Management
Guidelines
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PKU Nutrition Management Guidelines
First Edition
March 2015, v.1.12
Updated: August 2016
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Nutrition Recommendations
Question
1. For individuals with PKU what nutrient intakes are associated with positive outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Because individuals with PKU are unable to convert excess PHE to TYR, daily intact protein intake must be limited to only the amount that provides the PHE required for anabolism. PHE-restricted medical foods provide amino acids to meet the remaining protein and energy recommendations, and supplemental TYR. Most medical food products provide vitamins, minerals, carbohydrates and fats that would ordinarily be consumed in foods that are restricted for individuals with PKU. When free amino acids provide the bulk of protein equivalents, the recommendation for protein intake is increased. The Daily Recommended Intake (DRI) for nutrients other than total protein, PHE and TYR are not increased over that recommended for the healthy, general population. Either poor adherence to dietary and medical food recommendations, or reliance on an incomplete medical food can place the individual with PKU at risk for nutrient deficiencies. There is not sufficient evidence at this time to alter recommendations for energy or vitamin D and calcium for individuals with PKU.

Recommendation 1.1

Meet the individual’s recommended PHE intake (for anabolism and maintaining an appropriate blood PHE concentration) by adjusting intact protein intake. See TABLE #3, Recommended Intakes of PHE, TYR and Protein for PKU for recommended intake ranges by age.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 1.1.1  Link to Topic 1.1.1
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Evidence

PHE is an essential amino acid and must be provided from exogenous (dietary) sources. Because individuals with PKU cannot catabolize excess PHE, intake must be limited to the amount needed for anabolism. A recent study of 5 Canadian children (mean age 10.5 years) with classical PKU, indicated that mean PHE requirement was 14.2 mg PHE/kg/day as measured by C13O2 from labeled lysine (F.1278). The authors concluded that the PHE allowance for these children should not exceed 20 mg/kg/day (F.1278). In infancy, the PHE allowance (derived from intact protein) may be met with measured amounts of either breast milk or regular infant formula (F.2627, F.1172). Recommendations for PHE intake for the preterm infant with PKU is higher than for full term (G.102) and described in case studies (G.96). In older infants, children, and adults, these sources are replaced by solid foods containing an equivalent amount of PHE (F.2627, F.1172). In a recent study of 174 Dutch children with PKU, intact protein intake was shown to be positively associated with head circumference (F.1234). These authors suggest that the amino acid profile of an intact protein may be as important as its PHE content (F.1234). An individual’s PHE tolerance, defined as dietary PHE that can be consumed while maintaining blood PHE in the treatment range, can reliably be assessed by age 2-5 years (F.2627). It is influenced by many factors including genotype, age and gender, growth rate, illness, medical food and energy intake, pregnancy, and concurrent  tetrahydrobiopterin (BH4) supplementation (F.2626, F.2627, F.1172, F.1278). Recommended ranges for PHE intake by age are shown in TABLE #3, Recommended Intakes of PHE, TYR and Protein for PKU. Further discussion of this topic can be found in the evidence sections for Questions 4 and 6.

Consensus based on clinical practice

In the Delphi 1 survey, 100% of RD and MD respondents supported using breast milk as the PHE (intact protein) source in infants.

Recommendation 1.2

Provide a total protein intake (from a combination of intact protein and amino acid-based medical food) approximately 50% higher than the DRI for infants and children from birth to 4 years of age ( TABLE #5, Comparison of Recommendations for Dietary Protein Intake for Infants and Children under 4 Years of Age to the 2015 GMDI/SERC Guideline Recommendation) and 20-40% higher than the DRI for those over 4 years of age ( TABLE #3, Recommended Intakes of PHE, TYR and Protein for PKU). The amount of medical food prescribed is based on the difference between the total protein recommendation and the intact protein allowance.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

On average, amino acid-based medical food is prescribed to provide 75-85 % of the total protein equivalents in individuals with classical PKU (F.2627, F.2629, F.1344). Based on reviews of evidence, both Dutch (F.1172) and US healthcare providers (F.2627) recommend that, with adequate energy intake, total protein intake be 20- 40% higher than the Daily Recommended Intake, or DRI, (Y.12) for the general population. This increased allowance takes into account rapid absorption and oxidation of free amino acids (F.2627, G.105) in the medical food, and lower digestibility of fruits and vegetables that are the main source of intact protein after infancy (F.1172). A widely referenced resource, used in the US, suggests PRO intake for infants with PKU (0-3 mo of age) should be 233% of the DRI when consuming amino acid-based medical foods (G.102). A recent presentation summarized international data on PRO recommendations for this population and suggested 120-140% of the DRI, or greater, was appropriate for infants (G.105). This guideline uses a conservative approach for infants and children between birth and four years of age based on multiple sources shown in TABLE #5, Comparison of Recommendations for Dietary Protein Intake for Infants and Children under 4 Years of Age to the 2015 GMDI/SERC Guideline Recommendation. In a 12 month study of 58 children with PKU (2-12 years of age), whose protein intake was prescribed at 117-123% of the DRI, normal linear growth was documented (F.1344). When protein intake resulted in prealbumin levels < 20 mg/dL, decreased linear growth was seen in children with PKU (F.1234). In a recent study, 19 older adults with PKU (F.1408), all of whom were obtaining the majority of total recommended protein intake from highly fortified medical foods, exceeded recommended intake of folate, iron and vitamin B12. However, the amount of medical food prescribed in relation to ideal body weight was not given. Recommendations for PRO intake should be based on ideal rather than actual body weight, and should be guided by growth and monitoring of PRO status (G.91, G.105).

Consensus based on clinical practice

Delphi I respondents disagreed that PRO intake recommendations should be at the DRI for the general population. They strongly agreed that PRO recommendations should be based on adjusted weight for overweight and obese individuals (91% RD and 100% MD respondents) and on ideal weight for those underweight (82% RD and 83% MD respondents).

In Delphi 2, 100% of RD respondents supported the recommendation to provide 120-140% of the DRI for protein to individuals with PKU. Of the MDs surveyed, 67% were either neutral or disagreed with this recommendation, but offered no comments to explain their opinion. 62% of all respondents agreed the recommended total PRO intake should be higher when the amino acid-based medical food to total PRO ratio is increased. 100% of respondents considered growth and PRO status in determining recommended PRO intake.

Recommendation 1.3

Provide supplemental TYR if blood TYR concentrations are consistently below the normal range.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

TYR becomes a conditionally essential amino acid when PHE intake is restricted (F.2627), therefore PHE-restricted medical foods are generally supplemented with TYR. See TABLE #6, Classification of Medical Foods for PKU for classification and characteristics of medical foods for PKU. TYR has a low solubility and may settle out of prepared medical food on storage (F.2627, F.1172), which can compromise intake. Also, individuals who are not adherent with total recommended medical food consumption may have an inadequate intake of TYR (F.2627, F.1172). A Cochrane review concluded there is insufficient evidence to establish a TYR recommendation for individuals with PKU (F.1159). Presently, recommendations for intake are based on maintaining blood TYR in the normal range (F.1225, F.2627). It should be noted that assessment of adequate intake through monitoring of blood TYR is difficult because a large diurnal variation exists throughout any 24 hour period (F.2627, F.1225). A guide to TYR requirements has been suggested for infants <12 mos of age, but states that if blood concentrations are not in the appropriate range, then supplemental TYR should be added to medical food or mixed into solids (G.102).

Consensus based on clinical practice

The two Delphi surveys did not elicit a specific recommended intake for TYR, but respondents strongly agreed blood TYR concentrations should be maintained in the normal range for the general population.

In Delphi 2, 86% of respondents agreed that when blood TYR concentrations are less than 30 µmol/L, a subsequent test should be done to determine if results are affected by a diurnal variation in blood TYR. Comments suggested that when blood TYR is low, medical food intake should be evaluated to determine if the individual is mixing medical food correctly and consuming the total amount prescribed.

Recommendation 1.4

With the exception of recommended intake for protein, PHE and TYR, individuals with PKU should meet the same DRI for age- and gender-specific nutrient/micronutrients and energy as healthy individuals in the general population

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
Topic 1.4.1  Link to Topic 1.4.1
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Evidence

The evidence for increased prevalence of overweight/obesity in individuals with PKU is mixed (F.2627, F.2629, F.1172, F.1475, F.1476). When consuming incomplete medical foods that have a very high PRO:Kcal ratio, or are carbohydrate- or fat- free, adequate caloric intake must be provided from the rest of the diet. In some individuals, very low fat intake that may result in essential fatty acid deficiency has been observed (F.2627). Adequate energy intake has a protein sparing effect. At the same time, because fats and sugars are considered “free” foods (containing negligible PHE) they may also be over-consumed. At this time, energy recommendations for individuals with PKU remain the same as those for the general population (F.2627).

Consensus based on clinical practice

In Delphi 2, 71% of all respondents agreed that the DRI for energy should be sufficient for individuals with PKU who are consuming appropriate medical food.

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Evidence

Most evidence comes from studies comparing individuals who are not adherent to medical food and other dietary intake recommendations, with those who are. In addition, the composition of medical foods has continued to evolve as human nutrient requirements for the general population have been established and nutrient deficiencies have been observed in individuals on restricted diets (F.2626, F.2627). The evidence suggests that individuals who consume "complete" PHE-free medical foods and are adherent to their daily consumption recommendation, are not at risk for nutrient deficiencies or excesses (F.2626, F.2627). Studies reporting supplementation of individuals with PKU with DHA, long chain polyunsaturated fatty acids (LCPUFA) (F.2627, F.2629, F.2336, F.1007, F.904, F.1345, F.1348, F.2200, F.2228) and selenium (F.2627, F.1172, F.1475, F.1408) have led to inclusion of these nutrients in many medical foods available in the US (see TABLE #6, Classification of Medical Foods for PKU for a classification and characterization of medical foods). LCPUFA sources for individuals who are deficient may be provided by fish oil (G.87) to supplement both omega-3 and -6 essential fatty acids. Lower bioavailability of some minerals (e.g. zinc) that are added to medical foods, as compared to their bioavailability in natural food sources, may increase the amount of supplementation recommended to meet the needs of individuals on a PHE-restricted diet (F.1172). There is some evidence there may be abnormalities in bone metabolism in individuals with PKU that are not directly correlated with vitamin D or calcium intake (F.2627, F.1172).

Consensus based on clinical practice

In Delphi 1, there was strong agreement (91% RD and 100% MD respondents) that supplemental vitamins and minerals should be considered when individuals are consuming an incomplete medical food. Comments include statements that clinical and laboratory monitoring may reveal the need for specific supplementation in some individuals, especially if they are not adherent to dietary recommendations (including adequate medical food intake).

There was also strong agreement (100% RD and 83% MD respondents) that adequate LCPUFA intake is important. If infant formula is used, it should contain DHA/ARA and the diet of pregnant women should be supplemented with 200-300 mg/day (82% RD and 80% MD respondents). Other individuals with PKU require supplementation only when indicated by laboratory monitoring (100% RD and 80% MD respondents).

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