March 2015, v.1.10
Current version: v.2.5
Updated: April 2015
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- Overview
- Methodology
- Background
- Biochemical Pathway and Nutrition Treatment Rationale
- Nutrition Assessment
- Comparative Standards
- Nutrition Problem Identification
- Nutrition Intervention
- Nutrition Recommendations
- 1. Nutrition intervention for appropriate nutrient intake
- 2. Nutrition intervention to achieve appropriate blood PHE concentration
- 3. Strategies for nutrition intervention
- 4. Monitoring nutrition intervention
- 5. Nutrition intervention with alternative or adjunctive therapies
- 6. Nutrition intervention before, during and after pregnancy
- Monitoring and Evaluation
- Resources
- Benefits and Harms of Implementing the Recommendations
- Barriers to Implementation
- Areas for Future Research
- List of Tables
-
Literature Evidence Summary Tables
- T.1 Laboratory and Clinical Findings in PKU
- T.2 Classification of PKU
- T.3 Recommended intakes of PHE, TYR and Protein for PKU
- T.4 Nutrition Problem Identification for PKU
- T.5 Comparison of Recommendations for Dietary Protein Intake for Infants and Children under 4 Years of Age to the 2015 GMDI/SERC Guideline Recommendation
- T.6 Classification of Medical Foods for PKU
- T.7 Recommendations for Nutrient Intake and Sources in the Dietary Treatment of PKU
- T.8 Monitoring Nutritional Management of PKU
- T.9 Recommendations for Neurocognitive Testing in PKU
- References
- Contributors
- Appendix A: Recommendation Rating Definitions
- Appendix B: Terms
- Disclaimer
Laboratory Test or Clinical Symptoms1 | Newborn (Pre-treatment) | Untreated or Suboptimal Control2 | Treated (Lifetime Good Control)3 |
MS/MS NBS on blood spot | ↑ to ↑↑PHE, (flagged high if PHE >130 μmol/L)4 | n/a | n/a |
Blood PHE | ↑ to ↑↑ | ↑ to ↑↑ | slightly ↑ |
Blood TYR | normal or slightly ↓ | ↓ | normal or low normal |
PHE:TYR ratio | ↑ (>3)4 | >65 | <65 |
Microcephaly | − | +/− | − |
Musty body odor | +/− | +/− | − |
Decreased pigmentation of skin, hair, iris | − | +/− | +/− |
Eczema | − | +/− | − |
Intellectual disability | − | +6 | − |
Executive function deficits | n/a | +/− | - 7 |
Neurologic symptoms (e.g. seizures, tremors) | − | +/− | − |
Behavior problems, attention deficits | − | + | − |
Depression, anxiety, agoraphobia | − | +/− | − |
1 Laboratory and clinical symptoms typically seen in severe or classic PKU
2 Blood PHE > 360 μmol/L
3 Lifetime blood PHE 120-360 μmol/L
4 L.198
5 F.1171
6 Severity of intellectual disability is related to lifetime exposure to elevated blood PHE (L.192)
7 No studies of executive function are reported in patients with lifetime blood PHE <360 μmol/L
Severity of PAH Deficiency | Blood PHE Concentration Pre-treatment | Dietary PHE Tolerance (Intake to Maintain Blood PHE Concentration 120- 360 µmol/L) | PAH Genotype | |
PHE intake (mg/kg/day) | PHE intake (mg/day) | |||
Classical PKU | >1200 μmol/L | <20 | 250-350 | 2 classic mutations (often null) |
Moderate PKU | 900-1200 μmol/L | 20-25 | 350-400 | 1 classic + 1 moderate, or 2 moderate mutations |
Mild PKU | 600-900 μmol/L | 25-50 | 400-600 | 1 classic, moderate, or mild mutation + 1 mild HPA mutation |
Mild HPA | 360-600 μmol/L | >50 | No data | 1 classic, moderate, or mild mutation + 1 mild HPA mutation |
Adapted from Camp et al. (2014), F.2629, Table 2- http://www.sciencedirect.com/science/article/pii/S1096719214000857#
Infants to <4 yr1 | |||
AGE
| PHE (mg/day) | TYR (mg/day) | Protein2 (g/kg/day) |
0 to <3 mo3 | 130-430 | 1100-1300 | 2.5-3.0 |
3 to <6 mo | 135-400 | 1400-2100 | 2.0-3.0 |
6 to <9 mo | 145-370 | 2500-3000 | 2.0-2.5 |
9 to <12 mo | 135-330 | 2500-3000
| 2.0-2.5 |
1 to <4 years4 | 200-320 | 2800-3500 | 1.5-2.1 |
After Early Childhood5 | |||
AGE
| PHE (mg/day) | TYR (mg/day) | Protein2 (g/day) |
>4 yr-adult | 200-1100 | 4000-6000 | 120-140% DRI for age6 |
Pregnancy and Lactation7 | |||
AGE
| PHE (mg/day) | TYR (mg/day) | Protein2 (g/day) |
Trimester 1 | 265-770 | 6000-7600 | >70 |
Trimester 2 | 400-1650 | 6000-7600 | >70 |
Trimester 3 | 700-2275 | 6000-7600 | >70 |
Lactation8 | 700-2275 | 6000-7600 | >70 |
1 Adapted from Acosta (G.102), recommendations for PHE and TYR intake are for infants and children <4 yrs with more severe PKU and treated with PHE-restricted diet alone. TYR intake recommendations may require adjustment based on blood TYR monitoring.
2 Protein recommendations are for individuals consuming medical foods as the major protein source.
3 PHE recommendations for premature infants may be higher.
4 PHE tolerance is usually stablized by 2-5 years of age (F.2627). Recommendations are based on size (increases with age) and growth rate (decreases with age). Individual PHE intake recommendations should be adjusted based on frequent blood PHE monitoring.
5 Adapted from Acosta (G.102). Range of recommended PHE intake applies to spectrum of PKU severity (mild to severe).
6 Recommended protein intake greater than the DRI is necessary to support normal growth in PKU.
7 Recommendations are slightly higher for pregnant women ≤19 years of age.
8 Recommended nutrient intake during lactation is same as for third trimester of pregnancy for all women.
Nutrition Diagnosis (Problem) | Related to (Etiology) | As Evidenced By (Signs and Symptoms) |
Based on assessment findings, specify the current nutrition-related problem(s) to be addressed through nutrition management. | Identify the most pertinent underlying cause(s) or contributing risk factors for the specific problem.The etiology is commonly the target of nutrition intervention. | List subjective and objective data that characterize the specific problem and are also used to monitor nutrition intervention and outcomes. |
Examples of specific nutrition problems: | Examples of underlying causes of the problem: | Examples of data used to determine and monitor the problem: |
Intake Domain Excessive protein intake Intake of types of protein or amino acids inconsistent with needs (specify) Predicted excessive energy intake Predicted suboptimal energy intake Excessive fat intake Inadequate fat intake Excessive enteral nutrition infusion Inadequate enteral nutrition infusion Enteral nutrition composition inconsistent with needs Clinical Domain Impaired nutrient utilization Altered nutrition-related lab values Food-medication interaction (specify) Growth rate below expected Underweight Overweight/obesity Behavioral-Environmental Domain Food and nutrition-related knowledge deficit Limited adherence to nutrition-related recommendations Limited access to food | Consumption Factors Lack of medical food consumption Suboptimal medical food consumption Excessive intake of (specify food or beverage) Provider Factors Nutrition prescription no longer meets protein needs Nutrition prescription no longer meets energy needs Introduction of adjunctive therapy Underlying Disease Factors New diagnosis of PKU Protein/PHE restriction necessary for PKU treatment Acute illness or infection Poor appetite due to (specify) Patient/Caretaker Knowledge and Behavior Factors Food choices suboptimal Lack of knowledge Limited adherence to dietary therapy recommendations Presentation to clinic for initial nutrition education Off diet Access Factors Lack of financial resources for medical food Inadequate insurance or denial of coverage for special metabolic formulas Lack of access to resources or care | From Biochemical Tests Laboratory value compared to norm or goal (specify) (e.g. plasma PHE of 700 umol/L) Elevated amino acids (specify) From Anthropometrics Growth pattern, weight, weight-for-height or BMI compared to standards (specify) Weight gain/loss (specify weight change) over the past (specify time frame) From Clinical/Medical Exam or History New diagnosis of PKU New or adjusted prescription for adjunctive therapy EFA deficiency (physical sign or lab value) From Diet History Estimated or calculated intake from diet record or dietary recall, compared to recommendation or dietary prescription (specify) From Patient Report Verbalized lack of skill or understanding to implement nutrition prescription Denial of medical food coverage by insurance company Lack of social or familial support |
Table content is based on Nutrition Care Process (NCP) terminology developed by the Academy of Nutrition and Dietetics. NCP uses the following structure for documenting nutrition problems: nutrition diagnosis (Problem), related to (Etiology), and as evidenced by (Signs and Symptoms). Examples listed identify concerns particular to PKU and are grouped in domains of: Intake, Clinical, and Behavioral-Environmental. Problems identified may relate to any Etiology and be evidenced by any Signs and Symptoms within a domain.
Age | Dewey1 | WHO/FAO/UNU2 | DRI3 | 120-140% of | Ross Protocol4 | GMDI/SERC Guideline |
General population | Individuals with PKU | |||||
grams protein per kg ideal body weight | ||||||
0 to <3 mo | 1.5-2.7 | 1.3 | 1.5 | 1.8-2.1 | 3-3.5 | 2.5-3 |
3 to <6 mo | 1.2-1.4 | 1.3 | 1.5 | 1.8-2.1 | 3-3.5 | 2.0-3 |
6 to <12 mo | 1.0-1.1 | 1.1 | 1.5 | 1.8-2.1 | 2.5-3 | 2.0-2.5 |
1 to <4 yr | 1.1 | 0.9-1.1 | 1.1 | 1.3-1.5 | 2.1 | 1.5-2.1 |
1 L.199
2 World Health Organization (WHO), Food and Agriculture Organization of the United Nations (FAO), United Nations University (UNU) 2007.
3 Derived from RDA for protein.
4 Nutrition Support Protocols, 4th edition (G.102)
Classification | Complete | No Added Fat | Amino Acids | Glycomacropeptide | Large Neutral Amino Acids |
Nutrient Profile | Amino acids, carbohydrates, fats, vitamins and minerals | Amino acids, carbohydrates, vitamins and minerals | No carbohydrates or fats; few or no vitamins and minerals | Modified whey protein with limited PHE; supplemented with HIS, LEU, TYR, TRP, ARG, variable carbohydrates, fats, vitamins and minerals | Variable carbohydrates, fats, vitamins, and minerals |
Protein:energy ratio (PRO g/100 Kcal)1 | Low to medium | Medium to high | High | Variable | Variable |
Forms | Powder, ready-to-drink | Powder, ready-to-drink, gel | Powder, capsules, tablets, bars | Powder, ready-to-drink, bars, pudding | Powder, tablets |
Products designed for infants2 | Periflex Infant5 Phenex-16 Phenyl-Free 17 | None | None | None | None |
Products designed for children3 | Camino Pro AA8 Milupa PKU 25 Periflex Advance5 Periflex Jr Plus5 Periflex Junior5 Periflex LQ5 Phenex-26 PhenylAde5 PhenylAde Essential5 Phenyl-Free 27 Phenyl-Free 2HP7 | Lophlex LQ5 PhenylAde RTD5 PhenylAde 405 PhenylAde 605 Phlexy-10 system5 PKU Coolers 109 PKU Coolers 159 PKU Coolers 209 PKU Express 159 PKU Express 209 PKU Gel9 XPhe Maxamaid5 XPhe Maxamum5 | None | Glytactin BetterMilk8,10 Glytactin Complete 10 Bars8 Glytactin Complete 15 Bars8 Glytactin RTD 108 Glytactin RTD 158 Glytactin Restore8 Glytactin Restore Lite8 Glytactin Swirl8,10 | None |
Products designed for adolescents and adults4 | Camino Pro AA8 Milupa PKU 35 Periflex Advance5 Phenex-26 PhenylAde Essential5 Phenyl-Free 27 Phenyl-Free 2HP7 | Lophlex LQ5 Lophlex5 PhenylAde 405 PhenylAde 605 PhenylAde RTD5 Phlexy-10 system5 PKU Coolers 109 PKU Coolers 159 PKU Coolers 209 PKU Express 159 PKU Express 209 XPhe Maxamum5 | PhenylAde Amino Acid Blend MTE5 PhenylAde Amino Acid Blend5 PhenylAde Amino Acid Bars5,11 Phlexy-105 | Glytactin Better Milk8,10 Glytactin Complete 10 Bars8 Glytactin Complete 15 Bars8 Glytactin RTD 108 Glytactin RTD 158 Glytactin Restore8 Glytactin Restore Lite8 Glytactin Swirl8,10 | Lanaflex5 PheBloc5 |
This table contains examples of products available in the United States as of November 2014. Inclusion of any product does not represent endorsement.
1 Protein to energy categories (PRO g/100 Kcal): High 11-25, Medium 5-10, Low <5
2 Suitable for infants and children <1 year of age
3 Products not appropriate for children <1 year of age; check manufacturer's information for nutrient profile
4 Some products may be appropriate for children depending on clinical circumstances, especially if used in combination with other products
5 Nutricia North America
6 Abbott Nutrition
7 Mead Johnson Nutrition
8 Cambrooke Therapeutics
9 Vitaflo USA
10 Also supplemented with MET
11 Contains fat and carbohydrate, but no vitamins or minerals
Nutrient | Recommendation | Source |
PHE | Provide sufficient PHE intake to allow adequate protein synthesis for growth and health maintenance, and to achieve blood PHE concentrations 120-360 µmol/L. PHE tolerance is dependent on residual PAH activity, age, weight, sex, and life stage. | Intact protein In infants: breast milk or infant formula In children and adults: foods such as fruits vegetables and some grains/cereals |
Protein | Provide DRI1 Provide an additional 50% for infants and children 0-4 years, and 20-40% for older children and adults if medical food is the major source of protein. | PHE-free medical food Amino acid-based or GMP protein-based Intact PRO As described above for PHE source |
TYR | Provide DRI1 TYR becomes a conditionally essential amino acid when PHE intake is restricted. | PHE-free medical food Intact PRO Supplemental TYR2 |
KCAL | Provide DRI1 | PHE-free medical food Intact PRO Free foods3 Modified low protein foods4
|
Other Nutrients, Minerals and Vitamins5 | Provide DRI1 | PHE-free medical food Intact protein Supplemental nutrients, vitamins and minerals6
|
1 For age, size, sex, and life stage
2 Tyrosine is added in sufficient amounts to PHE-free medical foods. Low plasma TYR may occur in those individuals: not consuming adequate medical food, consuming medical foods prepared incorrectly with TYR poorly dissolved, or having increased demands as seen in MPKU.
3 Free foods contain no detectable PHE or protein, and consist primarily of sugars, pure starches and fats.
4 Modified low protein specialty foods (e.g. pastas, baked goods) are formulated to replace higher protein grains/flours with protein-free starches.
5 Includes essential fatty acids and DHA, vit D, vit A, Ca, Fe, Zn, and Se.
6 Many PHE-free medical foods are supplemented with nutrients and micronutrients that may be deficient in a PHE restricted diet, and adherence to the full medical food prescription is important to meet these nutrient requirements. Some medical foods (e.g. products modified to improve taste or decrease calories or volume) may have insufficient supplementation of micronutrients, vitamins and minerals.
Domain Measures | Infants (0- <1 yr) | Children (1- <8 yrs) | Children & Adults (8-18 yrs) | Adults
| Planning Pregnancy or Pregnant | Postpartum and Lactation |
Assessment of Clinical Status | ||||||
Nutrition visit in clinic (dietary intake and nutrient analysis1, nutrition-related physical findings, nutrition counseling, diet education) | Weekly to every 3 months | Monthly to every 6 months | Every 6-12 months | Every 6-12 months | Monthly to per trimester | At 6 weeks postpartum, then every 6 months |
Interim nutrition contact (diet adjustment based on blood PHE and TYR, or counseling at clinic or by phone/electronic communication) | Twice weekly to weekly | Weekly to monthly | Weekly to monthly | Monthly | Once to twice weekly | Weekly to monthly |
Anthropometrics2 (weight, length or height, weight for length or BMI, head circumference through 36 months and as indicated) | At every clinic visit | At every clinic visit | At every clinic visit | At every clinic visit | At every clinic visit | At every clinic visit |
Quality of life (QoL)3 | Yearly | |||||
Neurocognitive testing4 | As appropriate for age | |||||
Assessment of Biochemical Status (Routine) | ||||||
PHE (plasma, serum, or whole blood5) | Twice weekly to weekly | Weekly to monthly | Weekly to monthly | Monthly | Once to twice weekly | Monthly |
TYR (plasma, serum, or whole blood)5 | Twice weekly to weekly | Weekly to monthly | Weekly to monthly | Monthly | Twice weekly to weekly | Monthly |
Complete amino acid profile5 | As indicated6 | At every clinic visit | At every clinic visit | At every clinic visit | Weekly to monthly | At every clinic visit |
Transthyretin (prealbumin) | 6-12 months | 6-12 months | 6-12 months | 6-12 months | Monthly to per trimester | |
Albumin or total protein | 6-12 months or as indicated | 6-12 months or as indicated | 6-12 months or as indicated | 6-12 months or as indicated | Per trimester | 6-12 months or as indicated |
Complete blood count | 6-12 months | 6-12 months | 6-12 months | 6-12 months | Per trimester | 6-12 months |
Ferritin | 6-12 months | 6-12 months | 6-12 months | 6-12 months | Per trimester | 6-12 months |
Vitamin D 25-OH | 6-12 months | 6-12 months | 6-12 months | 6-12 months | Per trimester | 6-12 months |
Assessment of Biochemical Status (Conditional)7 | ||||||
Comprehensive metabolic panel, serum vitamin B12, erythrocyte folate, zinc, copper, essential fatty acids | Yearly or as indicated | Yearly or as indicated | Yearly or as indicated | Yearly or as indicated | At first visit and then as indicated | Yearly or as indicated |
Assessment of Bone Density | ||||||
DXA scan (Dual-energy X-ray absorptiometry) | n/a | Every 5 years beginning with baseline at age 5 | Every 5 years | Every 5 years | n/a | n/a |
Recommendations are derived from the NIH Scientific Review Conference report (F.2629), ACMG Practice Guidelines (F.2626), Delphi Survey and Nominal Group consensus, and clinical practice resources (G.101, G.102, G.105). Recommended frequency of clinical and laboratory assessments represent practice goals, but may not be possible under all clinical circumstances or appropriate for all individuals with PKU. Clinicians should apply professional judgment in making individualized monitoring choices. More frequent monitoring may be necessary if the individual is not in good metabolic control.
1 Whenever blood PHE is monitored, a mechanism for assessing dietary intake should be in place. MetabolicPro (http://www.metabolicpro.org) is a computer program available for dietary analysis of amino acid-restricted diets.
2 To evaluate growth: the Centers for Disease Control and Prevention (CDC) recommends the 2006 World Health Organization (WHO) Child Growth Standards for infants from birth to 24 months, and the 2000 CDC Growth Charts for children from 2 to 20 years. Techniques for measurement are described on the CDC website (http://www.cdc.gov/growthcharts/cdc_charts.htm).
3 QoL instruments specific for individuals with PKU have not yet been published. Studies using existing QoL instruments to assess individuals with PKU compare outcomes to individuals with other chronic disorders or to control groups (F.1256, F.2348, F.2372, F.2533, F.2555).
4 See TABLE #9, Recommendations for Neurocognitive Testing in PKU
5 Monitoring protocols may include mail-in blood specimens (using filter paper cards or capillary tubes), or use of local or state public health laboratories, and are optimal for assuring effective monitoring frequency. When plasma amino acid analysis is the only available means of PHE and TYR monitoring, access and cost may limit monitoring frequency.
6 There was consensus from the Delphi 2 Survey and the Nominal Group that a complete amino acid profile is not necessary at ≤ 1 year of age when PHE and TYR monitoring is adequate.
7 Monitoring is indicated when: nutrition assessment shows poor adherence to prescribed therapy (diet, medical food, or pharmacotherapy), incomplete medical food is consumed, clinical symptoms of nutritional inadequacy are present (e.g. poor growth), or there is serious intercurrent illness. If laboratory values are abnormal, reassessment of appropriate specific analytes should be scheduled.