappner et al., 1999). Thus, it appears that the majority of patients are initiating treatment at the age that professionals recommend.

Recommended levels of phenylalanine

There is no consensus concerning optimal levels of PHE and tyrosine, either across different countries or among treatment centers in the United States. The British policy for dietary treatment recommends that blood PHE levels in infants be maintained between 120-360 µM/L (2-6 mg/dL) in infants and young children. The British guidelines are relaxed after children reach the school years (with recommendations that PHE levels be maintained at 480 µM/L or less in school-aged children, and at 700 µM/L (11.6 mg/dL) or less in older children, but the policy statement acknowledges that these higher limits in older children may be associated with impaired intellectual performance and decision-making ability (Cockburn et al, 1993). In contrast, a French study recommended discontinuing diets supplemented by amino acid mixtures at 5 years of age and thereafter recommended PHE levels below 1200-1500 µM/L (20-25 mg/dL) (Rey et al., 1996). The German Working Group for Metabolic Diseases recommended blood PHE levels between 40 and 240 µM (0.7-4 mg/dL) until the age of 10 years, 40-900 µM/L (0.7-15 mg/dL) between 10 and 15 years, and 40-1200 µM/L (0.7-20 mg/dL) after 15 years (Burgard et al., 1999). However the recommendations also addressed the need for life-long follow-up to evaluate for possible late sequelae (Burgard et al., 1999). Interestingly, there are no U.S. recommended guidelines for blood PHE levels formally recommended by a group such as the American Academy of Pediatrics or the NICHD. However, the American Academy of Pediatrics and College of Obstetrics and Gynecology conducted a review of the status of PKU management in the U.S., including a survey of all PKU directors in the U.S. (with 87 of 111 responding). The most common (50% of clinics) threshold for PHE level at initial treatment was < 10 mg/dL (Wappner et al., 1999). The most commonly reported blood PHE recommendations in those clinics were 2 to 6 mg/dl for patients <= 12 years and 2 to 10mg/dL for patients > age 12 (Wappner et al., 1999). Nevertheless, in practice, only half of clinics in the U.S. and Canada recently surveyed expected PHE levels below 5 mg/dL in the 1 ^st year of life, while 94% attempted to maintain levels under 10 mg/dL (Fisch et al., 1997). The important question of whether greater stringency in management of PHE levels at school age and beyond is needed remains to be addressed (Seashore et al., 1999). Some professionals recommend monitoring performance and decision-making abilities and adjusting blood PHE levels downward if difficulties in these areas are apparent (Cockburn et al., 1993).

Other issues which remain unresolved in regard to monitoring of blood phenylalanine levels is the optimal time for monitoring and the role of the ratio of PHE to blood tyrosine levels. There is no consensus regarding whether blood PHE levels should be based on fasting or postprandial concentrations (Seashore et al., 1999). Some authorities recommend that the ratio of PHE to tyrosine be maintained at < 4 (Smith, 1994), but there is no consistency in regard to this in clinical practice.

PHE blood level monitoring

It is generally agreed that frequent monitoring of blood levels of PHE is necessary especially during the early years of life, with less frequent monitoring necessary at older ages. Ideally, blood PHE levels should be sampled in the morning at the time of natural peak levels. Recommendations regarding the frequency of monitoring during the first year range from once every week to once every 4 weeks (Cockburn et al., 1993; Fisch et al., 1997; De Freitas, et al., 1999; Diamond, 1994). A survey indicated that the mean frequency of monitoring for children below one year was 3.6 times per month (range from 1-8 times) (Wappner et al., 1999). Recommendations after one year of age range from once every month to once every 3 months (Cockburn et al., 1993; De Freitas et al., 1999; Diamond, 1994), and in actual practice the mean frequency by 18 years of age is 1.02 time per month, with a range of 0-4 (Wappner et al., 1999).

Discontinuation of treatment

There is not consensus concerning how long individuals with PKU should stay on diet, particularly across countries. Surveys of clinical practices in the US and Canada suggest that the majority of clinics recommend dietary treatment and control of blood PHE levels for life, especially for females (Fisch et al., 1997). Reinstitution of diet after discontinuation is believed to be very difficult and requires expertise in issues of adherence (Wappner et al., 1999). Discontinuation of diet is most likely to occur between 6-15 years of age. Over 90% of families recently surveyed indicated that their clinic recommended that the strict diet be continued for life. Only one-third of clinics, however, follow patients past 18 years (Fisch et al., 1997).

Issues pertaining to adherence, costs of treatment, independence, and prepregnancy management become salient during adolescent and young adulthood. Beginning in adolescence, and to a lesser extent in childhood, adherence is a major area of concern to professionals treating individuals with PKU (Wappner et al., 1999). Half of clinics use social service to help with nonadherence (Fisch et al., 1997).

Future directions: Gene therapy

Although dietary treatment is largely successful in reducing the adverse effects of PKU on mental and behavioral functioning, discontinuation of treatment and nonadherence continue to lead to poor outcomes, even in adults. In addition, poor dietary adherence during pregnancy in women with PKU can adversely affect the fetus, resulting in developmental problems and mental impairment in their offspring. Somatic gene therapy for PKU is currently being explored as a future treatment for this disease (Eisensmith and Woo, 1996). The initial attempts at developing a gene therapy for PKU were unsuccessful due to problems related to an immune response against the adenoviral vector. Current studies are aimed at modifying the adenoviral vectors to reduce expression of the adenoviral genes responsible for the immune response (Eisensmith and Woo, 1996). These and related studies hold promise for the possible success of gene therapy for PKU in the future.

Efficacy of Treatments for PKU

Failure to identify and treat individuals with PKU is invariably associated with significant mental deficiency. Early studies showed that while development in the first few months of life was variable, significant delays in the achievement of major developmental milestones were apparent over the first few years of life in children with untreated PKU (Knox, 1972). Neurologic abnormalities were common and the behavioral adjustment of children with untreated PKU was often poor. Aggression, temper tantrums, irritability, and hyperactivity were frequently reported, particularly in individuals with PKU who had evidence of a frank neurologic impairment (Wright and Tarjan, 1957). Prior to development of effective newborn screening methods and dietary interventions, mental retardation was almost invariable and eventual admission to institutional care was common. As Scriver and Clow (1980) stated, "The most important phenotypic component of PKU is mental retardation." It is therefore not surprising that the major endpoint for intervention research has been the prevention of mental retardation, so that the outcome literature of individuals with PKU is dominated by studies of intellectual development.

With screening and dietary control, mental retardation is no longer a common outcome and admissions for institutional care saw a significant decline (MacCready, 1974) even before the advent of attempts to reduce the frequency of institutional care for individuals with mental deficiency that is presently widely accepted as a societal goal. However, questions remain concerning the extent to which PKU – even with dietary control – is associated with more subtle problems involving cognitive functions, school achievement, behavioral adjustment, and quality of life. In particular, related issues concerning how long to maintain the diet, the effects of fluctuations in PHE levels on and off diet, the level of optimal control of PHE, and whether the diet should ever be discontinued are important topics for research. There is controversy around each of these issues, with variations across countries and even across PKU treatment centers in the United States that reflect the incompleteness of the knowledge concerning PKU and the long-term outcomes of early-treated individuals.

In the next sections, research on intellectual development, other cognitive skills, school achievement, and behavioral adjustment will be reviewed in relationship to issues involving effects of a) age at diet initiation; b) level of control and PHE levels; and c) diet relaxation and discontinuation. For this review, two sources were seminal. The first is the recent review of this literature by Welsh and Pennington (1999). The second was a systematic review of the literature on PKU from the National Library of Medicine. Searching the abstracts yielded by this review for keywords involving the specific outcomes and effects of intervention led to the creation of two tables. Table 1 summarizes studies of outcomes involving intelligence testing as well as whether the abstract reported analyses involving age of initiation of dietary intervention, effects of dietary discontinuation, and relationships of the intelligence measures with PHE levels. In addition, the table reports the country in which the study was conducted (if apparent from the abstract), age at which the patients were studied (i.e., length of follow-up from birth), and whether the study had some form of comparison group or simply compared results of the IQ tests to a normative population. Table 2 presents similar information for measures of school achievement, behavioral adjustment, and cognitive functions.

Intellectual Outcomes

Welsh and Pennington (1999) concluded that …"studies of intelligence provide evidence of the effectiveness of the dietary treatment when initiated very early in development. Early-treated PKU children exhibit intellectual levels well within the normal range (low to high 90s). However, it is also clear that their intellectual functioning does not achieve the levels predicted from their parents' and siblings' intelligence, and that IQ declines with age during the school years in some children. Declining mental abilities appear to be related to elevations in PHE caused by poor or absent dietary control." The observation that intelligence test scores tend to be slightly below average and below levels predicted by parental/sibling IQ test scores is important. If the population of all individuals with PKU has even a slight downward shift, the number of individuals with mental deficiency will likely be higher than expected. For example, Schmidt et al. (1996) reported that their sample achieved average intelligence scores of 97, only 3 points below the population-based average of 100. However, 4% of the sample had scores two or more standard deviations below the mean (70), a level that is one part of the legal definition of mental retardation. This represents a doubling of the number of individuals with scores below 70 that would be expected based on normative samples.

Table 1 supports the conclusions of Welsh and Pennington (1999). A total of 48 abstracts were identified that reported intellectual outcomes. Thirty-four of these 48 studies reported IQ scores as deficient, less than average, or with an excessive number of low IQ scores. Of the 14 studies that did not interpret results as indicating lower than average IQ test scores, 10 had no form of comparison group. Few studies reported IQ scores that exceeded 100, which would be expected if study results were randomly fluctuating around the average of 100.

Table 1 also shows that studies of intellectual functions have been completed in many countries, including North America (Canada, USA), United Kingdom, France, Germany, Austria, The Netherlands, Norway, Portugal, Hungary, Poland, Turkey, and various Balkan countries. Most studies attest to the benefits of early treatment. Obviously, in earlier studies in which a range of age of diet initiations were involved, intellectual outcomes were usually inversely correlated with the age at which dietary interventions were initiated. However, studies that evaluate outcomes in relation to age at dietary initiation and report ranges up to 3 months also report inverse relationships of age at initiation and intellectual outcomes.

In terms of whether the diet can be discontinued at some point in development, Table 1 only includes studies in which the abstract indicated that discontinuance was clearly evaluated by a random trial, or by comparing individuals who continued or discontinued the diet. Of the 15 studies that provided such an evaluation, 13 obtained findings indicating that dietary discontinuance has adverse effects on intellectual outcomes. These results are consistent with an earlier review of the literature by Waisbren et al. (1980).

In terms of relationships with PHE levels, studies were counted only if the abstract correlated IQ test scores with PHE levels, compared groups varying in PHE levels, or compared groups who continued/discontinued diets. Of these 34 studies, 31 reported that higher levels of PHE were related to lower scores on intelligence tests. These results do not appear strongly related to the age at evaluation, but few studies of adults are apparent. These results should be verified through a careful review of the entire article, and preferably through an empirical synthesis (meta-analyses), but results based solely on a review of abstracts support the conclusions reached by Welsh and Pennington (1999). The committee has commissioned a meta-analysis of these studies.

Achievement, behavioral adjustment, and cognitive outcomes

Table 2 (at the end of this chapter) summarizes the results of 37 studies reporting outcomes that involved school achievement, behavioral adjustment, or cognitive functions beyond IQ tests. Many of these studies are more recent than the IQ outcome studies and reflect the move away from issues involving global intellectual deficiencies to more subtle effects of PKU in individuals under treatment. The majority of these studies (29 of 37) that examined these domains found poorer performance of individuals with PKU. The most predominant findings are diminished school achievement and increased difficulties on achievement tests. A variety of cognitive problems are reported, with an emphasis on measures of executive functions (planning, problem solving, self-regulation) and attention. The former reflects the hypothesis prominent in the PKU literature relating reduced dopamine levels to increase levels of PHE and subsequent problems on tasks presumably mediated by the prefrontal cortices (Diamond et al., 1997; in press; Welsh et al., 1990). Diamond et al. (1997) found that children with PKU, who had been on a low-PHE diet since the first month of life, but who had moderately elevated plasma PHE levels were impaired on several tasks dependent on the dorsolateral prefrontal cortex that tapped working memory and inhibitory abilities. Other investigators have reported similar findings (Smith et al., 1996; Welsh et al., 1990). These findings suggest that even moderately elevated plasma PHE levels can have significant effects on cognitive functioning.

Anecdotal reports associate PKU with increased behavioral difficulties and diminished attentional skills. Such findings could potentially relate to the possible effects of PHE on myelin and cerebral white matter. No studies of individuals with PKU have attempted to relate quantitative indices of brain structure (e.g., size of prefrontal cortices, amount of white matter) to cognitive functions, an approach that has proven useful with a variety of other childhood disorders. Results of magnetic resonance imaging studies do show an increase in white matter abnormalities, particularly as PHE levels increase (Cleary et al., 1994; 1995). However, these abnormalities diminish as PHE levels decrease and their significance – particularly since the findings are largely based on radiologists' reviews of clinical scans – is unclear.

Several studies manipulated PHE levels by dietary adjustments or actually loading an individual with PKU on PHE. Two studies by Griffiths et al. (1997; 1998) involved a triple blind cross-over, comparison of individuals with PKU fed supplements containing PHE for 3 months. There were no differences in intellectual, memory, attention, motor, and behavioral functions when the children were on and not on the supplement. An earlier study by Realmuto et al. (1986) evaluated the effects of acute loading of PHE on attention in a double blind cross-over design. Although there was a decrement in attentional skills in the PHE condition, the change was not statistically significant. In contrast, Schmidt et al. (1994) found that manipulating PHE levels so that they were higher through dietary manipulations led to decrements in reaction time and calculation speed that improved when PHE levels were lowered. In a study involving MR spectroscopy, Pietz et al. (1996) showed that an oral load of PHE in four individuals with PKU led to a steep increase in plasma levels of PHE. An increase in brain PHE was also apparent, but was delayed and less steep. PHE levels were not associated with changes in attention and fine motor control. Altogether, these studies do not show strong relationships of PHE levels and cognitive functions when PHE levels are manipulated through dietary supplementation measured in individuals with PKU.

These studies, however, are characterized by small samples. As Table 2 shows, 18 of 28 studies report a relationship of PHE levels and outcome, largely in studies that either correlate PHE levels with performance or compare individuals with varying levels of dietary control. Since this set of studies tends to be more recent, few abstracts (7) report relationships of age of initiation and outcome, with the results of 4 indicating such a relationship. Finally, of the 11 studies that evaluated effects of dietary discontinuation, 9 obtained results indicating that the diet should not be discontinued.

Not addressed in Tables 1 and 2 is the tentative evidence that extremely high plasma PHE levels during the first two weeks of life can permanently affect the structural development of the visual system, which is maturing very rapidly at that time (Diamond, in press). Although the visual deficits that result are mild, efforts at intervention at birth may be warranted.

Barriers to adherence to the treatment regimen

Given the evidence that treatment is effective, why do individuals with PKU fail to adhere to the diet, particularly over their lifetime as recommended by many individuals involved in the treatment of PKU? Adherence in the context of this report refers to the extent to which a person's behavior (e.g., diet and monitoring practices) coincides with medical or health advice (Sacket and Snow, 1988). The term adherence has largely replaced "compliance," which carries a connotation of patients doing what they are told (Lutfey and Wishner, 1999). Use of the term adherence recognizes the fact that individuals with PKU are independent of health care providers and are free to make decisions about their self-care behaviors.

Numerous barriers to adherence to the treatment plan for PKU have been identified. These can be grouped into four categories: 1) factors associated with the treatment regimen itself, such as palatability, cost, and availability of medical nutrition therapy (MNT), 2) physiologic factors, 3) psychosocial issues, and 4) factors related to the health care system.

Treatment-related factors affecting adherence

The more complex a treatment regimen, the more difficult it is to adhere to the regimen (Jay et al., 1984). The PKU treatment regimen is very complex, requiring regular collection of blood samples; recording of dietary intake; maintenance of a highly restrictive diet consisting of a medical food, special low protein foods, and a strict vegetarian diet; and visiting a PKU clinic several times a year. MNT is a major hurdle in achieving adherence to the treatment regimen. All treatment centers recommend long-term MNT; the majority advocate that MNT be followed for life (Fisch et al., 1997; Wappner et al., 1999). Long-term MNT is not unique to PKU treatment, of course, but PKU therapy poses some especially difficult problems. The low PHE formula is the mainstay of MNT. It provides 100% of the kilocalories needed by the young infant and up to 75% of the kilocalorie requirements of the 1- to 2-year-old child. Formula intake decreases as the child ages and consumes more solid foods, but the formula is still the source of approximately 40% of the kilocalories consumed by 5- to-15-year-old children with PKU (California Department of Health Services [CDHS], 1997) and remains a dietary staple for those who continue the PKU MNT into adulthood. Moreover, solid foods must include special low PHE (low protein) foods.

Palatability, accessibility, convenience, and cost affect the degree of adherence to MNT, and MNT for PKU impacts upon all of these areas. Low protein products lack some of the chemical and sensory properties of their normal counterparts; this can alter taste, texture, odor, and overall quality of the formula and food products. Most tasters judge these low PHE products to be relatively unpalatable, with the PKU formula being rated as poor tasting and malodorous (Buist et al., 1994). In addition, MNT for PKU is inconvenient in many respects. Most families must obtain low protein foods primarily via mail order from specialty dietary suppliers, although some PKU centers stock them for their clients (Buist et al., 1994). Even by mail order, low protein convenience foods are uncommon. The lack of convenience products and the altered properties of the low protein products mean that more time and skill is required to prepare an acceptable low PHE diet than a diet consisting of commonly available foods, although no objective data are available regarding the quantity of time needed for preparation of the PKU diet, in comparison to an average diet. Another factor increasing the inconvenience of MNT for PKU is the need to have low protein foods and formula available when dining away from home. Eating while at school, work, social events, and during travel must be carefully planned so that low PHE products are available. Moreover, social stigmata may attach to the individual needing a special diet in social settings. This is especially a problem in adolescence.

The costs of low PHE or phenylalanine-free formula and low protein foods, as well as for monitoring of blood PHE levels, can be substantial. A 1997 survey of California families with children with PKU ranging in age from less than 1 year to 13 years of age (mean age 6 years) revealed that the mean weekly formula cost was $98.51 (CDHS, 1997). The price of low protein foods ranged from 110% to >3500% of the price of comparable regular food items, with the average being approximately 700% (CDHS, 1997; Magol, 1995). In comparison to food costs for unaffected individuals, annual food costs for individuals with PKU have been estimated to range from 14% more (for infants) to approximately 400% more (for individuals 11 years and older) (CDHS, 1997). In the California survey, the mean weekly food costs for children with PKU was $77 (CDHS, 1997). Blood testing for PHE costs between $10 and $80 per assay, although some PKU centers provide blood testing as a free service to their patients (Wappner et al., 1999). Only 49% of families in a nationwide survey reported that insurance covered the costs of blood testing (Wappner et al., 1999).

In a convenience sample of 1064 parents and young adults with PKU from all 50 states, most families reported that the state or insurance companies paid for the formula, but 82% of the families paid for the food themselves (Wappner et al., 1999). For some of the families the low protein food created a significant financial burden. The effect of high formula and food prices on adherence to the PKU diet and control of PKU were explored most extensively in the California survey. Thirty-nine of the 141 families (27.6%) reported experiencing problems obtaining formula and 49 of the families (34.7%) reported problems in obtaining low protein foods. Cost was the primary factor leading to difficulties obtaining formula; for low protein foods, both cost and availability created difficulties. Of the 39 families having difficulty in obtaining formula, 8 families (20.5%) reported that the problem was responsible for excessive blood PHE levels, and 11 families (28.2%) stated that the lack of access to formula had had deleterious effects on their children's school performance (California Department of Health Services, 1997). Similarly, 28 of the 49 families (57.1%) having problems with access to low protein food reported that the problems had resulted in high blood PHE levels, and 22 families (44.9%) stated that the lack of access to food had adversely affected the children's school performance (CDHS, 1997).

Problems associated with reinstitution of the diet

Reinstitution of the PKU diet by an individual who was on the diet but discontinued is reported to be very difficult (Wappner et al., 1985). It has been suggested that the longer an individual has been off the diet, the more difficult it is to resume the diet (Matalon et al., 1986). However, in a nationwide survey of 72 patients (9 with severe/profound mental retardation and 63 with normal intelligence to mild retardation) who had returned to the PKU diet after discontinuing it, there was no relationship between the length of time the subjects had been off the diet and their success or failure in remaining on the diet the second time (Schuett, 1999). Nevertheless, the failure rate was high for reinstitution of the diet. Twenty-two of the 72 individuals (31%) discontinued the diet a second time after a median of 10 months on the diet (Schuett, 1985). The reasons for the second discontinuance included poor dietary control, poor tolerance of formula, lack of motivation by parents and/or the patient, and lack of perceived improvements in symptoms despite following the diet. Moreover, only 7 of the 63 individuals with normal intelligence/mild retardation managed to keep blood PHE levels under 10 mg/dL while on the diet, and 41 of them had blood PHE levels >15 mg/dL. The difficulty in reinstituting the PKU diet has led some PKU clinics to recommend that the diet never be discontinued (Matalon et al., 1986).

Physiologic factors impacting upon adherence to PKU treatment

Recent work that indicates that the biochemical phenotype in PKU can be predicted from the type of PAH mutation in as many as 79%-85% of cases (Guldberg et al., 1998; Güttler et al., 1999; Kayaalp et al., 1997). On the other hand, it is clear from these same data (Guldberg et al., 1998; Kayaalp et al., 1997) that genotype alone is insufficient to explain variation in blood PKU levels or IQ scores in a large minority of affected individuals. Different phenotypes have been observed in both related and unrelated individuals with identical genotypes (DiSilvestre et al., 1991; Popescu et al., 1994; Ramus et al., 1993). Thus, while blood PHE concentrations and the stringency of dietary restriction required for adequate treatment may be determined in large part by the genotype, other factors apparently modify the genotypic effects and alter PHE tolerance. Inter-individual variations in the transport of PHE across the blood-brain barrier (Weglage, Möller et al., 1998; Weglage, Wiedermann et al., 1998), time of diet initiation and discontinuation (if applicable) (Güttler et al., 1999), and genetic predisposition for cognitive development (Ramus et al., 1993) are among the likely modulating factors.

The age of the individual is another physiologic factor impacting on the PHE requirement. In older children and adolescents, the need for PHE (per unit of body weight) declines by approximately 50% relative to needs during infancy and early childhood (Elsas and Acosta, 1999). This reflects a reduction in the rate of protein synthesis in older children and adolescents. Thus, as energy needs increase during adolescence, the individual must consume more energy (calories), but not from phenylalanine-containing sources. Mean serum PHE concentrations in treated children have been shown to rise progressively, from approximately 7 mg/dL in the preschool years to 10-11 mg/dL at 10 years of age and 13-15 mg/dL during adolescence (Weglage et al., 1998). Whether the rise in PHE levels with age is primarily a result of the physiologic changes associated with development, deteriorating adherence to the treatment regimen due to psychosocial and familial issues, or a combination of factors is not clear. Nevertheless, guidelines for treatment of PKU often acknowledge the difficulty in maintaining optimal control as children age and suggest higher acceptable limits for blood PHE concentrations in older children and adolescents. Whether or not attempts should be made to maintain circulating PHE in older children, adolescents, and adults at the same levels as those recommended for younger children is unknown (Levy and Waisbren, 1994).

One theory of the pathogenesis of PKU is that elevated PHE concentrations interfere with myelination. Since myelination appears to be complete by 6 years of age, this has provided a rationale for discontinuing or relaxing dietary restrictions after age 6. However, evidence suggests that myelin turnover continues throughout life (Hommes and Moss, 1992). It follows that hyperphenylalaninemia at any age could impair myelination, although perhaps not as severely as hyperphenylalaninemia in infancy and early childhood.

Psychosocial Issues

Adolescents face particular challenges in adhering to MNT for PKU. The social and emotional changes occurring during adolescence, increase in peer pressure, and the growing independence from parents or other authority figures create an environment where a stringent diet may be difficult to follow. In a recent survey of all PKU clinic directors in the United States, 4669 patients were under care, with the number approximately evenly divided between individuals who were 12 years old or younger and individuals older than 12. The majority of the clinics recommended MNT for life, with 79% of them advocating such treatment for males and 85% for females (Wappner et al., 1999). Of the patients who were 12 or younger, 93% were on the phenylalanine-restricted diet. In contrast, only 54% of those older than 12 remained on the diet (Wappner et al., 1999)., demonstrating that adherence to the clinic recommendations was much lower in adolescent and adult patients than in younger children. In a study of 34 German adolescents with PKU, 32 (94%) stated that they wanted to discontinue the diet immediately because it was too hard to follow (Weglage et al., 1992).

Perceived value of treatment

Adherence to MNT for PKU diet in adolescence and young adulthood may be related to gender-specific motivators. In a group of 72 patients that returned to the PKU diet after having discontinued, there was a tendency for more females to remain on the diet than males (Schuett et al., 1985). Males who experienced improvements in cognitive function, school work, mood, and/or who were told of EEG findings related to resumption of the diet were more likely to be successful in reinstituting the diet than males that did not perceive improvements. For females, there was no significant relationship between improvements in signs or symptoms and success in maintaining the diet. Females may be more motivated to adhere to the diet because of their awareness of the problems associated with maternal PKU.

Knowledge of PKU

Knowledge about PKU and its treatment is likely to be an important determinant of adherence to the treatment regimen. Adolescents with insulin-dependent diabetes, a disease that requires a treatment program similar in complexity to that of PKU, demonstrated better adherence when they had a high level of knowledge about diabetes (Burroughs et al., 1993; Ingersoll et al., 1986). Knowledge was also a predictor of adherence in a meta-analysis of metabolic control in diabetics of all ages (Brown and Hedges, 1994). In a 4-month pilot program designed to help adolescents with PKU improve their metabolic control, only 7 of 16 participants were considered to have successfully completed the program by earning at least 75% of the possible "points" given for desirable behaviors (Gleason et al., 1992). The 7 successful subjects significantly increased their knowledge of PKU and decreased their blood PHE levels during their program participation, but the 9 unsuccessful participants did not.

Weglage et al. (1992) found that adolescents with PKU had a poor understanding of the disease and its etiology; the mothers of these adolescents also displayed knowledge deficits in regard to PKU. In contrast to individuals with other chronic disorders such as diabetes and cystic fibrosis, where adolescents and older children are encouraged to develop self-management skills, the adolescents with PKU were lacking in such skills. Of the 34 patients examined (mean age 14.6 ± 2.0 years), 20 (59%) reported that they could not manage their diets without their mothers' help. There was no difference between patients less than 15 and those over 15 in regard to their competence to manage their own diets (Weglage et al., 1992).

Locus of control

Adherence with treatment regimens in other chronic illnesses, including asthma, diabetes, and obesity, has been found to be better in individuals with an internal locus of control, or perception that their own actions affect their health (Reynaert et al., 1995; Taggart et al., 1991; Uzark et al., 1988). Moreover, in children and adolescents with asthma and diabetes, development of self-management skills was associated with an increase in internal locus of control (Hindi-Alexander, 1983; Moffatt and Pless, 1983; Taggart et al., 1991). In a study of factors affecting adherence in maternal PKU, locus of control was an important determinant of adherence to treatment recommendations (Waisbren et al., 1995), as would be expected based on locus of control data from other chronic health conditions. An external locus of control (belief that factors outside the individual are responsible for most of life's circumstances) was a risk factor for inconsistent use of contraception among sexually active women with PKU (16 to 35 years of age), as well as for poor gestational control of PKU in women who became pregnant (Waisbren et al., 1995). In contrast, locus of control appeared to have little effect on the success of adolescents in a pilot treatment program designed to improve knowledge of PKU and self-management skills. Individuals who successfully completed the 4-month program did not exhibit a more internal locus of control at baseline than those individuals who were unsuccessful in the program. In addition, even though the successful participants significantly increased their knowledge of PKU during the program, they did not become more internal in locus of control (Gleason et al., 1992). One explanation for the latter findings is that the early introduction of treatment for PKU leaves the individual feeling that he or she is controlled by "powerful others," i.e., parents and the PKU clinic staff, without the initiative to take responsibility for personal care (Gleason et al., 1992). In support of this explanation, adolescents with PKU described themselves as significantly less autonomous than individuals without PKU did (Weglage et al., 1992). The discrepancy between the findings in the study of maternal PKU and those in the adolescent pilot project may indicate that there are gender differences in the impact of locus of control on adherence in PKU. Five of the seven successful subjects in the pilot project were male.

Family factors

Adherence to the PKU diet and metabolic control were found to be directly related to the educational level obtained by both parents and to family cohesion (closeness and a sense of cooperation within the family) (Shulman et al., 1991). Additionally, paternal perception that the family was flexible and adaptable was related to the child's IQ (Shulman et al., 1991). Furthermore, problem-solving skills were found to be better in "compliant" parents (those whose children's PHE levels were maintained in the recommended range) than in "noncompliant" parents (those whose children's PHE concentrations exceeded the recommended limits) (Fehrenbach and Peterson, 1989). Stress reduced problem-solving ability in both compliant and noncompliant parents, but compliant parents demonstrated a higher quality of problem solving even during periods of high stress (Fehrenbach and Peterson, 1989). Strong social support systems and belief in the value of treatment also enhance adherence (Spitalnik, 1982; Waisbren et al., 1995).

Social and emotional factors

Young women with PKU (who, because of the risks associated with maternal PKU, have been more extensively studied than men) often have lower IQ than the average, a high incidence of emotional disorders, and low socioeconomic status (Platt et al., 2000; Waisbren et al., 1995; Waisbren and Zaff, 1994). All of these factors may interfere with adherence.

Factors related to the health care system

The care of people with PKU is concentrated in large medical centers; each state usually has only one or only a few PKU treatment centers. Some patients report there may be problems related to access to care, particularly those from low income, rural families, or those that are geographically remote from a treatment center.

In the current health care climate, reimbursement and funding for PKU centers are complicated issues. Reimbursement and funding for formula, foods, and testing of adult patients is often difficult because historically few adult patients have remained under treatment, and thus there is little precedent for funding for adults. Not all states have a designated source of funds, such as revenue from newborn screening programs, earmarked for PKU treatment. Many health maintenance organizations do not recognize a need for specialist management for PKU. Institutional cost-saving measures often include staff reductions, jeopardizing critical staff positions such as nutritionists experienced in the care of individuals with PKU (Wappner et. al., 1999).

Improving adherence to PKU treatment

A variety of approaches have been explored in attempts to improve adherence with the PKU treatment regimen, but no single solution has proved universally successful. Making the diet more palatable and accessible may improve adherence. However, development of improved systems of education, follow-up, and social support are essential to achieving a high degree of adherence to the treatment regimen.

Diet-Related Measures

In the United States a single phenylalanine-free or low PHE amino acid product is prescribed to provide much of the nutritional intake for the person with PKU. This makes the diet easy to prescribe, distribute, and monitor and prevents catabolism, which would release additional PHE into the circulation (Duran et al., 1999). However, the heavy reliance on the unpalatable amino acid mixture (AAM), usually served as a liquid formula, also makes the diet extremely monotonous and unenjoyable. The impact of monotony and lack of palatability on adherence to the treatment regimen is widely recognized (Buist et al., 1994; Life Sciences Research Office, 1991; Seashore et al., 1999). One small long-term randomized trial of products designed to improve the palatability and acceptability of the amino acid module used in the PKU diet has been conducted in the United States (Buist et al., 1994; Prince et al., 1997). The experimental AAM was modified to eliminate the unpalatable nonessential dicarboxylic amino acids aspartic acid and glutamic acid and reduce the content of the unpalatable sulfuric acids methionine and cystine. In addition, the AAM was incorporated into a variety of different amino acid-containing products, rather than serving it in a single form. These varied products were nutritionally incomplete (i.e., lacking in vitamins and minerals) in order to improve their flavor, and a separate vitamin-mineral supplement was provided. The majority of subjects (15/25) preferred the nutritionally incomplete products to the nutritionally complete experimental and control drinks. Improved palatability did not appear to translate into improved adherence, however. The PKU clinic was the only source of AAM and low protein foods for the study participants, and clinic records indicated that individuals in the experimental and control groups purchased only 69% and 78%, respectively, of the products that were prescribed (Buist et al., 1994).

The Committee on Nutrition of the American Academy of Pediatrics (Committee on Nutrition, 1994) has recognized that special medical foods are indispensable for the treatment of disorders of amino acid metabolism. Furthermore, the Committee has recommended that the costs of these medical foods should be reimbursed. However, the decision whether to provide governmental coverage for food necessary to PKU and/or to mandate coverage by third party payers has been left to the individual states. A compilation of relevant laws from 33 states (Schuett, 1999) indicates that 12 of the states (36%) have a state program that provides the formula for all individuals diagnosed with PKU. Eleven states (33%) have no state program to cover the costs of formula but have enacted laws requiring insurance carriers to provide reimbursement for the formula to individuals covered by their policies. Ten of the 33 states (30%) have both a program for state provision of formula and a mandate for insurance carriers to provide reimbursement. Reimbursement for low protein food products is less common than reimbursement for formula; only 17 of the 33 states have a state program to cover the costs of dietary foods or require insurance carriers to provide reimbursement for the special foods (Schuett, 1999).

Additional sources of formula and low protein foods are available to some low income families. In 43 of the 50 states the Women's, Infant's, and Children (WIC) Program provides low-PHE formula for eligible participants (California Department of Health Services, 1997). In some states funds provided by the Health Care Financing Administration (HCFA) for Early Periodic Screening, Diagnosis and Treatment (EPSDT) programs and by the Health Resources and Services Administration (HRSA) under Title V of the Social Security Act for Maternal and Child Health and for Children with Special Health Care Needs have been used to provide formula to needy families. However, there is no uniform program to ensure that all families receive the financial assistance they may need. The United States is far from achieving the standard of reimbursement recommended by the American Academy of Pediatrics .

Education and social support

Education of individuals and their families so that they have a clear understanding of PKU and the benefits of treatment, and development of social support hold promise for improving adherence in PKU (Levy and Waisbren, 1994; Waisbren et al., 1995). In comparison to individuals with other chronic diseases, such as diabetes and asthma, individuals with PKU are frequently less able to assume their own care (Waisbren et al., 1995; Weglage et al., 1992). The British guidelines for PKU management (Cockburn et al., 1993) strongly recommend that strategies be developed to help children take responsibility for their own diets and blood testing by school age. Results from a small pilot study indicate that increased knowledge of PKU and its care and increased assumption of responsibility by the patient is associated with improved adherence and lower blood PHE levels (Gleason et al., 1992). Self-management would be simplified by the development of a rapid, inexpensive method for home measurement of blood PHE levels. This would permit more frequent and timely assessment of the success of metabolic control, similar to self-monitoring of blood glucose by patients with diabetes (Wendel and Lagenbeck, 1996).

Several programs have been developed to improve social support and education for individuals with PKU and their families. Mentoring by well-trained mothers of children with PKU (St. James et al., 1999), PKU camps and a peer counselor program (Levy and Waisbren, 1994), and a national listserv and newsletter provide additional methods for improving support and education of families dealing with PKU.

Diet in women of child bearing years

There is a lack of consensus concerning the dietary management of women of child-bearing age with phenylketonuria. Some of the differences in management are caused by the lack of unanimity of what age, if any, age dietary restrictions should be removed in individuals with PKU. In their survey of treatment centers for PKU in the United States and Canada, Fisch et al. (1997) reported that while most clinics recommended diet for life, only one-third of the clinics followed patients beyond 18 years of age. As mentioned above, there was lack of agreement regarding the acceptable range of blood PHE levels. While most clinics in the United States and Canada consider the target levels of less than 10 mg/dL for individuals ages one through 18 years, some clinics accept the level of less than 15 mg/dL.

Similar to the lack of consensus among PKU clinics in the United States and Canada, there is a lack of consensus at the international level. The British Medical Research Council Working Party on PKU suggested that the management of pregnant women PKU control needs to be, if anything, even stricter than in children with PKU (Cockburn et al., 1993). The report also indicated the importance of counseling and supporting women of child bearing age in order to achieve optimal PHE control. One of the major difficulties associated with dietary recommendations for women of childbearing age is the need to achieve dietary control early in the pregnancy in order to prevent the adverse consequences of high PHE levels. Since it can not be predicted when any given woman might conceive, many researchers recommend that women remain on a low PHE diet for life. For those women who are not in dietary control at the time of conception, it is important that control be achieved by age 8 weeks to reduce the risk of adverse outcomes in their offspring (Koch et al., 1999).

The current recommendation for level of control of PHE during pregnancy among affected women in the United States is 2-6 mg/dL (120-360 µM/L) (Rouse et al., 1997). This recommendation differs from the levels of 0.99-4.1 mg/dL (60-250 µM/L) recommended by the British Medical Research Council Working Party on PKU (Cockburn et al., 1993). The need for dietary control prior to conception is particularly important because the rate of unplanned pregnancies among women with PKU is similar to that of the general population in the United States. However, the negative impact on the offspring is significantly greater for the mother who has PKU. Waisbren et al. (1995) indicated that more than 60% of women with PKU who became pregnant did so unintentionally. Thus, dietary management beyond childhood is of critical importance in order to protect the fetus from negative outcomes.

It is not always possible to identify women at risk for bearing an infant affected with PKU. Handley et al. (1999) recommended that physicians and nurse midwives consider a protocol of selective prenatal screening or case finding to detect undiagnosed phenylketonuria among their patients. Women who were born before mandatory testings was required in their locality, who were identified by newborn screening and subsequently lost to follow-up, and women with PKU who have an IQ within the reference range are at risk for delivering an affected infant. They recommended mandatory prenatal screening for women with a definite or suggestive history of PKU, women whose previous offspring have microcephaly or mental retardation, and women whose intelligence has been measured within the retarded or borderline range. Prenatal PKU screening should be considered for women born before neonatal screening was introduced to their country or jurisdiction, or who had an uncertain screening result. Screening should also be considered for women whose previous offspring had congenital heart disease.

Several factors, including age, socioeconomic status, and support group, affect maternal adherence to dietary regimens. Women with lower mental functioning are less likely to adhere to their dietary regimen than are women who function at a higher intellectual level. For individuals who are not in dietary control it generally requires 7-14 days to reduce the PHE levels below 300 µM/L (Brenton and Lilburn, 1996). Once that level has been achieved, it is safe to stop contraceptive measures. However, in the dietary management of PKU it is important not to rely on mean values, which are a mixture of high and low results. Instead, the individual readings should be recorded and plotted. Unfortunately, women who are not in dietary control at the onset of pregnancy are at higher risk for having damaged offspring. This is due, in part, because the highest PHE level occurs in the first trimester. However, the first trimester is also a time at which dietary tolerance is at its lowest, and nausea and vomiting are most frequent. Pregnancy in the woman with PKU is a stressful experience (Brenton and Lilburn, 1996). Because many women with PKU have difficulty coping with the dietary regimen, St. James et al. (1999) used resource mothers, who are individuals with PKU specially trained on issues of confidentiality, PKU, maternal PKU, dietary treatment, cooking with low protein products, and home visitation. The resource mothers met with pregnant women and provided them with a source of support and encouragement. The time required to attain metabolic control among this group of women was decreased from 16 weeks to 8 weeks. However, only 32% of the women in the resource group were in metabolic control, and the time to attain control varied from 0-34 weeks compared to 0-40 weeks in the control group. Nevertheless, children of women in the intervention group had larger head circumferences and higher developmental quotients at 6-12 months. (St. James et al., 1999).

In order to attain better dietary adherence among women of child-bearing age with PKU, Cartier et al. (1982) proposed the use of a register as a resource to improve the recall of all individuals with PKU and hyperphenylalaninemia subjects at the time of puberty regardless of their prior history of dietary control. Facts concerning the risk to the offspring of women with PKU who are not under dietary control are explained prior to their 12 ^th birthday and again at the time of the 12 ^th birthday. The use of the registry reduces the risk of losing affected individuals to follow-up.

The impact of mild maternal hyperphenylalaninemia (MHP) is the subject of controversy. Farquhar et al. (1987) reported on the fetal outcomes of two women, one with hyperphenylalaninemia and an IQ of 87, the other with classical PKU and an IQ of 77. Both women had difficulty regulating their diet as out-patients and required a period of hospitalization with intensive dietary interaction. This intervention resulted in a lowering of PHE to less than 600 mg/dL. The women were able to maintain their pre-conceptual diet and delivered infants without evidence of microcephaly, congenital heart disease, or low birth weight. Levy et al. (1994) studied two sisters with MHP and identical biochemical phenotype and PAH genotype. The offspring from the two untreated pregnancies in the older sister are normal and seem to be progressing as well as the offspring from the treated pregnancy in the younger sister. However, it is possible the MHP may produce cognitive deficits that may not become apparent until the adolescent or adult years. Levy et al. (1994) postulated that if most cases of MHP and maternal MHP are benign, the effort and expense required to treat these individuals with diet are unnecessary. However, if MHP and maternal MHP are not benign and are similar to classical PKU and maternal PKU, dietary treatment may be required.

Effects PKU on fetal development

The fetus is at significant risk for serious consequences from maternal PKU as a result of elevated PHE levels during pregnancy that have about 50% greater concentration in the fetal circulation than in the mother's blood. Unfortunately, few women begin treatment before conception and maintain metabolic control during pregnancy (Waisbren, 1999). Even in treated pregnancies, developmental and neuropsychosocial factors also contribute to the outcomes of infants born to women with PKU (Waisbren, 1999). Most of the observed adverse consequences originate in the first trimester, since development of most organ systems is largely completed by the end of the first twelve weeks of gestation. However, the detrimental effects of hyperphenylalaninemia are not restricted to any specific time during pregnancy but may occur throughout gestation, resulting in microcephaly (Fisch et al., 1986). Increased permeability of the blood brain barrier is thought to be related to the higher incidence of mental deficiency. An international survey of untreated maternal PKU pregnancies documented a 92% risk of mental deficiency, 73% risk of microcephaly, 40% risk of low birth, and 12% risk of congenital heart disease in the offspring (Lenke and Levy, 1980). The same study also indicated that women with maternal PKU who are in poor control prior to conception and in the first eight weeks of pregnancy also have an increased risk for spontaneous miscarriage (24%) and intrauterine growth retardation.

The relationship of increasing levels of PHE and abnormalities in the offspring is striking. For instance, the incidence of microcephaly in the normal population is 2.7% (Nelson and Ellenberg, 1979). This compares to an increasing incidence of microcephaly with progressive increases of phenylalanine levels: PHE 3-10 mg/dL, 24% incidence; 11-15 mg/dL, 35%; 16-19 mg/dL, 68%; and > 20 mg/dL, 73%. A similar risk exists for the incidence of congenital heart disease: PHE <10 mg/dL, 0%; 11-15 mg/dL, 6%; 16-19 mg/dL, 15%; and > 20mg/dL, 12% (Lenke and Levy, 1980).

Congenital abnormalities associated with maternal PKU primarily involve the heart, particularly if the woman is not in metabolic control prenatally and during the first eight weeks of gestation (Koch et al., 1999). Virtually no offspring acquire congenital heart disease if the PHE levels are in acceptable levels during the first eight weeks of gestation. However, current research suggests that improved intakes of protein, vitamin B12, and folate may decrease the risk of congenital heart disease even in the presence of elevated blood PHE concentrations (Matalon et al., 1999).

Maternal IQ is affected by the timing of the mother's own treatment for PKU during infancy and her degree of metabolic control during childhood, while offspring IQ is related to the toxic effects of maternal PKU on the fetus (Waisbren, 1999). The mother's mental status is an important factor in determining the potential risk to the offspring of women with maternal PKU. The better the metabolic control, the closer the infant IQ is likely to correlate with the maternal IQ score (Dobson et al., 1986)

Acosta and Wright (1992) emphasized the importance of the nurses' role in preventing birth defects in the offspring of women with PKU. They suggested that nurses have an important role in the management of women of childbearing age with PKU. Nurses should be involved in locating at risk women of childbearing age, counseling these women, and discussing options with couples. They should participate in developing ways to improve adherence to a PHE restricted diet and establishing ongoing monitoring and support systems for mother and child. As previously mentioned, women functioning at a low mental level without support groups are less likely to maintain dietary control, so their offspring are at greater risk. In addition, a group at high risk for lack of adherence and resulting adverse consequences for the offspring are adolescent females. These women are at greater risk of not being in compliance by the 8 ^th week of gestation. Therefore, their offspring would be at risk for being among the 12% of infants with congenital heart disease, where offspring of women who are in dietary control by eight weeks are unlikely to develop congenital heart disease.

Breastfeeding and PKU

The American Academy of Pediatrics (1997) endorsed breastfeeding as the preferred method of infant feeding and recommends that women at least partially breast feed infants for the first year of life. As with all women the decision of a woman with PKU to breastfeed her infant is a personal decision. However, the infant's physician and members of the women's social network can provide positive support for the initiation and continuation of breastfeeding. Mature breast milk has a mean PHE content of 40.4 mg/dL (range 24.3-57.8) compared to a mean value in cow's milk of 185 mg/dL (range 150-220). This is a ratio of 1:4.5. An infant formula based on cow milk would provide much more PHE than human milk. Although the much greater intake of PHE would occur among formula fed infants for only a few months, it would be at an important period of brain growth when the development of synapses and myelination would be taking place (Primrose, 1983). Hinrichs et al. (1994) evaluated 5 infants with PKU who were primarily breastfed and compared them with 5 infants with PKU who received infant formula as their primary PHE source. No significant differences were observed between both groups for weight gain, daily PHE intake and mean PHE concentrations.

A retrospective study compared IQ score of 26 school age PKU children who were either breastfed or formula fed for 20-40 days prior to dietary intervention. The results indicated that the children who had been breastfed as infants scored significantly better on IQ tests (IQ advantage of 14.0 points, p< 0.01) than children who had been formula fed. The advantage persisted after adjusting for social and maternal education status. The authors suggested that breastfeeding in the prediagnostic stage may help infants and children with PKU to improve neurodevelopmental performance (Riva et al., 1996).

McCabe et al. (1989) found no significant differences between breastfed and formula fed infants for several factors including serum PHE, serum tyrosine, weight, head circumference and total calorie intake. Breastfed infants had a lower PHE intake at 2, 4, 5, and 6 months of age. Breast fed infants also had lower protein intake at 1, 2, 3, 4, 5, and 6 months of age. Thus they concluded that breastfeeding could be continued in newly diagnosed PKU infants without apparent adverse nutritional consequences. Moreover, McCabe and McCabe (1986) suggested that human milk may be superior to formula or cow's milk because of the emotional support it provides the mother during the difficult period of initial diagnosis and management. In addition, the bioavailability of trace metals in human milk may protect infants from subtle abnormalities attributable to these nutritional deficits.

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Table 1. Summary of IQ Outcome Studies of Individuals with PKU

Abstract #	Sample Size	Country	Length of Follow-Up (years)	Relationship with Diet Initiation?	Relationship with Diet Discontinuation?	Relationship with Phe Levels?	IQ Deficient?	Controls
100	25	Norway	Yes	10-16			Yes	No
104	27	France		11 & up	Yes	No	Yes	Yes
179	23	Scandinavia		8-18	Yes – if Phe low		No	No
298		North America		12	No	Yes	Yes	Yes
299	95	North America	Yes	12	No	Yes	No	Yes
400	192	United Kingdom		18		Yes	Yes	No
720	27	North America				Yes	Yes	Yes
757	89	Germany		4,5,9		Yes	Yes	Yes
797	123	Poland		3-7			No	No
802	560	Poland		Inf-adult	No	Yes	Yes if control poor	No
856	58	Czech.		15		Yes	Yes if control poor	No
9169	49	North America	Yes	1-16	No	Yes	No	No
967	77			14-49			No	No
1039	42	Turkey				No	No (in 14/18 case)	No
1040	82		No	4		Yes	Yes	No
1216	16	North America		9			Yes if control poor	Yes
1558	15						Yes.	Yes
1559	19	North America		4-13	No	Yes	No change if diet discontinued	No
2136	119		No	10		Yes	Yes	Yes
2578	81	United Kingdom, Poland		8		Yes	Yes	Yes
2590	43	North America	Yes	Adult	No	Yes	Yes (if discontinued)	No
2592	115	North America		6,8	No	Yes	Yes (if discontinued)	No
2591	55	North America		8	No	Yes	Yes (if Phe )	Yes
2859	46		Yes		No	Yes	Yes (if untreated)	No
3465	119	North America	Yes				Yes (if treatment delayed)	No
3736	34		No	4-15		Yes	No	No
3737	57		No	Adult		Yes	Yes	No
3745							IQ fluctuated with dietary control	No
3917	41			Sch.age			Yes if Phe	No
4150	60	Austria		6-16			Yes	No
4170	19			Adult	No	Yes	No	Yes
4174	51	Germany		Adult		Yes	Yes	Yes
4202	160	Hungary		Sch.age			No	No
4219	25	Germany	Yes	Sch.age			No	No
4247	14	North America	No	Sch.age	No	Yes	Yes	No
4358	69	Netherlands		6			No	No
4363	808	Netherlands	Yes			Yes	Yes	No
4370	599	United Kingdom	Yes	4-14		Yes	Yes	No
9758		North America					No	Yes
9796	25		No	10-22		No	Yes
4640	25	Germany		14		Yes	Yes	No
4720	20			9		Yes	Yes	No
4882	91			Adults	No	Yes	Yes	No
4941	41			Adults		Yes	Yes	No
4976	34			Adol.		Yes	Yes	No
4979	20			10		Yes	No	Yes
4984				4	No	Yes	Yes	No
5220	81	Czech.	Yes	15-19		Yes	No	No

Table 1 Bibliography

Abstract # and Citation

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104. Abadie V, Rey F, Plainguet F, Rey J. [Intellectual development after relaxing the diet at the age of 5 years in typical phenylketonuria]. Arch Fr Pediatr 1992 Nov;49(9):773-8. (Fre).

179. Alm J, Bodegard G, Larsson A, Nyberg G, Zetterstrom R. Children with inborn errors of phenylalanine metabolism: prognosis and phenylalanine tolerance. Acta Paediatr Scand 1986 Jul;75(4):619-25.

298. Azen C, Koch R, Friedman E, Wenz E, Fishler K. Summary of findings from the United States Collaborative Study of children treated for phenylketonuria. Eur J Pediatr 1996 Jul;155 Suppl 1:S29-32.

299. Azen CG, Koch R, Friedman EG, Berlow S, Coldwell J, Krause W, Matalon R, McCabe E, O'Flynn M, Peterson R, et al. Intellectual development in 12-year-old children treated for phenylketonuria [see comments]. Am J Dis Child 1991 Jan;145(1):35-9. Comment in: Am J Dis Child 1991 Jan;145(1):33.

400. Beasley MG, Costello PM, Smith I. Outcome of treatment in young adults with phenylketonuria detected by routine neonatal screening between 1964 and 1971. Q J Med 1994 Mar;87(3):155-60.

720. Brunner RL, Jordan MK, Berry HK. Early-treated phenylketonuria: neuropsychologic consequences. J Pediatr 1983 Jun;102(6):831-5.

757. Burgard P, Schmidt E, Rupp A, Schneider W, Bremer HJ. Intellectual development of the patients of the German Collaborative Study of children treated for phenylketonuria. Eur J Pediatr 1996 Jul;155 Suppl 1:S33-8

797. Cabalska B, Duczynska N, Nowaczewska I, Bozkowa K. Hyperphenylalaninemia in Polish children's population. Acta Anthropogenet 1985;9(1-3):91-102.

802. Cabalska MB, Nowaczewska I, Sendecka E, Zorska K. Longitudinal study on early diagnosis and treatment of phenylketonuria in Poland. Eur J Pediatr 1996 Jul;155 Suppl 1:S53-5.

856. Cechak P, Hejcmanova L, Rupp A. Long-term follow-up of patients treated for phenylketonuria (PKU). Results from the Prague PKU Center. Eur J Pediatr 1996 Jul;155 Suppl 1:S59-63.

9169. Chang Pi-nian, Cook RDennis, Fisch Robert O. Prognostic factors of the intellectual outcome of phenylketonurics: On and off diet. J of Psychiatric Treatment & Evaluation 1983;Vol 5(2-3):157-163.

967. Cleary MA, Walter JH, Wraith JE, Jenkins JP, Alani SM, Tyler K, Whittle D. Magnetic resonance imaging of the brain in phenylketonuria. Lancet 1994 Jul 9;344(8915):87-90.

1039. Coskun T, Topcu M, Ustundag I, Ozalp I, Renda Y, Ciger A, Nurlu G. Neurophysiological studies of patients with classical phenylketonuria: evaluation of results of IQ scores, EEG and evoked potentials. Turk J Pediatr 1993 Jan-Mar;35(1):1-10.

1040. Costello PM, Beasley MG, Tillotson SL, Smith I. Intelligence in mild atypical phenylketonuria. Eur J Pediatr 1994 Apr;153(4):260-3.

1216. Dennis M, Lockyer L, Lazenby AL, Donnelly RE, Wilkinson M, Schoonheyt W. Intelligence patterns among children with high-functioning autism, phenylketonuria, and childhood head injury. J Autism Dev Disord 1999 Feb;29(1):5-17.

1558. Fisch RO, Chang PN, Sines L, Weisberg S, Bessman SP. Relationship between phenylalanine tolerance and psychological characteristics of phenylketonuric families. Biochem Med 1985 Apr;33(2):236-45.

1559. Fisch RO, Chang PN, Weisberg S, Guldberg P, Guttler F, Tsai MY. Phenylketonuric patients decades after diet. J Inherit Metab Dis 1995;18(3):347-53.

2136. Holtzman NA, Kronmal RA, van Doorninck W, Azen C, Koch R. Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. N Engl J Med 1986 Mar 6;314(10):593-8.

2578. Knoll E, Wehle E, Thalhammer O. [Psychometry and psychological observations in early treated children with phenylketonuria (PKU) during 12 years (author's transl)]. Klin Padiatr 1980 Nov;192(6):599-607. (Ger).

2590. Koch R, Azen C, Friedman EG, Fishler K, Baumann-Frischling C, Lin T. Care of the adult with phenylketonuria. Eur J Pediatr 1996 Jul;155 Suppl 1:S90-2.

2591. Koch R, Azen C, Friedman EG, Williamson ML. Paired comparisons between early treated PKU children and their matched sibling controls on intelligence and school achievement test results at eight years of age. J Inherit Metab Dis 1984;7(2):86-90.

2592. Koch R, Azen CG, Friedman EG, Williamson ML. Preliminary report on the effects of diet discontinuation in PKU. J Pediatr 1982 Jun;100(6):870-5.

2859. Legido A, Tonyes L, Carter D, Schoemaker A, Di George A, Grover WD. Treatment variables and intellectual outcome in children with classic phenylketonuria. A single-center-based study. Clin Pediatr (Phila) 1993 Jul;32(7):417-25.

3465. Netley C, Hanley WB, Rudner HL. Phenylketonuria and its variants: observations on intellectual functioning. Can Med Assoc J 1984 Oct 1;131(7):751-5.

3736. Pietz J, Benninger C, Schmidt H, Scheffner D, Bickel H. Long-term development of intelligence (IQ) and EEG in 34 children with phenylketonuria treated early. Eur J Pediatr 1988 May;147(4):361-7.

3737. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 1998 Oct;157(10):824-30

3745. Pietz J, Schmidt E, Matthis P, Kobialka B, Kutscha A, de Sonneville L. EEGs in phenylketonuria. I: Follow-up to adulthood; II: Short-term diet-related changes in EEGs and cognitive function. Dev Med Child Neurol 1993 Jan;35(1):54-64.

3917. Reber M, Kazak AE, Himmelberg P. Phenylalanine control and family functioning in early-treated phenylketonuria. J Dev Behav Pediatr 1987 Dec;8(6):311-7.

4150. Scheibenreiter S, Tiefenthaler M, Hinteregger V, Strobl W, Muhl A, Ewald A, Schadler M. Austrian report on longitudinal outcome in phenylketonuria. Eur J Pediatr 1996 Jul;155 Suppl 1:S45-9.

4170. Schmidt E, Rupp A, Burgard P, Pietz J, Weglage J, de Sonneville L. Sustained attention in adult phenylketonuria: the influence of the concurrent phenylalanine-blood-level. J Clin Exp Neuropsychol 1994 Oct;16(5):681-8.

4174. Schmidt H, Burgard P, Pietz J, Rupp A. Intelligence and professional career in young adults treated early for phenylketonuria. Eur J Pediatr 1996 Jul;155 Suppl 1:S97-100.

4202. Schuler A, Somogyi C, Toros I, Pataki L, Mete M, Kiss E, Nagy A. A longitudinal study of phenylketonuria based on the data of the Budapest Screening Center. Eur J Pediatr 1996 Jul;155 Suppl 1:S50-2.

4219. Schwarz HP, Pluss C, Triaca H, Schutz B, Kaufmann R, Scherz R, Bachmann C, Zuppinger K. [Disease course in 20 patients with an early diagnosis of phenylketonuria and hyperphenylalaninemia]. Schweiz Med Wochenschr 1988 Jan 23;118(3):94-9. (Ger).

4247. Seashore MR, Friedman E, Novelly RA, Bapat V. Loss of intellectual function in children with phenylketonuria after relaxation of dietary phenylalanine restriction. Pediatrics 1985 Feb;75(2):226-32.

4358. Slijper FM, Huisman J, Hendrikx MM, Kalverboer AF, van der Schot L. [Intellectual development of phenylketonuria children treated early a longitudinal study. 10 years' concomitant psychological study in The Netherlands]. Monatsschr Kinderheilkd 1989 Oct;137(10):662-5. (Ger).

4363. Smijers JJ. [15 years of national screening for phenylketonuria in The Netherlands; 4th report of the National Advisory Commission Phenylketonuria (letter)]. Ned Tijdschr Geneeskd 1991 Apr 27;135(17):776-7. (Dut).

4370. Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991 Mar;66(3):311-6.

9758. Skarin Susan Marne. Sensory mtor integration, school, achievement, and behavior of with phenyldetonuria [dissertation]. University of Southern California; 1981.

9796. Stern Alan Mark. Psychoeducational status in relation to duration and quality of treatment in early and later diagnosed and treated children, adolescents, and young adults. [dissertation]. University of Southern California; 1982.

4640. Theile H, Graustein I, Wasser S, Buhrdel P. [Effect of dietary non-adherence on development in phenylketonuria studies of 14 year old patients]. Padiatr Padol 1990;25(1):19-23. (Ger).

4720. Trefz FK, Batzler U, Konig T, Michel U, Schmidt E, Schmidt H, Bickel H. Significance of the in vivo deuterated phenylalanine load for long term phenylalanine tolerance and psycho-intellectual outcome in individuals with PKU. Eur J Pediatr 1990;149 Suppl 1:S25-7.

4882. Waisbren SE, Schnell R, Levy HL. Intelligence and personality characteristics in adults with untreated atypical phenylketonuria and mild hyperphenylalaninemia. J Pediatr 1984 Dec;105(6):955-8.

4941. Wasser S, Theile H. [The interaction of biological and social factors on the effect of treatment in cases of phenylketonuria (author's transl)]. Padiatr Padol 1981;16(4):417-26. (Ger).

4976. Weglage J, Funders B, Wilken B, Schubert D, Ullrich K. School performance and intellectual outcome in adolescents with phenylketonuria. Acta Paediatr 1993 Jun-Jul;82(6-7):582-6.

4979. Weglage J, Pietsch M, Funders B, Koch HG, Ullrich K. Deficits in selective and sustained attention processes in early treated children with phenylketonuria result of impaired frontal lobe functions? Eur J Pediatr 1996 Mar;155(3):200-4.

4984. Weglage J, Ullrich K, Pietsch M, Funders B, Guttler F, Harms E. Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria. Pediatr Res 1997 Sep;42(3):378-84.

5220. Zeman J, Pijackova A, Behulova J, Urge O, Saligova, Hyanek J. Intellectual and school performance in adolescents with phenylketonuria according to their dietary adherence. The Czech-Slovak Collaborative Study. Eur J Pediatr 1996 Jul;155 Suppl 1:S56-8.

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Table 2. Summary of Achievement, Behavioral and Cognitive Outcomes of Individuals with PKU

Notes: Adol = adolescent; Sch. age = school age; EF = executive functions; Beh. probs. = Behavior Problems; ach.= achievement, attn. = attention; lang. =language; arith. = arithmetic; NL = normal;  = increase; = decrease

Abstract #	Sample Size	Country	Diet Relationships with Initiation?	Length of Followup (years)	Diet Discontinuation?	Relationship with Phe Levels?	Outcome	Controls
262	18	Canada		1-8		Yes	motor, Beh. probs. EF	No
718	16	North America				Yes	spatial, EF	Yes
720	27	North America			No	Yes	ach., EF	Yes
9132	22	North America		13		No	No effects on attn.	Yes
753	60	Germany		13		No	Beh. probs. (Stress)	Yes
755	66	Germany, France			Yes – if mild	Yes	attn. If Phe	Yes
958	9	Canada			No	Yes	attn. Off diet	Within/subj.
1198	22			8	No	Yes	attn., math	Yes
1507							motor, spatial, ach., EF	No
1566	19			Adol-adult			Beh. Probs.	Yes
1584				6-10	No	Yes	arith., lang., perceptual	No
1585				6-10	No	Yes	arith., lang., perceptual	No
1788	14	United States		Sch.age		Yes	interhemispheric transmission	Yes
1825	11	United Kingdom		Sch.age		No	No difference related to Phe supplement	Within/subj.
1826		United Kingdom		Adol-adult	Yes	No	Slight reductions in cognitive skills	No
1827	16	United Kingdom		10-16		No	No diff. related to PHE supplement	Within/subj.
1828				10-13		No	NL cognitive, Beh. Probs, EF	No
2136	119		N	10	No	Yes	ach., Beh. Probs.	Yes
9558	17	North America		Sch.age		No	NL EF	Yes
3737	57		N	adult		Yes	motor	Yes
3738	35			adult		Yes	Beh. probs.	Yes
3739	8					No	No relationship Phe/cognition	No
3916							attn & Beh. Probs.	Within/subj.
4169	103			8-9,adult	No	Yes	attn., arith.	No
4170	19			adult	No	Yes	attn	Yes
4372	544	United Kingdom		8		Yes	Beh. probs.	Yes
9758		North America					spatial, reading	Yes
4481	33						NL EF	Yes
9796	25		N	10-22		No	spatial, ach., spell
4979	20			10		Yes	attn, even if Phe controlled	Yes
9885	11	North America				Yes	EF	Yes
4884	28	North America	Y	adults		No	Beh. probs. if treatment late
4972	58	Germany		10			Beh NL
4975	34		Y				Beh. probs.
4981	58	Germany		10			Beh NL
5006	11	North America	Y			Yes	EF	Yes
4878	50		Y	adult	No		Beh. probs.	Yes

Table 2 Bibliography

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4372. Smith I, Beasley MG, Wolff OH, Ades AE. Behavior disturbance in 8-year-old children with early treated phenylketonuria. Report from the MRC/ DHSS Phenylketonuria Register. J Pediatr 1988 Mar;112(3):403-8.

9758. Skarin Susan Marne. Sensory mtor integration, school, achievement, and behavior of with phenyldetonuria [dissertation]. University of Southern California; 1981.

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9796. Stern Alan Mark. Psychoeducational status in relation to duration and quality of treatment in early and later diagnosed and treated children, adolescents, and young adults. [dissertation]. University of Southern California; 1982.

4878. Waisbren SE, Levy HL. Agoraphobia in phenylketonuria. J Inherit Metab Dis 1991;14(5):755-64.

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4975. Weglage J, Funders B, Wilken B, Schubert D, Schmidt E, Burgard P, Ullrich K. Psychological and social findings in adolescents with phenylketonuria. Eur J Pediatr 1992 Jul;151(7):522-5.

4979. Weglage J, Pietsch M, Funders B, Koch HG, Ullrich K. Deficits in selective and sustained attention processes in early treated children with phenylketonuria result of impaired frontal lobe functions? Eur J Pediatr 1996 Mar;155(3):200-4.

4981. Weglage J, Rupp A, Schmidt E. Personality characteristics in patients with phenylketonuria treated early. Pediatr Res 1994 May;35(5):611-3.

5006. Welsh MC, Pennington BF, Ozonoff S, Rouse B, McCabe ER. Neuropsychology of early-treated phenylketonuria: specific executive function deficits. Child Dev 1990 Dec;61(6):1697-713.

9885. Welsh Marilyn C, Pennington Bruce F, Ozonoff Sally, Rouse Bobbye, et al. Neuropsychology of early-treated phenylketonuria: Specific executive function deficits. Annual Progress in Child Psychiatry & Child Development 1991;466-491.

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